M G Cosio

University of Padova, Padua, Veneto, Italy

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Publications (82)664.04 Total impact

  • Manuel G Cosio, Riccardo Cazzuffi, Marina Saetta
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a disease that usually presents clinically at an advanced age, after years of smoking cigarettes. It is usually believed that aging and its biological consequences are important mechanisms in the disease pathogenesis. This concept has maintained the focus of studies on COPD in old-age individuals. Here we analyze the possible role of aging from a different point of view and introduce different concepts that might be considered useful additions to the understanding of the disease. Essentially, we propose and show evidence that COPD is a disease of the young susceptible smoker that progresses over time and manifests in older age because we live longer and not so much because of the effect of aging itself; we examine the concept of cell senescence, the basis of tissue aging, and how stressors like the ones produced by smoking can accelerate cell senescence with all of its untoward consequences in COPD. We thus finally suggest that COPD might accelerate aging rather than be a consequence of it. In conclusion, we suggest that COPD could be considered a disease of the predisposed young individual that manifests clinically in old age because we live longer, with all of its consequences. © 2014 S. Karger AG, Basel.
    Respiration 05/2014; · 2.62 Impact Factor
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    ABSTRACT: ABSTRACT BACKGROUND. D6 is an atypical chemokine receptor involved in chemokines degradation and resolution of acute inflammatory responses in mice. Emerging evidence suggests that D6 might behave differently in human chronic inflammatory conditions. We therefore investigated the involvement of D6 in the immune responses in COPD, a chronic inflammatory condition of the lung. METHODS. D6 expression was quantified by immunohistochemistry in surgical resected lung specimens from 16 patients with COPD (FEV1: 57 ± 6 % predicted) and 18 controls with normal lung function (9 smoking and 9 non-smoking). Bronchoalveolar lavage (BAL) was also obtained and analysed by flow cytometry, immunofluorescence, and molecular analysis for further assessment of D6 involvement. RESULTS. D6 expression in the lung was mainly detected in alveolar macrophages (AM). The percentage of D6+ AM was markedly increased in COPD patients as compared to both smoking and non-smoking controls (p<0.0005 for both). D6 expression was detected at both transcript and protein level in AM but not in monocyte-derived macrophages. Finally, D6 expression was positively correlated with markers of immune activation (CD8+ T lymphocytes, IL-32, TNFα, BAFF, phospho-p38 MAPK) and negatively with lung function (FEV1, FEV1/FVC). CONCLUSIONS. D6 is expressed in alveolar macrophages from COPD patients and its expression correlates with the degree of functional impairment and markers of immune activation. Up-regulation of D6 in alveolar macrophages could indicate that, besides its known scavenger activity in acute inflammation, D6 may have additional roles in chronic inflammatory conditions possibly promoting immune activation.
    Chest 07/2012; · 7.13 Impact Factor
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    ABSTRACT: COPD is a complex disease with heterogeneous manifestations. Attempts have been made to define different phenotypes that could guide toward better disease understanding. We described before that smokers can develop either panlobular (PLE) or centrilobular emphysema (CLE). The latter has worse small airways remodeling and narrowing, which account for the airflow obstruction similar to asthma. Because of the small airways involvement in CLE similar to asthma, we hypothesized a role for mast cells in CLE but not in PLE. Hence, we investigated mast cell infiltration, along with overall inflammation, and their relation with hyperreactivity and emphysema type in COPD. We studied lung function, emphysema type, mast cells, and overall inflammation in small airways and alveolar walls, along with alveolar wall thickening in 67 subjects undergoing lung resection (59 smokers, 8 nonsmokers). Twenty-seven smokers had CLE, 24 had PLE, and 8 had no emphysema. Mast cells were significantly increased in CLE compared with PLE and control subjects. Especially relevant was the mast cell increase in airway smooth muscle in CLE, which related significantly to airway hyperreactivity. CD4(+)T cells, neutrophils, and macrophages, but not eosinophils and CD8(+)T cells, were significantly higher in CLE than PLE. Alveolar wall thickness was increased in all smokers, but significantly more in CLE. The pathological phenotypes of COPD CLE and PLE show important differences in their overall inflammation with a protagonism of mast cells, which are related to airway reactivity. These findings highlight the distinctness of these COPD phenotypes and the role of mast cells in the pathophysiology of COPD.
