[Show abstract][Hide abstract] ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a major cause of death worldwide. No therapy stopping progress of the disease is available.
To investigate the role of the soluble guanylate cyclase (sGC)-cGMP axis in development of lung emphysema and pulmonary hypertension (PH) and to test whether the sGC-cGMP axis is a treatment target for these conditions.
Investigations were performed in human lung tissue from COPD patients, healthy donors, mice, and guinea pigs. Mice were exposed to cigarette smoke (CS) for 6 hours/day, 5 days/week for up to 6 months and treated with BAY 63-2521. Guinea pigs were exposed to CS from 6 cigarettes/day for 3 months, 5 days/week and treated with BAY 41-2272. Both BAY compounds are sGC stimulators. Gene and protein expression analysis were performed by quantitative real-time PCR and western blotting. Lung compliance, hemodynamics, right ventricular heart mass alterations, alveolar and vascular morphometry were performed, as well as inflammatory cell infiltrate assessment. In vitro assays of cell adhesion, proliferation and apoptosis have been done.
The functionally essential sGC β1-subunit was downregulated in COPD patients and in CS-exposed mice. sGC stimulators prevented the development of PH and emphysema in the two different CS-exposed animal models. sGC stimulation prevented peroxynitrite-induced apoptosis of alveolar and endothelial cells, reduced CS-induced inflammatory cell infiltrate in lung parenchyma and inhibited adhesion of CS-stimulated neutrophils.
The sGC-cGMP axis is perturbed by chronic exposure to CS. Treatment of COPD animal models with sGC stimulators can prevent CS-induced PH and emphysema.
American Journal of Respiratory and Critical Care Medicine 04/2014; · 11.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In chronic obstructive pulmonary disease (COPD), decreased progenitor cells and impairment of systemic vascular function have been suggested to confer higher cardiovascular risk. The origin of these changes and their relationship with alterations in the pulmonary circulation are unknown.
PLoS ONE 01/2014; 9(8):e106163. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Little is known about the structure and function relationships of pulmonary vessels in the most severe chronic obstructive pulmonary disease (COPD) spectrum. We investigated morphometric, cellular, and physiologic characteristics of pulmonary arteries from COPD patients undergoing bilateral lung transplant.
Seventeen patients with very severe COPD (forced expiratory volume in 1 second, 24% ± 7%) were assessed using inert gas exchange and pulmonary hemodynamics while breathing ambient air and 100% oxygen. Morphometry, in vitro reactivity to hypoxia, and inflammatory cell counts of pulmonary arteries were measured in explanted lungs.
Patients had moderate ventilation-perfusion imbalance along with mild release of hypoxic pulmonary vasoconstriction. Mild pulmonary hypertension was observed in 7 patients. Explanted lungs had predominant emphysema with mild small airway involvement. In vitro reactivity was modestly altered, with relatively preserved endothelium-dependent relaxation, and vascular remodelling was discrete, with intense CD8(+) T lymphocytes infiltrate. In vitro reactivity correlated with pulmonary vascular resistance (on ambient air) and oxygen-induced pulmonary artery pressure changes. Patients with pulmonary hypertension had more severe morphologic and physiologic emphysema.
In end-stage COPD patients undergoing lung transplant, pulmonary vascular involvement is unexpectedly modest, with low-grade endothelial dysfunction. In this sub-set of COPD patients, pulmonary emphysema may constitute the major determinant of the presence of pulmonary hypertension.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 12/2013; 32(12):1262-1269. · 3.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with chronic obstructive pulmonary disease (COPD) often suffer other concomitant disorders, such as cardiovascular diseases (CVD) and metabolic disorders, that influence significantly (and independently of lung function) their health status and prognosis. Thus, COPD is not a single organ condition and disturbances of a complex network of inter-organ connected responses occur and modulate the natural history of the disease. Here, we propose a novel hypothesis that considers a vascularly connected network with: (1) the lungs, as the main external sensor of the system and a major source of "danger signals"; (2) the endothelium, as an internal sensor of the system (also a potential target tissue); and, (3) two key responding elements, bone marrow and adipose tissue, which produce both inflammatory and repair signals. According to the model, the development of COPD, and associated multimorbidities (here we focus on CVD as an important example), depend on the manner in which the vascular connected network responds, adapts or fails to adapt, (dictated by the genetic and epigenetic background of the individual) to the inhalation of particles and gases, mainly in cigarette smoke. The caveats and limitations of the hypothesis, as well as the experimental and clinical research needed to test and explore the proposed model, are also briefly discussed.
