Involvement of type II pneumocytes in the pathogenesis of chronic obstructive pulmonary disease

  • Chun-zhen Zhao
    Affiliations
    Zhejiang Respiratory Drugs Research Laboratory of State Food and Drugs Administration of China, College of Medical Sciences, Zhejiang University, China
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  • Xiao-cong Fang
    Affiliations
    Zhejiang Respiratory Drugs Research Laboratory of State Food and Drugs Administration of China, College of Medical Sciences, Zhejiang University, China

    Department of Respiratory Medicine, Zhongshan Hospital, Fudan University, China
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  • Diane Wang
    Affiliations
    Zhejiang Respiratory Drugs Research Laboratory of State Food and Drugs Administration of China, College of Medical Sciences, Zhejiang University, China
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  • Fa-di Tang
    Correspondence
    Corresponding author. Tel.: +86 46 46 125 931.
    Affiliations
    Zhejiang Respiratory Drugs Research Laboratory of State Food and Drugs Administration of China, College of Medical Sciences, Zhejiang University, China
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  • Xiang-dong Wang
    Correspondence
    Corresponding author. Zhejiang Respiratory Drugs Research Laboratory of State Food and Drugs Administration of China, College of Medical Sciences, Zhejiang University, China
    Affiliations
    Zhejiang Respiratory Drugs Research Laboratory of State Food and Drugs Administration of China, College of Medical Sciences, Zhejiang University, China

    Department of Respiratory Medicine, Zhongshan Hospital, Fudan University, China
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Open ArchivePublished:July 21, 2010DOI:https://doi.org/10.1016/j.rmed.2010.06.018

      Summary

      Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality, but the cellular and molecular mechanisms are still not fully understood. Type II pneumocytes are identified as the synthesizing cells of the alveolar surfactant, which has important properties in maintaining alveolar and airway stability. Lung surfactant can reduce the surface tension and prevent alveolar collapse and the airway walls collapse. Pulmonary surfactant components play important roles in normal lung function and inflammation in the lung. Surfactant has furthermore been shown to modulate the process of innate host defense, including suppression of cytokine secretion and transcription factor activation, in the inflammatory network of COPD. Abnormalities of lung surfactant might be one of the mechanisms leading to increased airway resistance in COPD. The increased expression of Granzyme A and B was found in lung tissues of patients with COPD and type II pneumocytes was proposed to be involved in the pathogenesis of COPD. These novel findings provide new sights into the role of the type II pneumocytes in the pathogenesis of COPD.

      Keywords

      Introduction

      Chronic obstructive pulmonary disease (COPD) is a disease characterized by progressive, not fully reversible airflow limitation, a result of an abnormal inflammatory response of the lungs to inhaled noxious particles or gasses. Although the pathology of chronic airway inflammation and emphysema has been extensively explored,
      • Cazzola M.
      • Donner C.F.
      • Hanania N.A.
      One hundred years of chronic obstructive pulmonary disease (COPD).
      • Devendra G.
      • Spragg R.G.
      Lung surfactant in subacute pulmonary disease.
      pathogenesis of COPD is still under debate. Several mechanisms are involved in the development of the disease, e.g. inflammation, imbalance between proteolytic and anti-proteolytic activity, oxidative stress and apoptosis.
      • Demedts I.K.
      • Demoor T.
      • Bracke K.R.
      • Joos G.F.
      • Brusselle G.G.
      Role of apoptosis in the pathogenesis of COPD and pulmonary emphysema.
      The observational studies have shown that inflammatory cells, such as neutrophils, macrophages, CD8 + T and B lymphocytes, increased in airway and lung parenchyma of COPD patients.
      • Hogg J.C.
      • Chu F.
      • Utokaparch S.
      • et al.
      The nature of small-airway obstruction in chronic obstructive pulmonary disease.
      • Tetley T.D.
      Inflammatory cells and chronic obstructive pulmonary disease.
      Epithelial cells may also contribute to the pathogenesis of COPD,
      • Zhao M.Q.
      • Amir M.K.
      • Rice W.R.
      • Enelow R.I.
      Type II pneumocyte-CD8 + T-cell interactions: relationship between target cell cytotoxicity and activation.
      while the precise mechanism is not fully elucidated. These cell populations communicate and interact with the help of altered expression of various cytokines and adhesion molecules.
      • Barnes P.J.
      Chronic obstructive pulmonary disease.