    American Journal of Respiratory and Critical Care Medicine 06/2012; 186(3):233-9. · 11.04 Impact Factor
  • Manuel G Cosio, Marina Saetta
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    ABSTRACT: Investigations toward the understanding of chronic obstructive pulmonary disease (COPD) have been directed, so far, to the study of mechanisms leading to the disease. We believe that understanding why ~80% of smokers evade COPD and how this evasion is accomplished might be a fruitful endeavour that could advance knowledge of the development of the disease. Since the inflammatory infiltrate smokers develop seems to be the key element leading to the lung destruction in COPD, the understanding of the possible ways inflammation can be dampened, as well as its consequences, ought to be important. We review here some of the mechanisms by which inflammation is controlled: by the post-translational regulons, by the mechanisms preventing full activation of dendritic cells and by the regulatory T-cells. The potential role of the M2 alveolar macrophage phenotype and the newly described myeloid-derived suppressor cells is mentioned. We also point out that evasion comes at a price, as healthy smokers might be immunosuppressed to some extent and unable to prevent the development of cancer, certainly less so than in severe COPD, where immunity is heightened. Probably, the knowledge of the mechanisms of evasion from COPD could add significantly to the understanding of those leading to the disease.
    European Respiratory Journal 10/2011; 39(6):1298-303. · 6.36 Impact Factor
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    ABSTRACT: Little is known about the clinical factors associated with the development of lung cancer in patients with chronic obstructive pulmonary disease (COPD), although airway obstruction and emphysema have been identified as possible risk factors. To explore incidence, histologic type, and factors associated with development of lung cancer diagnosis in a cohort of outpatients with COPD attending a pulmonary clinic. A cohort of 2,507 patients without initial clinical or radiologic evidence of lung cancer was followed a median of 60 months(30–90). At baseline, anthropometrics, smoking history, lung function,and body composition were recorded. Time to diagnosis and histologic type of lung cancer was then registered. Cox analysis was used to explore factors associated with lung cancer diagnosis. A total of 215 of the 2,507 patients with COPD developed lung cancer (incidence density of 16.7 cases per 1,000 person-years). The most frequent type was squamous cell carcinoma (44%). Lung cancer incidence was lower in patients with worse severity of airflow obstruction. Global Initiative for Chronic Obstructive Lung Disease Stages I and II, older age, lower body mass index,and lung diffusion capacity of carbon monoxide less than 80%were associated with lung cancer diagnosis. Incidence density of lung cancer is high in outpatients with COPD and occurs more frequently in older patients with milder airflow obstruction (Global Initiative for Chronic Obstructive Lung Disease Stages I and II) and lower body mass index. A lung diffusion capacity of carbon monoxide less than 80% is associated with cancer diagnosis. Squamous cell carcinoma is the most frequent histologic type. Knowledge of these factors may help direct efforts for early detection of lung cancer and disease management.
    American Journal of Respiratory and Critical Care Medicine 07/2011; 184(8):913-9. · 11.04 Impact Factor
  • Simonetta Baraldo, Marina Saetta, Manuel G Cosio
    American Journal of Respiratory and Critical Care Medicine 05/2010; 181(9):879-80. · 11.04 Impact Factor
  • Manuel G Cosio, Marina Saetta, Alvar Agusti
    New England Journal of Medicine 07/2009; 360(23):2445-54. · 54.42 Impact Factor
  • Joanne L Wright, Manuel Cosio, Andrew Churg
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    ABSTRACT: The mechanisms involved in the genesis of chronic obstructive pulmonary disease (COPD) are poorly defined. This area is complicated and difficult to model because COPD consists of four separate anatomic lesions (emphysema, small airway remodeling, pulmonary hypertension, and chronic bronchitis) and a functional lesion, acute exacerbation; moreover, the disease in humans develops over decades. This review discusses the various animal models that have been used to attempt to recreate human COPD and the advantages and disadvantages of each. None of the models reproduces the exact changes seen in humans, but cigarette smoke-induced disease appears to come the closest, and genetically modified animals also, in some instances, shed light on processes that appear to play a role.