American Journal of Respiratory and Critical Care Medicine 10/2013; · 11.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Long-acting muscarinic antagonists (LAMAs) are widely used to treat chronic obstructive pulmonary disease (COPD). In addition to bronchodilation, muscarinic antagonism may affect pulmonary histopathological changes. The effects of LAMAs have not been thoroughly evaluated in experimental models of COPD induced by chronic exposure to cigarette smoke (CS). We investigated the effects of aclidinium bromide on pulmonary function, airway remodeling, and lung inflammation in a CS-exposed model of COPD. 36 guinea pigs were exposed to CS and 22 sham-exposed, for 24 weeks. Animals were nebulized daily with vehicle, aclidinium 10 or 30 μg/mL, resulting in six experimental groups. Pulmonary function was assessed weekly by whole-body plethysmography, determining the enhanced pause (Penh) at baseline, after treatment, and after CS/sham exposure. Lung changes were evaluated by morphometry and immunohistochemistry. CS exposure increased Penh in all conditions. CS-exposed animals treated with aclidinium showed lower baseline Penh than untreated animals (P=0.02). CS induced thickening of all bronchial wall layers, airspace enlargement, and inflammatory cell infiltrate in airways and septa. Treatment with aclidinium abrogated the CS-induced smooth-muscle enlargement in small airways (P=0.001) and tended to reduce airspace enlargement (P=0.054). Aclidinium also attenuated CS-induced neutrophilia in alveolar septa (P=0.04). We conclude that in guinea pigs chronically exposed to CS, aclidinium has anti-remodeling effect on small airways, which is associated with improved respiratory function, and attenuates neutrophilic infiltration in alveolar septa. These results indicate that in COPD, aclidinium may exert beneficial effects on lung structure in addition to its bronchodilator action.
American Journal of Respiratory Cell and Molecular Biology 09/2013; · 4.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract Cigarette smoke (CS) induces an inflammatory process in the lung that may underlie the development of chronic obstructive pulmonary disease (COPD). The nature and characteristics of this process have not been fully established in animal models. We aimed to evaluate the pulmonary inflammatory reaction and its involvement in structural changes in guinea pigs chronically exposed to CS. 19 Hartley guinea pigs were exposed to 7 cigarettes/day, during 3 or 6 months. 18 control guinea pigs were sham-exposed. Numbers of neutrophils, macrophages and eosinophils and lymphoid follicles were assessed in different lung structures. Airway and vessel morphometry, alveolar space size and collagen deposition were also quantified. After 6 months of exposure, CS-exposed guinea pigs showed increased numbers of neutrophils, macrophages and eosinophils in the airways, intrapulmonary vessels and alveolar septa, as well as lymphoid follicles. Increased numbers of muscularized intrapulmonary vessels were apparent at 3 months. After 6 months of exposure, the airway wall thickened and the alveolar space size increased. Collagen deposition was also apparent in airway walls and alveolar septa after 6 months' exposure. The magnitude of airway wall-thickening correlated with the number of infiltrating inflammatory cells, and the extension of collagen deposition correlated with alveolar space size. We conclude that in the guinea pig, 6 months of CS exposure induces inflammatory cell infiltrate in lung structures, at an intensity that correlates with airway remodelling. These changes resemble those observed in COPD, thus endorsing the pathogenic role of CS and the usefulness of this animal model for its study.