      Type II pneumocytes

      The pulmonary alveoli are lined with two types of cells, the type I and type II pneumocytes, of whom the type II pneumocyte is a roughly cuboidal cell that is usually found at the alveolar septal junctions. Type II pneumocytes cover about 5% of the surface area of the lung alveoli and are more resistant to injury, whereas type I pneumocytes with squamous shape and more vulnerable cover 95% of the total area. Type II cells act as the progenitor cells for type I cells. When type I cells are damaged, type II cells proliferate, migrate, and spread along the denuded basement membrane surface, reform the epithelium, and then differentiate into type I cells. Thus it is suggested to play an important role in the repair process of alveolar epithelial barrier. Type II cells synthesize, store, and secrete pulmonary surfactant, which reduces alveolar surface tension and stabilizes alveolar units for efficient gas exchange. Moreover, they secrete a variety of cytokines and proteins that can modify the inflammatory response and oxidative stress response and inhibit fibroblast proliferation and collagen synthesis which are implicated in the pathogenesis of COPD.
      • Serrano-Mollar A.
      • Nacher M.
      • Gay-Jordi G.
      Intratracheal transplantation of alveolar type II cells reverses bleomycin-induced lung fibrosis.

      Type II pneumocytes in pathogenesis of COPD

      Smoking plays an important role in the pathogenesis of the destruction in the lung parenchyma and airway inflammation found in patients with COPD, though only a proportion (10–20%) of smokers develop progressive airflow limitation.
      • Cazzola M.
      • Donner C.F.
      • Hanania N.A.
      One hundred years of chronic obstructive pulmonary disease (COPD).
      • Devendra G.
      • Spragg R.G.
      Lung surfactant in subacute pulmonary disease.
      As reviewed by Devendra and Spragg, abnormalities of lung surfactant may be of importance in subacute pulmonary disease, including COPD.
      • Devendra G.
      • Spragg R.G.
      Lung surfactant in subacute pulmonary disease.
      Type II Pneumocytes responsible for the production and secretion of surfactant were suggested to participate in the development of COPD (Fig. 1). Cigarette smoking can induce alterations of the surfactant system, while surfactant homeostasis and function might be broken down through both direct and indirect mechanisms.
      • Xue Y.
      • Williams T.L.
      • Li T.
      • et al.
      Type II pneumocytes modulate surfactant production in response to cigarette smoke constituents: restoration by vitamins A and E.
      Cigarette smoke injuries secretion of type II pneumocytes, resulting in the reduction of the total amount of lung surfactant.
      • Wirtz H.R.
      • Schmidt M.
      Acute influence of cigarette smoke on secretion of pulmonary surfactant in rat alveolar type II cells in culture.
      It was reported that the SP-A levels was significantly lower in patients with COPD and smokers when compared with nonsmokers.
      • Vlachaki E.M.
      • Koutsopoulos A.V.
      • Tzanakis N.
      • et al.
      Altered surfactant protein-A expression in type II pneumocytes in COPD.
      The particulate phase of cigarette smoke has been demonstrated to impair surfactant function directly.
      Figure thumbnail gr1
      Figure 1Cigarette smoke and noxious particles increase apoptosis and injury of type II pneumocytes, activating and enhancing macrophages and phagocytosis of those apoptotic cells and production and release of proteases. Impaired type II pneumocytes decreased the production and function of pulmonary surfactant, leading to the increased activities of proteases and oxidative stress.
      COPD is also characterized by an abnormal inflammatory reaction of the lungs involving activation of epithelial cells. Cigarette smoking causes airway inflammation with activated neutrophils and macrophages.
      • Dwyer T.M.
      Cigarette smoke-induced airway inflammation as sampled by the expired breath condensate.
      In a smoke inhalation induced acute inflammation model, the expression of p65, a marker of nuclear factor kappa B activation, was detected evidently in type II pneumocytes, suggesting that type II pneumocytes are activated to produce proinflammatory cytokines after injury.
      • Cox R.A.
      • Burke A.S.
      • Jacob S.
      • et al.
      Activated nuclear factor kappa B and airway inflammation after smoke inhalation and burn injury in sheep.
      On the other hand, Vernooy et al. recently reported that the level of leptin were markedly higher in patients with severe COPD and ex-smokers than in never smokers.
      • Demkow U.
      The oxidative stress in emphysema and chronic obstructive pulmonary disaease (COPD).
      Leptin is a pleiotropic cytokine and plays an important role in the regulation of immune responses via its functional receptor Ob-Rb expressed on bronchial epithelial cells, type II pneumocytes and macrophages.
      Oxidative stress and airway inflammation together form a vicious cycle, responsible for the progression of the disease. The oxidative stress could increase the airway hyperresponsiveness, inflammation and epithelial destruction and impair the functions of antiproteases and surfactant.
      • Vernooy J.
      • Drummen N.
      • van Suylen R.J.
      • et al.
      Enhanced pulmonary leptin expression in patients with severe COPD and asymptomatic smokers.
      Type II pneumocytes secrete a variety of proinflammatory mediators in response to oxidative stress, which could be amplified by the mediators produced from alveolar macrophages.
      • McCourtie A.S.
      • Farivar A.S.
      • Woolley S.M.
      • et al.
      Alveolar macrophage secretory products effect type 2 pneumocytes undergoing hypoxia-reoxygenation.
      The nitric oxide synthase localized in type II pneumocytes was inducible in response to oxidative stress and increased in patients with severe COPD. Oxidative stress-induced enzyme – haem oxygenase-2 was expressed exclusively on type II pneumocytes and elevated in smokers, indicating the number of type II pneumocytes increased under this condition.
      • Maestrelli P.
      • Paska C.
      • Saetta M.
      • et al.
      Decreased haem oxygenase-1 and increased inducible nitric oxide synthase in the lung of severe COPD patients.
      Apoptosis is important for eliminating excess activated inflammatory cells and dead epithelial cells, while excess apoptosis of airway and alveolar epithelial cells may result in the reduction of host defenses. Apoptosis of BAL-derived lymphocytes and brushing-derived airway epithelial cells significantly increased in COPD.
      • Hodge S.
      • Hodge G.
      • Holmes M.
      • Reynolds P.N.
      Increased airway epithelial and T-cell apoptosis in COPD remains despite smoking cessation.
      • Vernooy J.H.
      • Dentener M.A.
      • van Suylen R.J.
      • et al.
      Intratracheal instillation of lipopolysaccharide in mice induces apoptosis in bronchial epithelial cells: no role for tumor necrosis factor-alpha and infiltrating neutrophils.
      It is suggested that destructive process as well as airway and lung tissue remodeling and fibrosis are involved in the pathogenesis of COPD. The matrix metalloproteinases (MMPs) and their inhibitors are a main component in the destructive part of the remodeling events,
      • Cataldo D.D.
      • Gueders M.M.
      • Rocks N.
      • et al.
      Pathogenic role of matrix metalloproteases and their inhibitors in asthma and chronic obstructive pulmonary disease and therapeutic relevance of matrix metalloproteases inhibitors.
      whereas in the tissue repair/fibrotic changes, basic fibroblast growth factor and transforming growth factor-beta (TGF-beta) play a main role. The increased presence of MMP-9 and TGF-beta have found in bronchial epithelial cells and alveolar type II cells.
      • De Boer W.I.
      • van Schadewijk A.
      • Sont J.K.
      • et al.
      Transforming growth factor beta1 and recruitment of macrophages and mast cells in airways in chronic obstructive pulmonary disease.
      • Takizawa H.
      • Tanaka M.
      • Takami K.
      • et al.
      Increased expression of transforming growth factor-beta1 in small airway epithelium from tobacco smokers and patients with chronic obstructive pulmonary disease (COPD).
      On the other hand, type II pneumocytes may play a potential protective role in the lung repair of this chronic disease process,
      • Frerking I.
      • Günther A.
      • Seeger W.
      • Pison U.
      Pulmonary surfactant: functions, abnormalities and therapeutic options.
      since type II pneumocytes can proliferate and transform to type I pneumocytes and can inhibit fibroblast proliferation and collagen synthesis.
      • Serrano-Mollar A.
      • Nacher M.
      • Gay-Jordi G.
      • et al.
      Intratracheal transplantation of alveolar type II cells reverses bleomycin-induced lung fibrosis.

