Article

Upper and lower airways: similarities and differences

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Abstract

In clinical practice the nose and the lungs are considered separately and are attended by different specialists. However, nasal and bronchial symptoms and diseases often coexist, as is commonly the case with rhinitis and asthma [1–3], The upper and lower respiratory airways form a continuous tract, share many anatomical and histological properties and one important function, the passage of air in and out of the lungs. Furthermore, the upper and lower airways share a common susceptibility to various agents such as allergens, infectious agents, occupational sensitizers and drugs, and respond to these in a similar fashion [4–11]. Nevertheless, each part of the airway has specialized functions: humidification, filtration of the air and the sense of smell in the nose, phonation in the larynx, and gas exchange in the lungs. In this chapter, the anatomy, histology, physiology and function of the respiratory tract is briefly described, the triggering mechanisms producing physiological and immunological responses and symptoms are discussed and the differences and simi-larities between the upper and lower airways are pointed out. Anatomy The respiratory tract is functionally divided into the conducting and the gas exchanging part. The conducting airways are anatomically subdivided into the nose and mouth, pharynx, larynx, trachea and bronchi, which keep branching down to the level of the respiratory bronchioles. The respiratory bronchioles, with the corresponding alveoli, represent the gas exchanging part of the lungs (fig. 1). Conventionally, the respiratory tract is divided into the upper and lower part and the larynx is the boundary between the two. The upper respiratory tract extends from the external nares and the mouth to the larynx and the lower from the larynx to the alveoli. The nasal cavity is surrounded by bone and divided into two halves by the nasal septum. The two separate airways extend from the anterior nares (nostrils) to the posterior ones, where they are united to form a single airway at the nasopharynx level. The nose has an external visible part surrounding the vestibule and an internal part containing the main nasal cavity. The nasal vestibules are trumpet-shaped orifices, narrowing towards the main nasal cavity. The junction between the vestibules and the main nasal cavity is the narrowest point of the airways and is called nasal valve or internal ostium. At this point the area of the airways is just 0.3 cm 2 expanding to nearly 1.3 cm 2 in the main cavity [12]. In the main nasal cavity three bony shelves project from Eur Respir Mon, 2001, 18, 1–15. Printed in UK -all rights reserved. Copyright ERS Journals Ltd 2001; European Respiratory Monograph; ISSN 1025-448x. ISBN 1-904097-18-9.

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... The respiratory bronchioles and alveoli compose the gas exchanging part of the lungs. Thus, upper respiratory tract is a part of conducting airways in the respiratory system (Gaga et al. 2001 ). ...
... The small hairs of vestibules act as a fi lter and remove any large dust particles in the inspirated air. These short stiff hairs are exceedingly sensitive to certain mechanical stimuli and respond immediately to the stimulation with itching and sneeze, protecting and notifying (Gaga et al. 2001 In the main nasal cavity, there are three bony structures protruding from the lateral wall on each side which are known as the nasal turbinates or conchae. Inferior, middle and superior turbinates increase the surface of the nose whereas at the same time narrow the lumen. ...
... Another cartilage is the epiglottis that lies on top of the larynx and prevents entrance of the food to the trachea during swallowing. The laryngeal mucosa is loosely bound to the supporting cartilage (Gaga et al. 2001 ). ...
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Various chemical agents have been used as a war weapon. Sulfur mustard (SM) due to its low cost, easy access and easy manufacture and storage are the most wildly used warfare agents in the world. It was used widely during Iraq-Iran conflict against Iranian troops. SM is a potent alkylating blistering agent that causes low mortality, but it could incapacitate a large number of soldiers in the war. SM exposure may occur in occupational or war exposure. SM can be absorbed from skin, eye, mouth and respiratory and the gastrointestinal systems. Among these organs, respiratory tract and skin are the main susceptible organs for SM intoxication and injury. Upper and lower respiratory tract may be affected by SM, however the acute and chronic effects of SM in upper respiratory tract has been less studied and most of studies have focused on lung injuries induced by SM. This study reviewed early and late clinical features and complications of SM in upper respiratory tract as well as its molecular mechanism of action and treatment.
... Altogether, these functions constitute the air conditioning within the upper respiratory airways [1]. In the vestibular region, these cavities are lined by a skinlike epithelium that gradually changes towards the nasal valves to the characteristic pseudo-stratified columnar ciliated lining termed the respiratory epithelium [2]. As part of the nose's functions, nasal epithelium (NE), along with mucous airway surface liquid (ASL), provides an important physicochemical and immunological barrier against different factors targeting lower airways [2]. ...
... In the vestibular region, these cavities are lined by a skinlike epithelium that gradually changes towards the nasal valves to the characteristic pseudo-stratified columnar ciliated lining termed the respiratory epithelium [2]. As part of the nose's functions, nasal epithelium (NE), along with mucous airway surface liquid (ASL), provides an important physicochemical and immunological barrier against different factors targeting lower airways [2]. These defence mechanisms depend on mucociliary clearance, its regenerative capacity and ability to participate in immune responses by secreting pro-and anti-inflammatory cytokines, among others [3]. ...
... These defence mechanisms depend on mucociliary clearance, its regenerative capacity and ability to participate in immune responses by secreting pro-and anti-inflammatory cytokines, among others [3]. In fact, all respiratory passages, from the nose to the terminal bronchioles share these features reflecting their common susceptibility to various agents such as irritants/occupational sensitizers, allergens and microorganisms [2]. In both upper and lower airways, physiological responses to these agents include: narrowing of the lumen, mucous secretion and inflammation [1,2]. ...
Article
A comprehensive proteomic profiling of nasal epithelium (NE) is described. This study relies on simple subcellular fractionation used to obtain soluble- and membrane-enriched fractions followed by 2-dimensional liquid chromatography (2D-LC) separation and tandem mass spectrometry (MS/MS). The cells were collected using a brushing technique applied on NE of clinically evaluated volunteers. Subsequently, the soluble- and the membrane-protein enriched fractions were prepared and analyzed in parallel using 2D-LC-MS/MS. In a set of 1482 identified proteins, 947 (63.9%) proteins were found to be associated to membrane fraction. Grand average hydropathy value index (GRAVY) analysis, the transmembrane protein mapping and annotations of primary location deposited in the Human Protein Reference Database (HPRD) confirmed an enrichment of hydrophobic proteins on this dataset. Ingenuity Pathway Analysis (IPA) of soluble fraction revealed an enrichment of molecular and cellular functions associated with cell death, protein folding and drug metabolism while in membrane fraction showed an enrichment of functions associated with molecular transport, protein trafficking and cell-to-cell signaling and interaction. The IPA showed similar enrichment of functions associated with cellular growth and proliferation in both soluble and membrane subproteomes. This finding was in agreement with protein content analysis using exponentially modified protein abundance index (emPAI). A comparison of our data with previously published studies focusing on respiratory tract epithelium revealed similarities related to identification of proteins associated with physical barrier function and immunological defence. In summary, we extended the NE molecular profile by identifying and characterizing proteins associated to pivotal functions of a respiratory epithelium, including the control of fluid volume and ionic composition at the airways' surface, physical barrier maintenance, detoxification and immunological defence. The extent of similarities supports the applicability of a less invasive analysis of NE to assess prognosis and treatment response of lung diseases such as asthma, cystic fibrosis and chronic obstructive pulmonary disease.
... Therefore, this technique does not appear appropriate to study asymptomatic babies. It is generally admitted that nasal epithelium characteristics and functions well reflect those of the lower airway epithelium [16,17,18] although some contradictory results about inflammation levels in CF and control patients have been reported. Noah et al. reported that nasal lavage fluid and BAL IL-8 levels are not significantly correlated [7]. ...
... However, these techniques requiring tracheal intubation under general anesthesia are rather aggressive for asymptomatic babies and we believe that less invasive techniques might be used. Nasal epithelium is generally considered to be representative of the lower airway epithelium [16][17][18]21]. The present pilot study shows that, by means of a simple nasal brushing technique easily performed and well tolerated, it is possible in infants to harvest respiratory cells in sufficient amounts to study the airway epithelium using a broad range of techniques. ...
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For a better understanding of the early stages of cystic fibrosis (CF), it is of major interest to study respiratory epithelial cells obtained as early as possible. Although bronchoalveolar lavage has been proposed for this purpose, nasal brushing, which is a much less invasive technique, has seldom been used in CF infants. The aim of the present study was to examine in a few infants the feasibility of a nasal brushing technique for studies of airway epithelial functions in very young CF infants. In 5 CF (median age 12, range 1-18 months) and 10 control infants (median age 5, range 1-17 months), a nasal brushing was performed by means of a soft sterile cytology brush, after premedication with oral paracetamol (15 mg/kg body weight) and rectal midazolam (0.2 mg/kg body weight). Samples were used for microbiological, cytological and functional studies. The procedure was well tolerated. Number of cells collected was similar in CF and non-CF patients (CF: median 230x10(3), range 42x10(3)-900x10(3); non-CF: median 340x10(3), range 140x10(3)-900x10(3)). Median number of viable cells was 67% (range 31-84%). Freshly obtained samples were successfully used for studies of ciliary beating frequency and cAMP-dependent chloride efflux. In 7 out of 17 cell cultures, confluence was obtained (CF: 2 out of 7; non-CF: 5 out of 10). The feasibility of studying protein release and mRNA expression of IL-8, IL-6 and TNF-alpha, under basal conditions and after stimulation by Pseudomonas aeruginosa, was demonstrated. By means of a simple nasal brushing technique easily performed and well tolerated, it is feasible, in infants, to harvest respiratory cells in sufficient amounts to study the airway epithelium using a broad range of techniques including cell culture.