[Show abstract][Hide abstract] ABSTRACT: The objective of this study is to analyse the frequency and levels of anti-citrullinated peptide/protein antibodies (ACPA) in the serum of non-rheumatoid arthritis (RA) heavy smokers with and without chronic obstructive pulmonary disease (COPD) and compare them with healthy never smokers and patients with RA. Serum samples of 110 heavy smokers without RA, 209 healthy never smokers and 134 patients with RA were tested for ACPA using a commercial anti-cyclic citrullinated peptide antibodies (CCP2) test and a homemade chimeric fibrin/filaggrin citrullinated synthetic peptide (anti-CFFCP) ELISA test. The frequency of positive results and autoantibody levels were compared between groups. The prevalence of the two types of ACPA was slightly higher in heavy smokers than in never smokers, although the difference was not significant, and significantly lower than in RA patients. The highest prevalence of positive ACPA in heavy smokers was found in subjects with COPD (7.4% of positive anti-CFFCP in patients with COPD in comparison with 2.4% in never smokers: OR 3.26; 95% CI 0.85-12.6, p = 0.089). Mean serum levels of ACPA in heavy smokers were not significantly different from those of never smokers. Heavy smokers with COPD had significantly higher levels of anti-CFFCP than those without COPD, although almost all patients had serum levels below the cut-off values. The prevalence of ACPA in heavy smokers without RA is low, but seems to be higher in heavy smokers with COPD. Larger studies are necessary to confirm these findings and determine the relationship between ACPA and lung disease.
[Show abstract][Hide abstract] ABSTRACT: Ventilatory effects of chronic cigarette smoke (CS) alone or associated to chronic hypoxia (CH), as frequently occurs in chronic obstructive pulmonary disease (COPD), remain unknown. We have addressed this problem using whole-body plethysmography in guinea-pigs, common models to study harmful effects of CS on the respiratory system. Breathing frequencies (Bf) in control (2-5 months old) guinea pigs is 90-100 breaths/min, their tidal volume (TV) increased with age but lagged behind body weight gain and, as consequence, their minute volume (MV)/Kg decreased with age. MV did not change by acutely breathing 10% O(2) but doubled while breathing 5% CO(2) in air. Exposure to chronic sustained hypoxia (15 days, 12% O(2), CH) did not elicit ventilatory acclimatization nor adaptation. These findings confirm the unresponsiveness of the guinea pig CB to hypoxia. Exposure to CS (3 months) increased Bf and MV but association with CH blunted CS effects. We conclude that CS and CH association accelerates CS-induced respiratory system damage leading to a hypoventilation that can worsen the ongoing COPD process.
Advances in experimental medicine and biology 01/2012; 758:325-32. · 1.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previously we have reported that association of cigarette smoke (CS) and chronic hypoxia (CH) interact positively to physiopathologically remodel pulmonary circulation. In present study we have exposed guinea pigs to CS smoke (four cigarettes/day; 3 months; CS) and to chronic hypoxia (12% O(2), 15 days; CH) alone or in combination (CSCH animals) and evaluated airways remodeling and resistance assessed as Penh (enhance pause). We measured Penh while animals breathe air, 10% O(2) and 5% CO(2) and found that CS and CH animals have higher Penh than controls; Penh was even larger in CSCH animals. A rough parallelism between Penh and thickness of bronchiolar wall and muscular layer and Goblet cell number was noticed. We conclude that CS and CH association accelerates CS-induced respiratory system damage, evidenced by augmented airway resistance, bronchial wall thickness and muscularization and Goblet cell number. Our findings would suggest that appearance of hypoxia would aggravate any preexisting pulmonary pathology by increasing airways resistance and reactivity.
[Show abstract][Hide abstract] ABSTRACT: Chronic obstructive pulmonary disease (COPD) is commonly associated with vascular changes in the pulmonary and systemic circulations. Pulmonary muscular arteries characteristically show intimal hyperplasia, which is produced in part by the proliferation of poorly differentiated smooth muscle cells. The origin of these cells has not been determined. Bone marrow has the capacity to produce and mobilize progenitor cells that may be recruited at sites of vascular damage and contribute to vascular repair through their differentiation into endothelial cells. Nevertheless, under some circumstances bone marrow-derived progenitor cells may migrate into the intima and differentiate into smooth muscle cells. Local factors and cell-to-cell contact are critical in determining the fate of progenitor cells in the vessel wall. Studies assessing the number of circulating bone marrow-derived vascular progenitor cells indicate that COPD is characterized by a reduction in circulating hemopoietic and vascular progenitors. The mechanisms of this reduction have not been elucidated. It has been suggested that this process may lead to reduced vascular repair capacity and increase the risk of cardiovascular complications, which are associated with significant morbidity and mortality in COPD. Further investigation in this field and elucidation of the underlying mechanisms will contribute to a better management of this major complication of COPD.
Proceedings of the American Thoracic Society 11/2011; 8(6):528-34.