    AJP Lung Cellular and Molecular Physiology 08/2008; 295(1):L1-15. · 3.52 Impact Factor
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    ABSTRACT: To compare lung morphology in chronic obstructive pulmonary disease (COPD) secondary to cigarette smoke (CS) and biomass smoke (BS). Necropsies of women with COPD diagnosis by lung pathology and unique exposure to BS (n = 27) or CS (n = 21) matched by age and place of origin. Lungs were macroscopically and microscopically examined to evaluate the extent of emphysema, pigment deposition, and abnormalities in pulmonary arteries, large airways (including the Reid index) and small airways (SAWs) by a semiquantitative method. Both groups had variable degrees of emphysema and SAWs disease. Patients exposed to BS had more lung fibrosis and pigment deposition and thicker pulmonary arterial intima than smokers, who had more emphysema and epithelial damage (goblet cell metaplasia). The Reid index was similar in both groups. Lengthy exposure to BS can produce emphysema and other lesions typically observed in cigarette smokers, but with a slightly different distribution. Whether the differences observed are the consequence of severity of exposure or smoke composition, or both, remains to be clarified.
    The International Journal of Tuberculosis and Lung Disease 08/2008; 12(8):972-7. · 2.76 Impact Factor
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    ABSTRACT: The receptor for advanced glycation end-products (RAGE) is a member of the immunoglobin superfamily of multiligand receptors. Following ligand binding, mechanisms associated with host defense, tissue remodeling, and inflammation are activated. RAGE is highly expressed in pulmonary epithelium transitioning from alveolar type (AT) II to ATI cells and is upregulated in the presence of ligand; however, the regulation and function of RAGE during development are less clear. Herein, immunohistochemistry demonstrated a temporal-spatial pattern of RAGE expression in pulmonary epithelial cells from embryonic day 17.5 to postnatal day 10. Cotransfection experiments revealed that the mouse RAGE promoter was activated by early growth response gene 1 (Egr-1) and inhibited by thyroid transcription factor-1 (TTF-1) via interaction with specific regulatory elements. A rat ATI cell line (R3/1) with endogenous RAGE expression also differentially regulated RAGE when transfected with TTF-1 or Egr-1. Because Egr-1 is markedly induced in pulmonary epithelial cells exposed to cigarette smoke extract (CSE; Reynolds PR, Hoidal JR. Am J Respir Cell Mol Biol 35: 314-319, 2006.), we sought to investigate RAGE induction by CSE. Employing RT-PCR and Western blotting, RAGE and common ligands (amphoterin and S100A12) were upregulated in epithelial (R3/1 and A549) and macrophage (RAW) cell lines following exposure to CSE. Immunostaining for RAGE in cells similarly exposed and in lungs from mice exposed to cigarette smoke for 6 mo revealed elevated RAGE expression in pulmonary epithelium. After the addition of glyoxylated BSA, an advanced glycation end-product that binds RAGE, real-time RT-PCR detected a 200-fold increase in Egr-1. These results indicate that Egr-1 regulates RAGE expression during development and the likelihood of positive feedback involving Egr-1 and RAGE in cigarette smoke-related disease.
    AJP Lung Cellular and Molecular Physiology 07/2008; 294(6):L1094-101. · 3.52 Impact Factor
  • Andrew Churg, Manuel Cosio, Joanne L Wright
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    ABSTRACT: Cigarette smoke-induced animal models of chronic obstructive pulmonary disease support the protease-antiprotease hypothesis of emphysema, although which cells and proteases are the crucial actors remains controversial. Inhibition of either serine or metalloproteases produces significant protection against emphysema, but inhibition is invariably accompanied by decreases in the inflammatory response to cigarette smoke, suggesting that these inhibitors do more than just prevent matrix degradation. Direct anti-inflammatory interventions are also effective against the development of emphysema, as are antioxidant strategies; the latter again decrease smoke-induced inflammation. There is increasing evidence for autoimmunity, perhaps directed against matrix components, as a driving force in emphysema. There is intriguing but controversial animal model evidence that failure to repair/failure of lung maintenance also plays a role in the pathogenesis of emphysema. Cigarette smoke produces small airway remodeling in laboratory animals, possibly by direct induction of fibrogenic growth factors in the airway wall, and also produces pulmonary hypertension, at least in part through direct upregulation of vasoactive mediators in the intrapulmonary arteries. Smoke exposure causes goblet cell metaplasia and excess mucus production in the small airways and proximal trachea, but these changes are not good models of either chronic bronchitis or acute exacerbations. Emphysema, small airway remodeling, pulmonary hypertension, and mucus production appear to be at least partially independent processes that may require different therapeutic approaches.