... The upper and lower respiratory airways form a continuous tract and share many anatomical and histological properties (13). Previous studies have shown that COPD is characterized by nasal inflammation with many similar features compared to the established bronchial inflammation (14,15). ...
... The aim of the present study was to assess the presence of MSI in nasal cytological samples of patients with COPD. The upper and lower respiratory airways form a continuous tract and share many anatomical and histological properties (13). Previous studies have shown that COPD is characterized by nasal inflammation with many similar features compared to the established bronchial inflammation (14,15). ...
Article
Genetic alterations in the microsatellite DNA level have been successfully detected in sputum samples of patients with COPD and have been shown to be disease specific. Furthermore, previous studies have shown that inflammation coexists in the nasal mucosa of patients with COPD. The aim of this study was to assess the presence of MSI in nasal cytological samples of patients with COPD comparing the results with sputum samples of the same individuals. Nasal brush samples, sputum samples obtained by induction, and peripheral blood from 20 patients with COPD were analyzed. DNA was extracted and analyzed for MSI using the following microsatellite markers: RH70958, D5S207, D6S344, D6S263, G29802, D13S71, D14S588, D14S292 and D17S250. Microsatellite analysis was also performed in 8 healthy non-smokers. MSI was detected in the sputum samples of 7 patients with COPD (35%). In contrast, no microsatellite DNA instability was noted in the nasal cytological samples of the same COPD patients. In addition, no genetic alteration was detected in the control group. These results suggest that MSI is a specific finding for the target organ of COPD, i.e. the lungs, despite the fact that inflammation coexists in the nasal mucosa of COPD patients. Our study supports the hypothesis that MSI could be an index of the somatic-acquired genetic alterations in the lungs of COPD patients.
... The nasal epithelium therefore represents an attractive alternative although it is unclear how well the nasal epithelium represents the bronchial epithelium in paediatric asthma. According to the 'united airway concept' there is a close connection between the upper and lower airways [12][13][14][15][16]. This suggests that changes found in the nasal epithelium might mirror similar changes occurring in the lower airways. ...
... This suggests that changes found in the nasal epithelium might mirror similar changes occurring in the lower airways. The link between allergic rhinitis and asthma has been underlined by epidemiological and clinical studies [12][13][14][15][16] which suggest that upper airway inflammation may reflect and provide an additional insight into lower airway involvement. Devalia et al have demonstrated that adult human nasal and bronchial epithelial cells cultured in vitro resemble the cells in vivo [17]. ...
Article
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Differentiated paediatric epithelial cells can be used to study the role of epithelial cells in asthma. Nasal epithelial cells are easier to obtain and may act as a surrogate for bronchial epithelium in asthma studies. We assessed the suitability of nasal epithelium from asthmatic children to be a surrogate for bronchial epithelium using air-liquid interface cultures. Paired nasal and bronchial epithelial cells from asthmatic children (n = 9) were differentiated for 28 days under unstimulated and IL-13-stimulated conditions. Morphological and physiological markers were analysed using immunocytochemistry, transepithelial-electrical-resistance, Quantitative Real-time-PCR, ELISA and multiplex cytokine/chemokine analysis. Physiologically, nasal epithelial cells from asthmatic children exhibit similar cytokine responses to stimulation with IL-13 compared with paired bronchial epithelial cells. Morphologically however, nasal epithelial cells differed significantly from bronchial epithelial cells from asthmatic patients under unstimulated and IL-13-stimulated conditions. Nasal epithelial cells exhibited lower proliferation/differentiation rates and lower percentages of goblet and ciliated cells when unstimulated, while exhibiting a diminished and varied response to IL-13. We conclude that morphologically, nasal epithelial cells would not be a suitable surrogate due to a significantly lower rate of proliferation and differentiation of goblet and ciliated cells. Physiologically, nasal epithelial cells respond similarly to exogenous stimulation with IL-13 in cytokine production and could be used as a physiological surrogate in the event that bronchial epithelial cells are not available.
... We first used a list of validated prokaryotic names, which contained 16,194 species with standing in nomenclature on 16 May 2016 [36]. We identified the 'keywords' that characterize the respiratory tract [37,38,39], the oral cavity, the specimens collected [40,41,42,43] from these locations and the culture-based method [43,44,45]. Based on our knowledge of the MEDLINE indexing method and with the help of the 'keywords' list, we established a list of medical subject headings (MeSHs) terms and subheadings relevant for our search focused on species identified in the human respiratory tract in MEDLINE [46]. ...
... Conventionally, the respiratory tract is divided into two sections: the upper respiratory tract (URT) and the lower respiratory tract (LRT); the larynx is the boundary between these two sections [38,49] (Supplementary Figure 2). The LRT extends from the larynx to the alveoli and includes the trachea, bronchi, bronchioles and lungs [39,49]. While sputum is the most common specimen obtained for microbiological analysis of the LRT [50], contamination of the sputum by oral flora led to the development of invasive procedures for sampling. ...
Article
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While the gut microbiota is currently in the spotlight, the airway microbiome has been recently associated with several pulmonary diseases and carcinogenesis. As there are several biases associated with high-throughput sequencing methods, cultivation techniques are crucial for the investigation of the human microbiome. We thus aimed to build an exhaustive database, including a list of microbes isolated by culture from respiratory specimens, by performing a review of the literature. Herein, we have listed a total of 756 species cultured from the human respiratory tract. This represents 27.23% of the overall bacterial richness captured from human being by culture methods. This repertoire could be valuable for the elucidation of the interactions between the respiratory microbiome and human health.
... Both components of the airway act together as a single physiologic unit showing similar reactions to noxious stimuli. The upper airway shares many properties with the lower airway suggesting the concept of 'united airway disease' [1,2]. ...
... The upper respiratory tract functions as a physical filter, resonator, heat exchanger, and humidifier of exchanged air. Failure of any of these functions clearly alters the homeostasis of the lower respiratory tract [1,2]. ...
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This study aimed to investigate the association of inflammatory changes of upper and lower airways in a rabbit model of acute rhinosinusitis. The study included six adult albino rabbits. The sinuses of one animal were injected with saline solution and the animal was served as sham control. Other animals were implanted with intranasal S. aureus soaked-absorbable gelatin sponge. Acute rhinosinusitis was induced and subjects were sacrificed at the end of the second week. Tissue samples from all levels of the airway were obtained. They were evaluated for the presence of inflammatory changes histologically. A scoring system for airway inflammation was used for quantitative assessment of the degree of inflammation. Structural changes in the epithelial and stromal layers of the upper and lower airway structures were analyzed, as well. The animal of which the sinuses were injected with saline solution developed neither acute rhinosinusitis nor lower airway inflammation. In contrast, the animals in which acute rhinosinusitis was induced demonstrated significant upper and lower airway inflammation histologically. Inflammatory changes ranged from engorgement of blood vessels and polymorphonuclear cell proliferation within the capillaries, in the perivascular tissue of the epithelium or in the lamina propria and to epithelial disruption. Nasal airway inflammation scores (2.86 ± 1.81) were significantly higher than lower airway scores (1.36 ± 0.77), (P < 0.01). We obtained a generalized mucosal inflammatory response against localized bacterial inflammation in a rabbit model of acute rhinosinusitis, confirming the suggestion of 'one airway--one disease' from a bacterial infection point of view.
... The nose is the part of the respiratory system in which it is easy to study morphological and pathophysiological changes due to inflammatory responses to various stimuli because of its accessibility [1]. The respiratory tract is constantly challenged with airborne and aspirated microbes and, as part of the nose's functions, the nasal epithelium along with a mucous airway surface liquid, which provides continuous removal of inhaled microbes targeting lower airways [2]. In particular, important defense functions are due to the presence in nasal secretions of AMP such as lactoferrin, defensins, lysozyme, peptide LL37, secretory leukocyte protease inhibitor (SLPI), β-microseminoprotein (β-MSP), statherin, and other antimicrobial components [3]. ...