[Show abstract][Hide abstract] ABSTRACT: Since human lungs are unlikely to repair or regenerate beyond the cellular level, cell therapy has not previously been considered for chronic irreversible obstructive lung diseases. To explore whether cell therapy can restore lung function, we administered allogenic intratracheal mesenchymal stem cell (MSC) in the trachea of rats with chronic thromboembolic pulmonary hypertension (CTEPH), a disease characterized by single or recurrent pulmonary thromboembolic obliteration and progressive pulmonary vascular remodeling. MSCs were retrieved only in high pressure-exposed lungs recruited via a homing stromal derived factor-1 alpha/CXCR4 pathway. After MSC administration, a marked and long-lasting improvement of all clinical parameters and a significant change of the proteome level were detected. Beside a variation of liver proteome, such as Caspase-3, NF- 〈B, Collagen1A1 and 〈-SMA, we also identified more than 300 resident and nonresident lung proteins, e.g. myosin light chain 3 (P16409) or mitochondrial ATP synthase subunit alpha (P15999). These results suggest that cell therapy restores lung function and the therapeutic effects of MSCs may be related to protein-based tissue reconstituting effects.
[Show abstract][Hide abstract] ABSTRACT: Cigarette smoke (CS) and chronic hypoxia (CH) can produce pulmonary hypertension. Similarities and differences between both exposures and their interaction have not been explored. The aim of the present study was to investigate the effects of CS and CH, as single factors or in combination, on the pulmonary circulation in the guinea pig. 51 guinea pigs were exposed to CS for 12 weeks and 32 were sham-exposed. 50% of the animals in each group were additionally exposed to CH for the final 2 weeks. We measured pulmonary artery pressure (P(pa)), and the weight ratio between the right ventricle (RV) and left ventricle plus the septum. Pulmonary artery contractility in response to noradrenaline (NA), endothelium-dependent vasodilatation and distensibility were evaluated in organ bath chambers. The number of small intrapulmonary vessels showing immunoreactivity to smooth muscle (SM) α-actin and double elastic laminas was assessed microscopically. CS and CH induced similar increases of P(pa) and RV hypertrophy (p<0.05 for both), effects that were further enhanced when both factors were combined. CH increased the contractility to NA (p<0.01) and reduced the distensibility (p<0.05) of pulmonary arteries. Animals exposed to CS showed an increased number of small vessels with positive immunoreactivity to SM α-actin (p<0.01) and those exposed to CH a greater proportion of vessels with double elastic laminas (p<0.05). We conclude that CH amplifies the detrimental effects of CS on the pulmonary circulation by altering the mechanical properties of pulmonary arteries and enhancing the remodelling of pulmonary arterioles.
European Respiratory Journal 02/2011; 38(3):617-27. · 6.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Endothelial progenitor cells (EPC) have been shown to repair pulmonary endothelium, although they can also migrate into the arterial intima and differentiate into smooth muscle-like (mesenchymal) cells contributing to intimal hyperplasia. The molecular mechanisms by which this process proceeds have not been fully elucidated. Here, we study whether genes involved in the endothelial-to-mesenchymal transition (EnMT) may contribute to the mesenchymal phenotype acquisition of EPC and we evaluate whether transforming growth factor β1 (TGFβ1) is involved in this process.
Our results show that co-culture of EPC with smooth muscle cells (SMC) increases the expression of the mesenchymal cell markers α-smooth muscle actin, sm22-α, and myocardin, and decreases the expression of the endothelial cell marker CD31. In the same conditions, we also observed a concomitant increase in the gene expression of the EnMT-related transcription factors: slug, snail, zeb1, and endothelin-1. This indicates that mesenchymal phenotype acquisition occurred through an EnMT-like process. Inhibition of TGFβ receptor I (TGFβRI) downregulated snail gene expression, blocked the EnMT, and facilitated the differentiation of EPC to the endothelial cell lineage. Furthermore, TGFβRI inhibition decreased migration of EPC stimulated by SMC without affecting their functionality and adhesion capacity.
These results indicate that EPC may differentiate into SMC-like cells through an EnMT-like process and that TGFβI plays an important role in the fate of EPC.