    AJP Lung Cellular and Molecular Physiology 05/2008; 294(4):L612-31. · 3.52 Impact Factor
  • Manuel G Cosio
    American Journal of Respiratory and Critical Care Medicine 11/2006; 174(8):847-8. · 11.04 Impact Factor
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    Paul R Reynolds, Manuel G Cosio, John R Hoidal
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide and is a progressive and irreversible disorder. Cigarette smoking is associated with 80-90% of COPD cases; however, the genes involved in COPD-associated emphysema and chronic inflammation are poorly understood. It was recently demonstrated that early growth response gene 1 (Egr-1) is significantly upregulated in the lungs of smokers with COPD (Ning W and coworkers, Proc Natl Acad Sci 2004;101:14895-14900). We hypothesized that Egr-1 is activated in pulmonary epithelial cells during exposure to cigarette smoke extract (CSE). Using immunohistochemistry, we demonstrated that pulmonary adenocarcinoma cells (A-549) and primary epithelial cells lacking basal Egr-1 markedly induce Egr-1 expression after CSE exposure. To evaluate Egr-1-specific effects, we used antisense (alphaS) oligodeoxynucleotides (ODN) to knock down Egr-1 expression. Incorporation of Egr-1 alphaS ODN significantly decreased CSE-induced Egr-1 mRNA and protein, while sense ODN had no effect. Via Egr-1-mediated mechanisms, IL-1beta and TNF-alpha were significantly upregulated in pulmonary epithelial cells exposed to CSE or transfected with Egr-1. To investigate the relationship between Egr-1 induction by smoking and susceptibility to emphysema, we determined Egr-1 expression in strains of mice with different susceptibilities for the development of smoking-induced emphysema. Egr-1 was markedly increased in the lungs of emphysema-susceptible AKR/J mice chronically exposed to cigarette smoke, but only minimally increased in resistant NZWLac/J mice. In conclusion, Egr-1 is induced by cigarette smoke and functions in proinflammatory mechanisms that likely contribute to the development of COPD in the lungs of smokers.
    American Journal of Respiratory Cell and Molecular Biology 10/2006; 35(3):314-9. · 4.15 Impact Factor
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    ABSTRACT: Only 20% of smokers develop chronic obstructive pulmonary disease. An important determinant of susceptibility is genomic variation. We undertook this study to define strains of mice with different susceptibilities for the development of smoking-induced emphysema because they could help identify genetic factors of susceptibility. NZWLac/J, C57BL6/J, A/J, SJ/L, and AKR/J strains were exposed to cigarette smoke for 6 months. Elastance (Htis), the extent of emphysema (mean linear intercept [Lm]), and the inflammatory cell and cytokine response were measured. NZWLac/J had no change in Lm or Htis (resistant). C57BL6/J, A/J, and SJ/L increased Lm, but not Htis (mildly susceptible). AKR/J increased Lm and Htis (super-susceptible). Only AKR/J had significant inflammation comprising macrophages, neutrophils, and T cells. The AKR/J showed an upregulation of Th1 cytokines whereas in the C57BL/6/J and NZWlac/J, cytokines did not change or were downregulated. We conclude that Lm, elastance, and inflammation are features that are needed to phenotype emphysema in mice. The inflammatory cell and cytokine profile may be an important determinant of the phenotype in response to cigarette smoke exposure. The identification of resistant and susceptible strains for the development of emphysema could be useful for genomic studies of emphysema susceptibility in mice and eventually in humans.
    American Journal of Respiratory and Critical Care Medicine 12/2004; 170(9):974-80. · 11.04 Impact Factor
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    Peter J Barnes, Manuel G Cosio
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    ABSTRACT: A new study adds to the mounting evidence implicating T cells as an important component of the inflammation in chronic obstructive pulmonary disease.
    PLoS Medicine 11/2004; 1(1):e20. · 15.25 Impact Factor
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    M G Cosio
    European Respiratory Journal 08/2004; 24(1):3-5. · 6.36 Impact Factor
  • Simonetta Baraldo, Marina Saetta, Manuel G Cosio
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    ABSTRACT: This review describes, in some detail, the normal structure of the small airways, how this structure is achieved during the development of the bronchial tree from embryogenesis to adulthood, and how the structure determines the function of the airways at different ages and in disease. We then describe the structural abnormalities in small airways in chronic obstructive pulmonary disease (COPD) and their relationship with the disordered pulmonary function found in this disease, as an example of the mechanisms leading to airflow limitation in diseased airways. We address the pathology of small airways in different stages of COPD, summarizing the structural abnormalities associated with the progressive deterioration of pulmonary function from smokers with normal lung function to smokers with severe COPD. The importance of the elastic recoil in the normal and abnormal function of the airways is also highlighted.