Article
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Background: Antimicrobial peptides (AMP) play a pivotal role in innate host defense and in immune response. The delineation of new MS-based profiling tools, which are able to produce panels of AMP of the nasal fluid (NF), may be attractive for the discovery of new potential diagnostic markers of respiratory disorders. Methods: Swabs collected NF from healthy patients and from patients with respiratory disorders. We used a fast procedure based on mesoporous silica particles (MPS) to enrich NF in its AMP component in combination with MALDI-TOF/TOF MS as a key tool for rapidly analyzing clinical samples. Results: Reproducible MS peptide fingerprints were generated for each subject and several AMP were detected including (Human Neutrophil Peptides) HNPs, Statherin, Thymosin-β4, Peptide P-D, II-2, β-MSP, SLPI, Lysozyme-C, and their proteo-forms. In particular, Statherin, Thymosin-β4, and Peptide P-D were accurately identified by direct MS/MS sequencing. Examples of applicability of this tool are shown. AMP fingerprints were obtained before and after a nasal polypectomy as well as before and post-treatment with azelastine/fluticasone in one case of allergic rhinitis. Conclusion: The potential of our platform to be implemented by new mesoporous materials for capturing a wider picture of AMP might offer an amazing opportunity for diagnostic clinical studies on individual and population scales.
... The upper and lower airways are in anatomical continuity, function as a single unit, and respond in similar ways to noxious stimuli. 1 In contrast to asthma where there is considerable work describing the relationship with rhinitis, 2 little has been published on upper airway involvement in patients with chronic obstructive pulmonary disease (COPD). This is despite the high prevalence of upper airway symptoms in COPD. ...
Article
To assess the impact on quality of life from upper airway symptoms in chronic obstructive pulmonary disease (COPD). Sixty-five patients with moderate-to-severe COPD were studied using the 20-item Sino-Nasal Outcome Test (SNOT-20) questionnaire, a validated disease-specific health-related quality of life tool for the assessment of rhinosinusitis. Patients also completed the St. George's Respiratory Questionnaire (SGRQ). Eighty-eight percent of patients experienced nasal symptoms on most days of the week, most commonly rhinorrhoea. The mean SNOT-20 score of 1.24 demonstrates that nasal symptoms cause impairment to quality of life. The SNOT-20 score correlated with the number of chronic nasal symptoms (rho = 0.51, P < 0.01): the more daily nasal symptoms experienced, the greater the impact on health status. There was no significant correlation between SNOT-20 and SGRQ (r = 0.21, P = 0.09) suggesting that both upper and lower airway symptoms contribute to the total quality of life burden. This is the first study to report on upper airway involvement in well characterised COPD patients using a previously validated assessment tool. Upper airway symptoms are frequent in these patients and cause impairment to the quality of life. These effects may not be detected using currently available quality of life tools that focus on lower respiratory tract symptoms.
... However, lower airway epithelial cells are difficult to obtain in a clinical setting, especially from healthy control patients and children. Data from several studies support the premise that epithelial cells from nasal mucosa are a valid and practical proxy for lower airway epithelial cells [13][14][15][16][17][18][19][20] , especially when studying responses to air pollutants and allergens. The nasal mucosa consists of more than 90% ciliated airway epithelial cells and sampling these nasal epithelial cells (NECs) can be readily performed in children as young as age four or five, as it is less invasive than other cell/tissue sampling techniques and is associated with minimal risk of adverse events such as infection [20][21][22][23] . ...
Article
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Nasal epithelial cells (NECs) are the part of the airways that respond to air pollutants and are the first cells infected with respiratory viruses. They are also involved in many airway diseases through their innate immune response and interaction with immune and airway stromal cells. NECs are of particular interest for studies in children due to their accessibility during clinical visits. Human induced pluripotent stem cells (iPSCs) have been generated from multiple cell types and are a powerful tool for modeling human development and disease, as well as for their potential applications in regenerative medicine. This is the first protocol to lay out methods for successful generation of iPSCs from NECs derived from pediatric participants for research purposes. It describes how to obtain nasal epithelial cells from children, how to generate primary NEC cultures from these samples, and how to reprogram primary NECs into well-characterized iPSCs. Nasal mucosa samples are useful in epidemiological studies related to the effects of air pollution in children, and provide an important tool for studying airway disease. Primary nasal cells and iPSCs derived from them can be a tool for providing unlimited material for patient-specific research in diverse areas of airway epithelial biology, including asthma and COPD research.
... The turbinates increase the surface of the nasal mucosa, while at the same time, they narrow the lumen. This design facilitates the nasal functions [5]. ...
Article
The nose and lungs have both histological and functional similarities and differences. Sinonasal and bronchial involvement are associated in many diseases. Cystic fibrosis, primary ciliary dyskinesia, Young's syndrome, and alpha-1 antitrypsin deficiency are diseases in which bronchiectasis and rhinosinusitis are both present. This review considers the diseases in which bronchiectasis occurs along with sinonasal manifestations. We propose examining sinonasal disease from a new perspective by observing it in patients with bronchiectasis.
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Polypose nasosinusienne (PNS), asthme et bronchopathie chronique obstructive appartiennent à la même entité physiopathologique des maladies inflammatoires chroniques des voies aériennes supérieures. Leur origine serait une agression de l'épithélium respiratoire dans un contexte inflammatoire chronique. Plusieurs études ont montré que les cellules épithéliales nasales lors de la PNS participaient à la surexpression de cytokines et de facteurs de croissance. Parmi ceux-ci, le Transforming Growth Factor β1 (TGF-β1) semble jouer un rôle important dans la genèse de la PNS. Des modèles de recherche reproduisant un épithélium différencié respiratoire tentent d'élucider les mécanismes étiopathogéniques de la PNS pour arriver à une meilleure compréhension et prise en charge thérapeutique des maladies des voies aériennes supérieures.
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The upper and lower airways are continuous. While upper airway symptoms are common in COPD patients, with accumulating evidence to suggest increased nasal inflammation, the relationships among upper airway, lower airway, and systemic inflammatory indexes have not been studied. We aimed to confirm that there is heightened nasal inflammation in COPD patients, to test the hypothesis that the degree of upper airway inflammation relates to the degree of lower airway inflammation, and to investigate the underlying associations with bacterial carriage and the systemic inflammatory response. Prospective cohort study. Outpatient Department, London Chest Hospital, London, UK. Forty-seven patients with COPD and 12 control subjects of similar age, sex, and smoking status. Serum, nasal wash fluid, and sputum samples were obtained from 47 stable patients with COPD for the analysis of inflammatory indexes and bacterial colonization. Nasal wash fluid specimens were obtained from 12 control subjects. COPD patients had an increased nasal interleukin (IL)-8 concentration compared to control subjects (difference, 97.2 pg/mL; p = 0.009). The nasal IL-8 concentration in COPD patients correlated with that in sputum (r = 0.30; p = 0.039). In both the upper and lower airways of patients with COPD, the IL-8 concentration was associated with indexes of bacterial colonization. Patients colonized with a sputum potentially pathogenic microorganism had a higher total nasal bacterial load (difference, 1.5 log cfu/mL; p = 0.016). We did not find significant relationships between the degree of upper or lower airway inflammation, or bacterial carriage, and the systemic inflammatory response. COPD is associated with an increased nasal concentration of the neutrophil chemoattractant protein IL-8, the degree of which reflects that present in the lower airway. A relationship between lower airway bacterial colonization, postnasal drip, and higher nasal bacterial load may suggest a mechanism underlying this finding. This study is the first to report a correlation between the degree of upper and lower airway inflammation in COPD.
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The nose and lungs have both histological and functional similarities and differences. Sinonasal and bronchial involvement are associated in many diseases. Cystic fibrosis, primary ciliary dyskinesia, Young's syndrome, and α-1 antitrypsin deficiency are diseases in which bronchiectasis and rhinosinusitis are both present. This review considers the diseases in which bronchiectasis occurs along with sinonasal manifestations. We propose examining sinonasal disease from a new perspective by observing it in patients with bronchiectasis.
Chapter
The administration of drugs through the pulmonary route has gained importance in the pharmaceutical field, especially for the treatment of several lung diseases. Lung epithelium has a high surface area, with low enzymatic activity and absence of first-pass metabolism. Moreover, alveolar epithelium is thin and vascularized, enabling good drug permeability and absorption to blood capillaries, so this route of administration is a good option for drug delivery with local and systemic effects. However, respiratory airways have anatomic features and clearance mechanisms that can compromise drug permeability and absorption affecting its bioavailability. Different in vitro models have been widely used to study permeability and absorption mechanisms, but they are still limited approaches. Isolated perfused lung, an ex vivo lung model, is more realistic and a better alternative to in vitro model, not only because of its structural complexity, but because it has different factors (metabolism, mucociliary clearance and phagocytic mechanisms) that can influence drug permeability and absorption. Thus, this chapter attempts to provide an overview of the main features of the respiratory system, discusses care that must be taken during harvest and maintenance of isolated perfused lung, and describe its use as an ex vivo model for studying drug permeability and absorption.