Cardiovascular research 12/2010; 88(3):502-11. · 5.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic obstructive pulmonary disease (COPD) is characterized by multiple cellular and structural changes affecting the airways, lung parenchyma and vasculature, some of which are also identified in smokers without COPD. The molecular mechanisms underlying these changes remain poorly understood. With the aim of identifying mediators potentially implicated in the pathogenic processes that occur in COPD and their potential relationship with cigarette smoking, we evaluated the mRNA expression of genes involved in inflammation, tissue remodeling and vessel maintenance. Lung tissue samples were obtained from 60 patients who underwent lung resection (nonsmokers, n=12; smokers, n=12; and moderate COPD, n=21) or lung transplant (severe-to-very severe COPD, n=15). PCR arrays containing 42 genes coding for growth factors/receptors, cytokines, metalloproteinases, adhesion molecules, and vessel maintenance mediators were used. Smoking-induced changes include the up-regulation of inflammatory genes (IL-1β, IL-6, IL-8, CCL2, and CCL8) and the decreased expression of growth factor/receptor genes (BMPR2, CTGF, FGF1, KDR and TEK) and genes coding for vessel maintenance factors (EDNRB). All these genes exhibited a similar profile in moderate COPD patients. The up-regulation of MMP1 and MMP9 was the main change associated with COPD. Inflammatory genes as well as the endothelial selectin gene (SELE) were down-regulated in patients with more severe COPD. Clustering analysis revealed a closer relationship between moderate COPD and smokers than between both subsets of COPD patients for this selected set of genes. The study reveals striking similarities between smokers and COPD patients with moderate disease emphasizing the crucial role of cigarette smoking in the genesis of these changes, and provides additional evidence of the involvement of the matrix metalloproteinase's in the remodeling process of the lung in COPD.
[Show abstract][Hide abstract] ABSTRACT: The prevalence of cigarette smoking (CS) is increased among obese subjects, who are susceptible to develop nonalcoholic fatty liver disease (NAFLD). We investigated the hepatic effects of CS in control and obese rats. Control and obese Zucker rats were divided into smokers and nonsmokers (n = 12 per group). Smoker rats were exposed to 2 cigarettes/day, 5 days/week for 4 weeks. The effects of CS were assessed by biochemical analysis, hepatic histological examination, immunohistochemistry, and gene expression analysis. Phosphorylation of AKT and extracellular signal-regulated kinase (ERK) and quantification of carbonylated proteins were assessed by western blotting. As expected, obese rats showed hypercholesterolemia, insulin resistance, and histological features of NAFLD. Smoking did not modify the lipidic or glucidic serum profiles. Smoking increased alanine aminotransferase serum levels and the degree of liver injury in obese rats, whereas it only induced minor changes in control rats. Importantly, CS increased the histological severity of NAFLD in obese rats. We also explored the potential mechanisms involved in the deleterious effects of CS. Smoking increased the degree of oxidative stress and hepatocellular apoptosis in obese rats, but not in controls. Similarly, smoking increased the hepatic expression of tissue inhibitor of metalloproteinase-1 and procollagen-alpha2(I) in obese rats, but not in controls. Finally, smoking regulated ERK and AKT phosphorylation. The deleterious effects of CS were not observed after a short exposure (5 days). CONCLUSION: CS causes oxidative stress and worsens the severity of NAFLD in obese rats. Further studies should assess whether this finding also occurs in patients with obesity and NAFLD.
[Show abstract][Hide abstract] ABSTRACT: Inflammation and oxidative stress contribute to muscle dysfunction in patients with chronic obstructive pulmonary disease (COPD). Oxidants contained in cigarette smoke (CS) induce adverse effects on tissues through oxidative phenomena.
To explore oxidative stress and inflammation in quadriceps of human smokers and in diaphragm and limb muscles of guinea pigs chronically exposed to CS.
Muscle function, protein oxidation and nitration, antioxidants, oxidized proteins, inflammation, creatine kinase activity, and lung and muscle structures were investigated in vastus lateralis of smokers, patients with COPD, and healthy control subjects and in diaphragm and gastrocnemius of CS-exposed guinea pigs at 3, 4, and 6 months.