    Seminars in Respiratory and Critical Care Medicine 11/2003; 24(5):465-72. · 2.75 Impact Factor
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    Thorax 11/2003; 58(10):832-4. · 8.38 Impact Factor
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    ABSTRACT: Cigarette smoking in humans is associated with various patterns of emphysema and functional consequences. We tested the hypothesis that variations in alpha1-antitrypsin expression modulate the pattern of emphysema and functional consequences in cigarette smoke-exposed mice. We compared the effects of up to 6 months of cigarette smoke exposure in C57BL/6J (C57) mice and in low-alpha1-antitrypsin, C57BL/6J pa+/pa+ (pallid) mice. At the end of the experiment, we determined lung mechanical properties, the extent (mean linear intercept) and type of emphysema, and the cellular inflammatory response. After 4 months of cigarette smoking, pallid smoking mice, but not C57 smoking mice, had a significant increase in mean linear intercept. After 6 months of smoke exposure, C57 smoking mice and pallid smoking mice had similar degrees of emphysema. The pattern of emphysema in pallid smoking mice was more diffuse than in C57 smoking mice, affecting all airspaces. Pallid mice, but not C57 mice, developed a T cell inflammation in the alveolar wall after 6 months of smoking (p < 0.01). Although lung compliance was not changed in C57 smoking mice after smoke exposure, it increased significantly in pallid smoking mice over the 6 months of exposure (p < 0.0082). In summary, cigarette smoking induces emphysema in C57 and pallid mice, but the emphysema, inflammatory infiltrate, and resulting physiologic abnormalities were substantially different in the two strains, with the C57 and pallid mice exhibiting features similar to centrilobular and panlobular emphysema, respectively.
    American Journal of Respiratory and Critical Care Medicine 12/2002; 166(12 Pt 1):1596-603. · 11.04 Impact Factor
  • Manuel G Cosio, Joaquim Majo, Monica G Cosio
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    ABSTRACT: A smoking-induced inflammatory reaction in the airways and lung parenchyma, comprised mainly of neutrophils and alveolar macrophages, has long been accepted to be the major cause of COPD in smokers. Recent reports have underlined the role of the T lymphocyte as a potentially important factor in the inflammatory process leading to COPD. It has been found that, in the airways and the lung parenchyma, the presence of T cells, predominantly CD8+ T cells, can distinguish between smokers with and without COPD. In addition to T cells, other inflammatory cell types such as neutrophils and macrophages are probably essential in the initial inflammatory process leading to the breakdown of lung tissue, perhaps producing peptides eventually recognized by T cells as antigenic. This would provide an explanation for the T-cell inflammation. Once activated, T cells are present in the lung, and their effector functions would include the attraction and enhancement of the inflammatory function in other inflammatory cells like neutrophils and macrophages. It seems likely that, only when all inflammatory cell types (ie, CD4+, CD8+, neutrophils, and macrophages) are present in the lung, the airways remodeling and parenchymal destruction characteristic of COPD will ensue. If T cells are responsible for the lung injury and progression of COPD, it would resemble a response to an antigenic stimulus originating in the lung. If that were the case, COPD could be considered to be an autoimmune disease triggered by smoking.
    Chest 06/2002; 121(5 Suppl):160S-165S. · 7.13 Impact Factor

Publication Stats

3k Citations
664.04 Total Impact Points

Institutions

  • 1994–2012
    • University of Padova
      • Department of Cardiac, Thoracic and Vascular Sciences
      Padua, Veneto, Italy
  • 1984–2011
    • McGill University
      • • Department of Medicine
      • • Respiratory Division
      • • Meakins-Christie Laboratories
      Montréal, Quebec, Canada
  • 2004
    • Imperial College London
      Londinium, England, United Kingdom
  • 2001
    • University Hospital Vall d'Hebron
      Barcino, Catalonia, Spain
  • 1991
    • Hôpital du Sacré-Coeur de Montréal
      Montréal, Quebec, Canada
  • 1989
    • University Hospital Brussels
      Bruxelles, Brussels Capital Region, Belgium