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In respiratory physiology the nose is an organ with a great importance that supposes 50% of the resistances to the airflow, and its pathology requires, in many occasions, of a multidisciplinary work. In recent years it has been demonstrated that bronchopulmonary pathologies are usually associated with nasosinusal pathology, thus creating the concept of rhinobronchitis and “one airway, one disease.” There are few studies that correlate bronchiectasis (BQs) and CRS. The most frequent symptoms of CRS in patients with BQs are anterior rhinorrhea, posterior rhinorrhea, and nasal obstruction. Seventy-seven percent of patients with BQs had CRS, while 25% had mild to moderate nasal polyposis. Patients with nasal polyposis were diagnosed with BQs more than 10 years earlier than patients without nasal pathology.
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The nose is an attractive source of airway epithelial cells, particularly in populations in which bronchoscopy may not be possible. However, substituting nasal cells for bronchial epithelial cells in the study of airway inflammation depends upon comparability of responses, and evidence for this is lacking. Our objective was to determine whether nasal epithelial cell inflammatory mediator release and receptor expression reflect those of bronchial epithelial cells. Paired cultures of undifferentiated nasal and bronchial epithelial cells were obtained from brushings from 35 subjects, including 5 children. Cells were subject to morphologic and immunocytochemical assessment. Mediator release from resting and cytokine-stimulated cell monolayers was determined, as was cell surface receptor expression. Nasal and bronchial cells had identical epithelial morphology and uniform expression of cytokeratin 19. There were no differences in constitutive expression of CD44, intercellular adhesion molecule-1, αvβ3, and αvβ5. Despite significantly higher constitutive release of IL-8, IL-6, RANTES (regulated on activation, normal T cell expressed and secreted), and matrix metalloproteinase (MMP)-9 from nasal compared with bronchial cells, the increments in release of all studied mediators in response to stimulation with IL-1β and TNF-α were similar, and there were significant positive correlations between nasal and bronchial cell secretion of IL-6, RANTES, vascular endothelial growth factor, monocyte chemoattractant protein-1, MMP-9, and tissue inhibitor of metalloproteinase-1. Despite differences in absolute mediator levels, the responses of nasal and bronchial epithelial cells to cytokine stimulation were similar, expression of relevant surface receptors was comparable, and there were significant correlations between nasal and bronchial cell mediator release. Therefore, nasal epithelial cultures constitute an accessible surrogate for studying lower airway inflammation.
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We have studied the immunohistology of the nasal mucosa in allergen-induced rhinitis. Sixteen grass pollen-sensitive patients were challenged twice by randomly allocated allergen or control solutions applied on filter paper disks to the inferior turbinate. All had immediate nasal responses, but late-phase responses were equivocal and only evident as nostril blockage. When cell counts in the nasal submucosa were compared with control values 24 h after allergen, there were no changes in CD45+ (total leukocytes), CD3+, or CD8+ cells. Significant increases were found in the numbers of CD4+ T-helper cells (p less than 0.05) and CD25+ [interleukin-2 receptor (IL-2R+)] cells (p less than 0.02). Increases in eosinophils (anti-major basic protein, p less than 0.01) and neutrophils (antineutrophil elastase, p less than 0.01) were also observed. There were increases in tissue macrophages and HLA-DR-positive immunostaining and a reduction in mast cells (tryptase positive), but none of these changes was statistically significant. No significant changes in epithelial thickness, cross-sectional area, or integrity were observed. There was a significant correlation between CD4+ and CD25+ cells (r = 0.61, p less than 0.01) but not between macrophages and CD25+ cells (r = 0.18). The changes in the nasal submucosa were not merely a reflection of alterations in circulating cell populations since it was shown that a significant increase in the lymphocyte CD4/CD8 ratio (p less than 0.05) was observed in nasal biopsies but not in peripheral blood after allergen challenge.(ABSTRACT TRUNCATED AT 250 WORDS)
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Vasoactive intestinal peptide (VIP), which is present with acetylcholine in parasympathetic nerve fibers, may have important regulatory functions in mucous membranes. The potential roles for VIP in human nasal mucosa were studied using an integrated approach. The VIP content of human nasal mucosa was determined to be 2.84 +/- 0.47 pmol/g wet weight (n = 8) by RIA. VIP-immunoreactive nerve fibers were found to be most concentrated in submucosal glands adjacent to serous and mucous cells. 125I-VIP binding sites were located on submucosal glands, epithelial cells, and arterioles. In short-term explant culture, VIP stimulated lactoferrin release from serous cells but did not stimulate [3H]glucosamine-labeled respiratory glycoconjugate secretion. Methacholine was more potent than VIP, and methacholine stimulated both lactoferrin and respiratory glycoconjugate release. The addition of VIP plus methacholine to explants resulted in additive increases in lactoferrin release. Based upon the autoradiographic distribution of 125I-VIP binding sites and the effects on explants, VIP derived from parasympathetic nerve fibers may function in the regulation of serous cell secretion in human nasal mucosa. VIP may also participate in the regulation of vasomotor tone.
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Human rIL-5 was found to selectively stimulate morphological changes and the function of human eosinophils. This molecule is thus a prime candidate for the selective eosinophilia and eosinophil activation seen in disease.
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To the Editor: In the excellent article by Weiss on tissue destruction by neutrophils (Feb. 9 issue),¹ there is an implicit assumption that neutrophils lack endogenous reducing substances that could quench intracellular or extracellular oxidants. We would therefore like to emphasize that ascorbic acid is present in human neutrophils, in concentrations 20 to 30 times higher than in plasma.² Although the function of ascorbic acid in neutrophils is unknown, it has been proposed that it quenches free radicals,³ either within or perhaps outside neutrophils. However, before this or other functions of neutrophil ascorbic acid can be addressed, it is of…
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The epithelial basement membrane and underlying collagen were examined by immunohistochemistry and electron microscopy in endobronchial biopsy specimens from 8 asthmatic and 3 control subjects. There was an excess of interstitial collagens beneath the basement membrane in the asthmatic subjects. There was no evidence of any epithelial contribution to this abnormality, nor was there any correlation with epithelial damage, disease duration, or severity. These findings contradict the long-held notion of basement membrane thickening in asthma and indicate that the subepithelial fibrosis is a result of fibroblast activation rather than bronchial epithelial cell dysfunction.
Article
Asthma is a common chronic disorder which may be increasing in prevalence. However, little is known of its distribution and determinants. The European Community Respiratory Health Survey (ECRHS) is a multicentre survey of the prevalence, determinants and management of asthma. This paper presents a descriptive account of the variation in self-reported attacks of asthma and asthma symptoms across Europe, and in part fulfils the first aim of the study. A screening questionnaire, including seven questions relating to the 12 month prevalence of symptoms of asthma, was distributed to representative samples of 20-44 year old men and women in 48 centres, predominantly in Western Europe. The median response rate to the questionnaire was 75% but, after removing from the denominator those who were the wrong age, were known to have moved out of the area, or had died, it was 78% (range 54-100). The prevalence of all symptoms varied widely. Although these were generally lower in northern, central and southern Europe and higher in the British Isles, New Zealand, Australia and the United States, there were wide variations even within some countries. Centres with a high prevalence of self-reported attacks of asthma also reported high prevalences of nasal allergies and of waking at night with breathlessness. The use of asthma medication was more common where wheeze and asthma attacks were more frequent. In most centres in The Netherlands, Sweden, New Zealand and the United Kingdom over 80% of those with a diagnosis of asthma were currently using asthma medication. In Italy, France and Spain the rate was generally less than 70%. These data are the best evidence to date that geographical differences in asthma prevalence exist, are substantial and are not an artefact of the use of noncomparable methods.
Article
There is established evidence supporting smoking, occupational and environmental exposure to dust and gases, and hereditary α1-antitrypsin deficiency as risk factors for chronic obstructive pulmonary disease (COPD). Studies concerning the possible contribution of other risk factors for COPD have examined the roles of air pollution, environmental tobacco smoke, respiratory infections, bronchial hyperresponsiveness, gender and genetics. Less clearly defined is the involvement of diet and racial and ethnic factors. A brief review of the known risk factors is presented here, together with an examination of current information relating to the other potential risk factors for COPD.
Article
Human rIL-5 was found to selectively stimulate morphological changes and the function of human eosinophils. This molecule is thus a prime candidate for the selective eosinophilia and eosinophil activation seen in disease.
Article
The internal surface of the nasal cavity is geometrically complicated and does not lend itself readily to direct measurement. Simple geometric shapes were used as a model for changes in the nasal cavity. Following the introduction of specific changes to a particular system, the effect of these changes on the acoustic evaluation of the space was studied. Cylinders were chosen, as the wave path could be assumed to be perpendicular to the model surface. The acoustic rhinometer's accuracy was assessed in the presence of small and large variations in cross sectional area, in the presence of a series of consecutive area changes, and a gradual change in diameter. The effect of the introduction of acoustic leak was also modelled. The acoustic data acquired from these models was used to reconstruct the model in three dimensions. These reconstructions were compared to the original model. The acoustic rhinometer was found to resolve with reasonable accuracy the dimensions of small spaces; however, if regions of sudden large area changes were present in the space, the data beyond these regions was highly unreliable. Furthermore, the presence of acoustic leak in a system had a similar effect. Unless precautions are taken in the set-up and operation of the acoustic rhinometer, the potential for misinterpretation of data and the introduction of bias is very high.