Compared with control subjects, quadriceps muscle force was mildly but significantly reduced in smokers; protein oxidation levels were increased in quadriceps of smokers and patients with COPD, and in respiratory and limb muscles of CS-exposed animals; glycolytic enzymes, creatine kinase, carbonic anydrase-3, and contractile proteins were significantly more carbonylated in quadriceps of smokers and patients with COPD, and in respiratory and limb muscles of CS-exposed guinea pigs. Chronic CS exposure induced no significant rise in muscle inflammation in either smokers or rodents. Muscle creatine kinase activity was reduced only in patients with COPD and in both diaphragm and gastrocnemius of CS-exposed animals. Guinea pigs developed bronchiolar abnormalities at 4 months of exposure and thereafter.
CS exerts direct oxidative modifications on muscle proteins, without inducing any significant rise in muscle inflammation. The oxidative damage to muscle proteins, which precedes the characteristic respiratory changes, may contribute to muscle loss and dysfunction in smokers and patients with COPD.
American Journal of Respiratory and Critical Care Medicine 04/2010; 182(4):477-88. · 11.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mutations of the gene that code bone morphogenic protein type 2 receptor (BMPR2) are involved in the pathogenesis of pulmonary arterial hypertension (PAH), both in its familial (FPAH) and its idiopathic (IPAH) forms.
With the aim of increasing the knowledge of these genetic factors in our area, the BMPR2 gene was studied in 17 patients with PAH, 8 with FPAH and 9 with sporadic IPAH. Additionally, a study was made to see whether the presence of BMPR2 mutations was associated with changes in the CO diffusing CO (DL(CO)) with the aim of evaluating the interest in this measurement in the pre-clinical diagnosis.
R491Q y R211X mutations were detected in 2 patients with FPAH (prevalence, 25%), and the R332X mutation in one case of IPAH (prevalence, 11%). The familial study of the patient with the R491Q mutation, 14 of the 28 subjects studied had the mutation, and 4 had the diseases (penetration, 36%). A decrease in the DL(CO)/alveolar volume (K(CO)) ratio was observed in asymptomatic family members who expressed the mutation, compared to those who did not express it (88+/-5% and 104+/-9% of the reference value, respectively; P<0.01).
We conclude that the frequency of mutations in the BMPR2 gene in the patients studied with FPAH is lower than was previously described. The decrease in the K(CO) observed in asymptomatic carriers of the mutation suggests a certain level of pulmonary vascular changes, therefore its measurement could be useful in the familial study of FPAH.
Archivos de Bronconeumología 03/2010; 46(3):129-34. · 2.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cigarette smoking may contribute to pulmonary hypertension in chronic obstructive pulmonary disease by altering the structure and function of pulmonary vessels at early disease stages. The objectives of this study were to evaluate the effects of long-term exposure to cigarette smoke on endothelial function and smooth muscle-cell proliferation in pulmonary arteries of guinea pigs.
19 male Hartley guinea pigs were exposed to the smoke of 7 cigarettes/day, 5 days/week, for 3 and 6 months. 17 control guinea pigs were sham-exposed for the same periods. Endothelial function was evaluated in rings of pulmonary artery and aorta as the relaxation induced by ADP. The proliferation of smooth muscle cells and their phenotype in small pulmonary vessels were evaluated by immunohistochemical expression of alpha-actin and desmin. Vessel wall thickness, arteriolar muscularization and emphysema were assessed morphometrically. The expression of endothelial nitric oxide synthase (eNOS) was evaluated by Real Time-PCR.
Exposure to cigarette smoke reduced endothelium-dependent vasodilatation in pulmonary arteries (ANOVA p < 0.05) but not in the aorta. Endothelial dysfunction was apparent at 3 months of exposure and did not increase further after 6 months of exposure. Smoke-exposed animals showed proliferation of poorly differentiated smooth muscle cells in small vessels (p < 0.05) after 3 months of exposure. Prolonged exposure resulted in full muscularization of small pulmonary vessels (p < 0.05), wall thickening (p < 0.01) and increased contractility of the main pulmonary artery (p < 0.05), and enlargement of the alveolar spaces. Lung expression of eNOS was decreased in animals exposed to cigarette smoke.
In the guinea pig, exposure to cigarette smoke induces selective endothelial dysfunction in pulmonary arteries, smooth muscle cell proliferation in small pulmonary vessels and reduced lung expression of eNOS. These changes appear after 3 months of exposure and precede the development of pulmonary emphysema.
Respiratory research 09/2009; 10:76. · 3.64 Impact Factor