Article
Chronic sinusitis has been recognized to be a contributing factor to asthma in some patients. We report a 5-year follow-up study of 16 patients who had undergone bilateral sphenoethmoidectomy after not responding to aggressive medical management of underlying sinusitis. Sixty-two percent had subjective improvement of their asthma with 88% of the patients reporting a significantly reduced prednisone requirement. All patients had improvement of their nasal and sinus symptoms at 5 years. The improvement in the asthma reported at 2 years had for the most part persisted at 5 years.
Article
Background: Apoptosis regulates inflammatory cell survival, and its reduction contributes to the chronicity of an inflammatory process. Apoptosis is controlled by suppressing or inducing genes, such as bcl-2 and p53, respectively. Objective: We sought to assess apoptosis of eosinophils, macrophages, and T lymphocytes in bronchial biopsy specimens from asthmatic subjects and to examine its regulation by evaluating the expression of B-cell lymphoma leukemia-2 (Bcl-2) and P53 proteins. We also sought to explore the relationships between cell apoptosis and GM-CSF, a cytokine able to increase eosinophil and macrophage survival. Methods: Apoptosis in eosinophils, macrophages, and T lymphocytes was evaluated in bronchial biopsy specimens obtained from 30 asthmatic subjects, 26 subjects with chronic bronchitis, and 15 control subjects by combining the terminal deoxynucleotidyl transferase-mediated dNTP nick end-labeling technique and immunohistochemistry. The expression of P53, Bcl-2, and GM-CSF was studied through immunohistochemistry by using specific mAbs. Results: The number of apoptotic eosinophils and macrophages was lower in subjects with asthma than in those with chronic bronchitis (P <.007 and P <.001, respectively) and inversely correlated with the clinical severity of asthma (P <.001 and P <.002, respectively). Few T lymphocytes were apoptotic in all groups studied. In asthma GM-CSF+ cells correlated with the number of nonapoptotic eosinophils and macrophages (P =.0001) and with the severity of the disease (P <.003). In asthma Bcl-2+ cells were higher than in control subjects and subjects with chronic bronchitis (P <.002 and P <.015, respectively), they outnumbered P53+ cells, and they correlated with the number of T lymphocytes (P <.001) and with the severity of the disease (P <.003). Conclusion: Airway inflammation in asthma is associated with an enhanced survival of different cell types caused by reduced apoptosis.
Article
Fourteen ragweed hay fever nonasthmatic patients comparably sensitive to a group of ragweed-allergic asthmatics by skin test and leukocyte histamine release were tested by quantitative inhalation bronchial challenge with ragweed extract. The provocation dose of ragweed extract producing 35% decrease in airway conductance was determined and designated PD35. PD35 values in the hay fever patients were not significantly different from PD35 values in the asthmatic group. These data suggest that carefully performed skin tests may be as diagnostically useful as bronchial challenge in routinely confirming the allergic etiology of seasonal asthma.
The effect of cessation of exposure to toluene diisocyanate (TDI) was studied in six patients with TDI-induced asthma, proved by a positive inhalation challenge with TDI. Bronchial challenges with TDI and methacholine were performed, and lobar bronchial biopsies were taken at diagnosis and 6 months later, after cessation of exposure. Biopsies from four nonasthmatic control subjects were also examined. At diagnosis, asthmatic subjects had thickened reticular basement membrane (p less than 0.05) and increased numbers of mononuclear cells (p less than 0.05) and eosinophils (p less than 0.05) in the lamina propria when compared with control subjects. Electron microscopy showed degranulation of eosinophils and mast cells in asthmatics. Six months after cessation of exposure, the thickness of reticular basement membrane was significantly reduced compared with that at diagnosis (p less than 0.05), and it decreased to values similar to those of control biopsies. Inflammatory cell numbers in bronchial mucosa of asthmatic subjects did not change significantly 6 months after removal from exposure, and degranulation of eosinophils and mast cells was still present. At the end of the study, airway hyperresponsiveness to methacholine and/or sensitivity to TDI persisted in most of the asthmatic patients despite the cessation of exposure and the disappearance of asthmatic symptoms. In conclusion, in patients with occupational asthma induced by TDI, the avoidance of exposure to the sensitizing agent for 6 months is able to reverse the reticular basement membrane thickening in the bronchial mucosa, but the inflammatory cell infiltrate, the specific sensitivity to TDI, and the nonspecific airway hyperreactivity may persist.
Using immunohistochemistry and a panel of monoclonal antibodies, we have compared T-lymphocyte, eosinophil, macrophage, and neutrophil infiltration in bronchial biopsies from 10 intrinsic (nonallergic) asthmatics (IA) and seven extrinsic (allergic) asthmatic (EA), with similar degrees of disease severity. The results were compared with 12 normal healthy nonatopic controls (NC). All subjects were nonsmokers and were not taking oral or inhaled corticosteroids. An intense mononuclear cell infiltrate was identified in IA with an increase in the number of CD45+ cells (total leukocytes), CD3+ and CD4+ lymphocytes, and CD68+ macrophages (p < 0.03, p < 0.01, p < 0.03, and p < 0.03, respectively), compared with NC. Increases were also found in CD4+ (p < 0.05) and CD68+ (p < 0.05) cell numbers between IA and EA. IL-2 receptor-bearing cells (CD25+) and the number of total (MBP+) and actively secreting (EG2+) eosinophils, were also increased in IA compared with NC (p < 0.01, p < 0.01, and p < 0.01, respectively). Similar increases in EG2+ eosinophils and CD25+ (IL-2 receptor-positive) cells were observed in EA (p < 0.01 and p < 0.02, respectively). No differences were detected in the three groups for the number of elastase-positive cells (neutrophils). EG2+ numbers in IA correlated with the Aas asthma symptoms score (r = 0.65, p < 0.05), whereas EG2+ cell numbers in all asthmatics (IA + EA) correlated with airway methacholine responsiveness (r = -0.55, p < 0.03) and with the Aas asthma symptom score (r = 0.54, p < 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)
Article
The tachykinins substance P (SP) and neurokinin A (NKA) were studied in human inferior turbinate nasal mucosa by radioimmunoassay, immunohistochemistry, and autoradiography and for their effect upon mucus release in an in vitro culture system in order to infer their potential functions in the upper respiratory tract. Similar amounts of SP (1.03 +/- 0.12 pmol/g wet weight; mean +/- SEM; n = 26) and NKA (0.76 +/- 0.23; n = 7) were found. NKA and SP immunoreactive nerve fibers were found in the walls of arterioles, venules, and sinusoids and as individual fibers in gland acini, near the basement membrane, and in the epithelium. [125I]SP bound to arterioles, venules, and glands. [125I]NKA bound only to arterioles. In short-term explant culture of fragments of human nasal mucosa, both 1 microM SP and 1 microM NKA stimulated release of [3H]glucosamine-labeled respiratory glycoconjugates. These results indicate that SP and NKA have similar distributions in nociceptive sensory nerves in human nasal mucosa. The distribution of [125I]SP binding sites is consistent with a role for SP as a vasodilator and mucous secretagogue. The presence of [125I] NKA binding sites on vessels suggests a primary role for NKA in regulating vasomotor tone.
Article
Little is known about the epidemiology of rhinitis, particularly the perennial and non-allergic forms. The aim of this study was to compare the symptoms, atopic state, and medical history of individuals with seasonal and perennial rhinitis. Of 7702 adults aged 16-65 years registered with a London general practice, 2969 (30%) were screened by postal questionnaire. Samples of 113 subjects without rhinitis, 51 with seasonal symptoms alone, 128 with perennial symptoms and seasonal exacerbations were then interviewed. Atopic and non-atopic subjects were distinguished by skinprick testing with five common allergens. The estimated minimum prevalence of rhinitis was 24%: 3% had seasonal symptoms only, of whom 78% were atopic; 13% had perennial symptoms only, of whom 50% were atopic; and 8% had perennial symptoms with seasonal exacerbations, of whom 68% were atopic. Seasonal rhinitis was characterised by sneezing, itching, and a high prevalence of diurnal variation in symptoms. The most common provoking factors were dust, pollens, and infections. By comparison, perennial rhinitis was characterised by a higher prevalence of nasal blockage and catarrh, and a lower prevalence of diurnal variation and provocation by pollen. There were no significant differences among the groups in the sociodemographic characteristics examined. Subjects with seasonal rhinitis were more likely to be atopic and to have eczema and a family history of hayfever than those without rhinitis. Those with perennial rhinitis were more likely to have past or current eczema or migraine, be wheezy or labelled asthmatic, or have a family history of nose trouble other than hayfever. Subjects with both seasonal and perennial symptoms presented an intermediate clinical picture. Seasonal and perennial rhinitis differ in their atopic state, clinical presentation, and medical history. The extent to which these differences are genetically or environmentally determined requires further investigation.
Mononuclear phagocytes have been investigated in biopsies taken from the nasal mucosa and in epithelial cell samples from 22 grass-pollen-allergic subjects before season, after allergen challenge and during season by means of immunohistochemistry and electron microscopy. The cells were positive for CD68/EBM11 and HLA-DR, but failed to react with CD1 and CD23/BB10. The cells increased in number during season as well as after allergen challenge, especially in the upper part of the mucosa. Heteromorphy of macrophages, as seen by transmission electron microscopy, confirmed the presence of diverse macrophage subpopulations in the nasal mucosa of allergic subjects. Using brush sampling techniques, CD68-positive and HLA-DR-positive cells significantly increased in epithelial cell samples 4-8 h after allergen challenge, indicating a central role of these cells not only in antigen processing but also in late phase reactions of allergic rhinitis.
Article
Intercellular communication of epithelial cells was examined by measuring changes in intracellular calcium concentration ([Ca2+]i). Mechanical stimulation of respiratory tract ciliated cells in culture induced a wave of increasing Ca2+ that spread, cell by cell, from the stimulated cell to neighboring cells. The communication of these Ca2+ waves between cells was restricted or blocked by halothane, an anesthetic known to uncouple cells. In the absence of extracellular Ca2+, the mechanically stimulated cell showed no change or a decrease in [Ca2+]i, whereas [Ca2+]i increased in neighboring cells. Iontophoretic injection of inositol 1,4,5-trisphosphate (IP3) evoked a communicated Ca2+ response that was similar to that produced by mechanical stimulation. These results support the hypothesis that IP3 acts as a cellular messenger that mediates communication through gap junctions between ciliated epithelial cells.
Article
The importance of eosinophils in the pathogenesis of bronchial asthma is not established. In an attempt to evaluate the role of eosinophilic inflammation in asthma, we compared 10 normal subjects with 43 patients with chronic asthma, 19 of whom had severe disease as assessed by a clinical scoring method described by Aas and by pulmonary-function tests. Eosinophils were counted in peripheral blood and bronchoalveolar-lavage fluid, and in biopsy specimens obtained from the patients and post mortem from 8 subjects without asthma, but not from the 10 normal controls. Eosinophil cationic protein was titrated by radioimmunoassay in the bronchoalveolar-lavage fluid from all subjects and studied by immunohistochemistry in the biopsy specimens. There was a significant increase in the number of peripheral-blood eosinophils in the patients that was correlated with the clinical severity of asthma (P less than 0.001) and pulmonary function (P less than 0.03). Levels of eosinophils and eosinophil cationic protein were increased in the bronchoalveolar-lavage fluid from the patients and were also correlated with the severity of asthma (P less than 0.001 and P less than 0.002, respectively). Hematoxylin-eosin staining of bronchial-biopsy specimens showed that intraepithelial eosinophils were present only in patients with asthma. Immunohistochemical analysis of eosinophil cationic protein revealed that normal subjects had only a few nondegranulated eosinophils deep in the submucosa, whereas all the patients had degranulated eosinophils beneath the basement membrane and among epithelial cells. In some patients there was a relation between the presence of degranulated eosinophils and epithelial damage. Eosinophilic inflammation of the airways is correlated with the severity of asthma. These cells are likely to play a part in the epithelial damage seen in this disease.
We have used fiberoptic bronchoscopy to obtain endobronchial biopsies in which mast cells and eosinophils were enumerated using monoclonal antibodies directed against mast cell tryptase (AA1) and the eosinophil cationic protein (EG2). Eleven symptomatic atopic asthmatics treated with beta 2-agonists alone and six normal subjects were studied. Over a period of 2 wk prior to bronchoscopy, patients recorded asthma symptom scores, bronchodilator usage, and twice-daily peak expiratory flow. Five days before bronchoscopy, methacholine responsiveness was assessed. Two biopsies were taken from the subcarinae, one of which was processed into araldite for immunostaining by the streptavidin biotin immunoperoxidase method and the other into Spurr resin for electron microscopy. The number of AA1 staining mast cells present in the bronchial mucosa was not significantly different in the epithelium or submucosa between the asthmatic and the normal subjects. However, in the biopsies from asthmatics, there were significantly greater numbers of EG2-staining eosinophils in the epithelium (median, 1.2/mm versus zero; p less than 0.005) and in the submucosa (median, 50/mm2 versus 1/mm2; p less than 0.001). Electron microscopy showed morphologic features of mast cell and eosinophil degranulation in the asthmatics. No correlation could be established between mast cell or eosinophil numbers and indices of disease activity of PC20 methacholine, which points to the complexity of mechanisms responsible for the symptoms and the airway hyperresponsiveness of asthma.
Article
A thickened bronchial epithelial basement membrane has long been regarded as a histopathologic characteristic of bronchial asthma. As we had previously demonstrated that this phenomenon is due to the deposition of interstitial collagens and fibronectin, we have now sought to determine the nature of the cell responsible for this process by studying endobronchial biopsies from eight normal and seven asthmatic volunteers by immunohistochemistry and electron microscopy. Biopsies were stained with PR 2D3, a monoclonal antibody to myofibroblasts of the pericrypt sheath of the colon and a monoclonal antibody to alpha-smooth muscle actin. The thickness of the subepithelial collagen and the organelle content of the cells therein were determined by electron microscopy. The subepithelial collagen thickness in the normal subjects ranged from 2.16 to 6.26 microns, while that in the asthmatic subjects ranged from 3.75 to 11.1 microns (Mann-Whitney test; P = 0.05). Elongated cells in the collagen layer were identified by staining with PR 2D3. As this antibody also stains smooth muscle, consecutive frozen sections were stained for alpha-smooth muscle actin and the number of positive cells per millimeter of basement membrane was subtracted from the count for PR 2D3. This yielded a count of 4.9 to 9.4 cells/mm in the normal subjects and 11.9 to 20.6 cells/mm in the asthmatics (P = 0.001). There was a highly significant correlation between the depth of subepithelial collagen and the number of PR 2D3-positive, alpha-smooth muscle actin-positive cells (Spearman rank correlation; r = 0.764 and P = 0.006). Electron microscopy confirmed the myofibroblastic nature of these cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Human nasal and bronchial epithelial cells were cultured in vitro and compared morphologically and functionally. Morphologic assessment by both light and electron microscope and indirect immunoperoxidase staining techniques confirmed the identity of the two cell types as being epithelial. Light microscopy of confluent cultures revealed tightly packed cell monolayers, whilst electron microscopy showed that cells were linked by tight junctions. Estimation of cell size by planimetry found these cells to have a mean width of 10.6 +/- 1.1 microns for nasal cells and a mean width of 10.2 +/- 1.0 microns for bronchial cells. A high proportion of both the nasal and the bronchial cells exhibited features of the mature ciliated cell types, and constituted between 50 and 76% of the total cells at the earlier stages of culture although this decreased to between 16 and 23% of the total by 4 weeks in culture. The ciliary beat frequencies of the nasal and bronchial cells were found to be similar at 10.8 +/- 0.7 Hz and 11.8 +/- 2.3 Hz, respectively. The cilial beat on adjacent cells was synchronous, suggesting the presence of intercellular communication between the neighbouring cells. These studies demonstrated that there was little difference between the cultured nasal and bronchial epithelial cells with respect to either their morphology or ciliary activity.
We have used immunohistochemistry and monoclonal antibodies to analyze the phenotypic composition and activation status of the cellular infiltrate of bronchial biopsies obtained by fiber optic bronchoscopy of 11 atopic asthmatic subjects (FEV1% predicted range 78 to 114), 9 atopic nonasthmatic control subjects, and 10 normal healthy subjects. Examination of mucosal biopsies obtained from both central (level I) and subsegmental (level II) bronchi showed that the highest number of CD45-, DC3-, DC4-, and CD8-positive cells were found in the group with asthma. There was a significant increase in the number of interleukin-2 receptor (CD25)-positive cells (a marker of lymphocyte activation) at airway level I in the asthmatic group compared with both nonasthmatic atopic (p less than 0.05) and normal control subjects (p less than 0.01). Eosinophil numbers were significantly increased in asthma at both airway levels and at airway level II in the nonasthmatic atopic group when compared with normal healthy control subjects (p less than 0.05). EG2-positive cells (an index of secretion of eosinophil cationic protein following activation) were found at both airway levels in the asthmatic group and at level I in the nonasthmatic atopic control group (p less than 0.05). When asthmatic subjects were compared with normal healthy subjects, there was a reduction in the number of neutrophil elastase-positive cells in the asthmatic subjects which, as a percentage of leukocytes, was significant (p = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Article
We challenge each of 55 consecutive ragweed (RW)-allergic patients with hay fever and with graded increasing doses of ragweed extract to investigate the frequency and relationship between the early (ER), late (LPR), and rechallenge reactions (RCRs) to nasal challenge. We evaluated the nasal response by measuring the levels of histamine, TAME-esterase activity, and kinins in the nasal lavage fluid and by grading symptoms. Fifty-one subjects (92.7%) had an ER consisting of a dose-dependent, concommitant increase in both mediators and symptoms. The total amount of TAME-esterase activity and kinins generated during ER correlated significantly with specific serum IgE (ssIgE), intradermal skin test (ST) sensitivity, and basophil histamine release (BHR) to antigen E (p less than 0.01 for each). Twenty-four (47%) subjects developed a late increase in mediators and 23 (45%) subjects in symptoms. None of the four subjects without an ER developed an LPR. The levels of the late-appearing mediators were not predicted by ST, ssIgE, or BHR. There was a significant but weak association between the intensity of ER and LPR, but there was no significant difference in the IgE antibodies, ST, BHR, and intensity or threshold of ER between dual and early only reactors. The number of eosinophils and neutrophils in the LPR lavages increased over the prechallenge baseline, and their numbers correlated (p less than 0.05) with ER kinins (r = 0.46, and 0.37, respectively), ER TAME-esterase activity (r = 0.28 and 0.24, respectively), and in the case of eosinophils, ER histamine (r = 0.29).(ABSTRACT TRUNCATED AT 250 WORDS)
Inhaling cold, dry air nasally induces in some persons symptoms of rhinitis that are associated with an increase in the level of mast-cell-associated mediators in nasal lavages. The present study, directed at understanding the mechanism of this reaction, showed that 9 subjects who displayed symptoms and inflammatory mediator release had significant (p less than 0.01) increments in nasal fluid osmolality, whereas the osmolality of the fluids of 6 subjects unaffected by cold, dry air challenge did not differ from baseline. Significant correlations were found between the mediator concentration and the osmolality of recovered nasal lavages (rs = 0.617, p less than 0.02; rs = 0.679, p less than 0.01 for histamine and TAME-esterase(s), respectively). No changes in the osmolality of nasal secretions were found in atopic subjects undergoing nasal challenge with antigen, despite the generation of symptoms and significant elevations in the levels of inflammatory mediators in their nasal lavages. Because increasing the osmolality of the medium surrounding isolated mast cells in vitro triggers mediator secretion, these observations support the concept that the response to cold, dry air nasal inhalation is caused by the release of mediators secondary to an increase in the osmolality of the mucosal secretions.
Article
The epithelial basement membrane and underlying collagen were examined by immunohistochemistry and electron microscopy in endobronchial biopsy specimens from 8 asthmatic and 3 control subjects. There was an excess of interstitial collagens beneath the basement membrane in the asthmatic subjects. There was no evidence of any epithelial contribution to this abnormality, nor was there any correlation with epithelial damage, disease duration, or severity. These findings contradict the long-held notion of basement membrane thickening in asthma and indicate that the subepithelial fibrosis is a result of fibroblast activation rather than bronchial epithelial cell dysfunction.
Article
This article has no abstract; the first 100 words appear below. WITH increasing frequency, the human neutrophil is being implicated as a mediator of tissue-destructive events in inflammatory diseases ranging from rheumatoid arthritis and myocardial reperfusion injury to respiratory distress syndromes, blistering skin disorders, and ulcerative colitis.¹,² In each of these diseases, as well as a variety of other acute inflammatory disorders, important components of these pathologic processes are being linked to the neutrophil's ability to release a complex assortment of agents that can destroy normal cells and dissolve connective tissues. Although these toxins normally defend the host against invading microbes, the neutrophil has little intrinsic ability to differentiate between foreign . . . Supported in part by grants (HL-28024, AI-21301, and AI-23876) from the National Institutes of Health. I am indebted to Vivek Reddy for helpful discussions. Source Information From the Division of Hematology and Oncology, Simpson Memorial Research Institute, Department of Medicine, University of Michigan Medical Center, Ann Arbor. Address reprint requests to Dr. Weiss at the Simpson Memorial Institute, 102 Observatory St., Ann Arbor, MI 48109.
Article
To investigate the mechanisms responsible for the late-phase response in patients with allergies, we measured four biochemical mediators (histamine, tosyl-L-arginine methyl ester [TAME]-esterase, kinin, and prostaglandin D2) in nasal secretions after nasal challenge with pollen antigen in 12 patients with allergy. Nine patients had an immediate response and a recurrence of symptoms 3 to 11 hours after challenge. The clinical symptoms during recurrence were accompanied by a second increase in levels of histamine, TAME--esterase, and kinin over base-line values, although kinin levels were lower than during the immediate response. In contrast, although the levels of prostaglandin D2 were significantly increased during the immediate response, they did not increase above base line during the late response. Rechallenge with allergen 11 hours after the initial provocation, however, was associated with reappearance of all four biochemical mediators, including prostaglandin D2. We conclude that the late response to nasal challenge with allergen is accompanied by a second increase in the concentrations of histamine and TAME--esterase but differs from the immediate response in the lack of prostaglandin D2 production and in the amount of kinin generated. Since histamine is released only by mast cells and basophils and prostaglandin D2 is not produced by basophils, we suggest that these cells are partly responsible for the late-phase response.
Article
Immunohistological investigations were performed on a series of samples from 37 patients with nasal polyps, 22 with chronic sinusitis, and 15 controls with healthy nasal and sinusal mucosa. Mean numbers of plasma- and mast cells were not different in the various groups. Immunoglobulin isotypes were always predominantly IgA and IgM; IgE were scarce. Deposited immune complexes were always absent. A statistically significant difference, however, was observed in the number of eosinophils within the mucosa. Patients with nasal polyps had up to ten times more eosinophils per surface unit than patients with sinusitis or healthy mucosa.
Article
Lung function and chest radiographs of 101 men who had worked for 1 or more years manufacturing copper-cadmium alloy were compared with those of a referent group matched for age, sex, and employment status. Cigarette consumption was similar in the two groups. The cadmium workers had an excess of abnormalities of lung function and of radiographic changes consistent with emphysema. Classification of the cadmium workers by exposure categories based on either estimated cumulative cadmium exposure or liver cadmium measured by neutron activation analysis showed that abnormalities of lung function were greatest in those with the highest cumulative cadmium exposure or liver cadmium. The difference in the transfer coefficient (KCO) between cadmium workers and referents increased linearly with increasing cumulative exposure without evidence for a threshold. The estimated mean decrement in KCO for a cadmium worker employed 5 or more years with a cumulative exposure of 2000 yr.microgram.m-3 (exposure to the current UK control limit of 50 micrograms.m-3 for a working lifetime of 40 yr) lies between 0.05 and 0.3 mmol.min-1.kPa-1.l-1 (95% confidence interval). This decrement is consistent with the functional and radiological changes of emphysema observed in this group of workers.
Article
The distribution and number of lymphocytes, monocytes/macrophages, and cells expressing HLA-DR antigen were studied in frozen biopsy sections of nasal mucosa from 40 healthy adults, using monoclonal antibody avidin-biotin immunoperoxidase techniques. The lymphocyte to monocyte/macrophage ratio was estimated to be 10:1; the T cell to B cell ratio was 3:1; and the T helper/inducer cell to T suppressor/cytotoxic cell ratio averaged 2.5:1. Regional differences were observed with a relatively increased number of T suppressor/cytotoxic cells around submucosal glands, and a relatively large number of B cells in lymphocyte aggregates in the lamina propria. The HLA-DR antigen was expressed in epithelial cells, suggesting involvement of surface epithelium of human airway in local immune responses.
Article
The proliferative potential of the various cell types present in airway epithelium have been described. The techniques used to assess their proliferative activity (MI and LI), growth fraction and length of each phase of the cell cycle have been given in outline. By use of a variety of techniques, there is ample capacity to recruit non-cycling cells rapidly into the cell cycle. Under certain circumstances (e.g. cigarette smoke exposure and mechanical trauma) the mucous (goblet) cell is proliferative and its role in epithelial repair has been clearly underestimated. Factors contributing to the variation seen in baseline proliferation include species, sex, hormonal status, airway level, age, diurnal rhythm and pathogen-free status. A variety of stimuli increase proliferation as part of a reparative process: 1) irritation by oxidants, chemical carcinogens or enzymes, 2) mechanical injury, 3) infection and 4) certain drugs, some of which stimulate division whilst others inhibit the proliferative response to irritation and may be useful in controlling the response. Increases in the numbers of some cell types may be due to differentiation rather than proliferation and the 3-compartment model can be applied to airway epithelium comprising: 1) the self renewing/proliferating compartment, made up of basal and secretory cells in the large airways, nonciliated bronchiolar (Clara) cells in the small airways, and type II cells in the alveolus; 2) the differentiation compartment containing mature functional cells, some of which retain the capacity to divide, e.g. serous, mucous (goblet), Clara, type II cells; 3) the fully-mature end stage cells (e.g. ciliated cells) which do not normally divide. The nervous system and lymphocytes present in epithelium and bronchus-associated lymphoid tissue may also have a part to play in controlling cell division and their roles should be investigated further. However, the lung remains relatively unexplored with regard to the factors which control the proliferation and differentiation of its many distinct cell types, both in health and disease.
Article
Neutrophils, the predominant phagocytes of circulating blood, are the first cells to arrive at sites of infection. Although neutropenia has long been recognized to predispose to infection, recently other syndromes marked by frequent infections have been shown to be caused by an underlying neutrophil dysfunction. Efforts to define the molecular pathology of such disorders have helped delineate the molecular basis of normal neutrophil function. Advances have been made in defining the roles of the neutrophil's varied receptors in recognition, movement, and adhesive phenomena. Progress in establishing the pathogenesis of chronic granulomatous disease has provided important insights into the enzymatic machinery that normal neutrophils use to produce antimicrobial oxidants. The identification and precise characterization of antimicrobial components, such as defensins, have outlined the potential roles of "natural antibiotics" in neutrophil-mediated host-defense functions. These areas of neutrophil function will be reviewed and placed in a clinical context to guide physicians in evaluating children and adults with frequent or unusual infections.
Article
Perceived nasal and bronchial hyperresponsiveness to tobacco smoke and cold air were assessed in 912 working men in the Paris area. Baseline lung function measurements and peripheral leucocyte counts with standard differential counts were performed. At least one perceived nasal or bronchial hyperresponsiveness symptom was reported by 15.7%. Current smoking was significantly less frequent among those with cough induced by tobacco smoke. Rhinitis induced by cold air was associated with lower FEV1 (p less than 0.01) and the association remained after adjustment for smoking, asthma, and wheezing (p = 0.06). Symptoms induced by cold air were related to circulating basophils. Neither perceived nasal nor perceived bronchial hyperresponsiveness was significantly related to the airway response to methacholine in a sample of the group (n = 324) surveyed again five years later. The result suggest that the symptom of rhinitis provoked by cold air is a possible "new" risk factor or marker for chronic airflow limitation.
Article
By utilizing the colloidal gold particle technique, we localized eosinophil granule major basic protein, eosinophil cationic protein (ECP), and eosinophil-derived neurotoxin (EDN) in human nasal polyp sections by immunoelectron microscopy. Sections stained with affinity chromatography purified rabbit anti-human major basic protein, and subsequently with gold colloidal particle-goat anti-rabbit IgG, showed gold particles predominantly within granule cores, and not within other eosinophil organelles, plasma cells, mast cells, lymphocytes, or neutrophils. Sections stained with anti-ECP or anti-EDN showed gold particles concentrated over the granule matrix with fewer particles centrally. Control sections treated with preimmunization sera showed no staining of cells or organelles. These results verify the localization of major basic protein to the crystalloid core of the human eosinophil granule and show that ECP and EDN reside in the granule matrix. This technique provides a means of accurately locating the sites of major basic protein, ECP, and EDN deposition and thus of identifying eosinophil degranulation patterns in human disease.
Several aspects of airway function are under autonomic control: airway smooth muscle tone, submucosal gland secretion, epithelial cell function, bronchial vascular tone and permeability, and probably secretion from mast cells and other inflammatory cells. Neural control of human airways is more complex than previously recognized. In addition to afferent nerves and cholinergic adrenergic mechanisms (including circulating catecholamines), there are nonadrenergic, noncholinergic nerves that may be both excitatory and inhibitory. The neurotransmitters of this third nervous system are uncertain, but there is some evidence that neuropeptides may be involved. Several neuropeptides have recently been identified in human airways and, although they have potent effects, their pathophysiologic role is uncertain. There is much evidence that autonomic control of the airways may be abnormal in airway disease, particularly in asthma, but the precise role of neural mechanisms in the pathogenesis of air-flow obstruction and bronchial hyperresponsiveness remains to be defined.
Article
The evidence reviewed here indicates that the eosinophil has the ability to kill many species of helminths and likely does so during worm infection. This toxic ability appears to be regulated by several other cells including mast cells, monocytes, and T lymphocytes. Eosinophils kill helminths through their ability to generate potent oxidants and through their content of cationic proteins, which likely achieve high concentrations at points of granule deposition. Eosinophils also participate in inflammation in human disease especially asthma, skin diseases, and heart disease. Though present concepts hold that the mast cell is the cornerstone of the allergic inflammatory response (450), the findings that eosinophils bind IgE and are activated by antigen-IgE complexes and that the eosinophil can elaborate many inflammatory mediators raise the possibility that the eosinophil might also be involved in the initiation of inflammatory responses. Finally, an eosinophil-related protein appears to play an undefined role in human reproduction.
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Nasal mucosal blood flow was investigated in patients undergoing a stellate ganglion blockade. Elimination of the sympathetic neurogenic control did not affect the resting blood flow in the mucosa, as registered with the 133Xe washout technique. This indicates that the basal sympathetic vasoconstrictor activity is low in the mucosal vessels that regulate blood flow. With laser doppler flowmetry, the normal pattern of spontaneous oscillations in blood flow was seen to be altered following stellate ganglion blockade. This suggests that vasomotion in the mucosa is partly dependent on sympathetic neurogenic activity. Furthermore, the decrease in blood flow normally induced by a peripheral cold provocation could not be elicited after the ganglion blockade, which means that the decrease is mediated by sympathetic vasoconstrictor fibres.
Article
Two established methods (active posterior and passive anterior rhinomanometry) and 2 new methods (peak nasal inspiratory flow rate and apparent nasal volume) were used in 12 volunteers to assess the patency of the nasal airways under each of 4 conditions (baseline, post-exercise, nasal histamine and nasal cocaine). All methods showed the congestant effect of histamine but the peak nasal inspiratory flow and apparent nasal volume techniques were more sensitive to the 'decongesting' manoeuvres, (exercise and cocaine). Useful objective quantitative data on the patency of the nasal airways and its changes in response to stimuli can be obtained by simple, cheap and readily available techniques. Subjective sensation is a poor guide to the state of patency of the nasal airways.
We measured bronchial reactivity to inhaled histamine and prepared electron micrographs from bronchial biopsies from 8 asthmatic patients who never smoked (2 females, 6 males, 18 to 62 yr of age). Judging from their clinical histories and the need for medication and long-term follow-up of PEF values, 2 of them had mild asthma, 3 moderately severe, and 3 severe asthma. They had not experienced respiratory infections for at least 2 months prior to the study. The result, obtained from the cumulative dose-response curve, was expressed as the provocative dose (PD20) of histamine producing a 20% fall in forced expiratory volume in one second (FEV1). In 5 patients, the PD20 varied from 0.049 mg to 2.234 mg. In the sixth patient, only PD15 could be measured (5.187 mg). In 2 patients, the low initial FEV1 values, because of severe, partly irreversible obstruction, prevented the measurement of bronchial reactivity. Bronchial biopsies were taken with rigid tube bronchoscopy from 3 levels: (1) at the carina of the right upper lobe, (2) at the opening of the right middle or lower lobe, and (3) inside the right lower lobe. The specimens were prepared for both light and electron microscopy. Fresh biopsies showed that asthma patients can have epithelial destruction at all levels of the airways. The ciliated cells appeared to be the most destroyed cell type in the epithelium. Intraepithelial nerves and mast cells were seen. Epithelial destruction in the respiratory tract of the asthma patients with mild to severe bronchial hyperresponsiveness was prominent enough to expose the epithelial nerves for specific or nonspecific stimuli.
Article
A description is given of organized lymphoid tissue bearing remarkable morphologic similarities to intestinal Peyer's patches in the bronchial mucosa of rabbits, guinea pigs, rats, mice, dogs, pigs, chickens, and man. This bronchus associated lymphoid tissue (BALT) is made up of lymphoid follicles, relating closely to the bronchial epithelium which they infiltrate to form a lymphoepithelium. This epithelium differs from the normal bronchial epithelium in that it no longer stains with periodic acid Schiff or Alcian Blue. Using morphologic, histochemical, and ultrastructural criteria, the authors failed to demonstrate any plasma cells within BALT. This finding was corroborated by the failure to reveal specifically staining immunoglobulin containing cells within BALT using fluorescein conjugated specific antisera to IgG (L + H chains), as well as heavy chain specific antisera directed against IgG, IgA, and IgM. Rabbits delivered by cesarean section 1 day before term lacked BALT, as did normal, conventionally raised hamsters. However, young adult rats raised in a germ free environment possessed BALT, although this was less developed than in conventionally raised rats. Review of the recent literature reveals little awareness of BALT and no functional studies have been reported. The possible relation of BALT to the lymphoid system in general and to mucosal immunity in particular is discussed.