      Pulmonary surfactant and COPD

       Surfactant physiology

      Lung surfactant is a surface active material that is synthesized by type II pneumocytes, composed of phospholipids and proteins (10%). Two of the hydrophilic surfactant-associated proteins, SP-A and SP-D, modulate host innate and adaptive immune response,
      • Pastva A.M.
      • Wright J.R.
      • Williams K.L.
      Immunomodulatory roles of surfactant proteins A and D: implications in lung disease.
      while the other two hydrophobic proteins, SP-B and SP-C, play an essential role in reducing surface tension.
      • Nogee L.M.
      Genetic mechanisms of surfactant deficiency.
      After synthesis, surfactant is packaged into lamellar bodies and then secreted into the thin, liquid hypophase that covers the alveolar epithelium. Surfactant recovered by lung lavage may be separated into two fractions by centrifugation: a highly surface active sedimenting fraction termed “large aggregates” and a poorly surface active, nonsedimenting “small aggregates”.
      • Devendra G.
      • Spragg R.G.
      Lung surfactant in subacute pulmonary disease.
      Surfactant not only maintains alveolar and airway stability, but also regulates airway liquid balance and bronchial clearance.
      • Hohlfeld J.
      • Fabel H.
      • Hamm H.
      The role of pulmonary surfactant in obstructive airways disease.
      It is now recognized as a crucial component in host immune defense, especially SP-A and SP-D.
      • Pastva A.M.
      • Wright J.R.
      • Williams K.L.
      Immunomodulatory roles of surfactant proteins A and D: implications in lung disease.

       Surfactant dysfunction and pathogenesis of COPD

      Varieties of mechanisms are involved in the process of surfactant modification, for instance, genetic mutation
      • Hamvas A.
      • Nogee L.M.
      • White F.V.
      • et al.
      Progressive lung disease and surfactant dysfunction with a deletion in surfactant protein C gene.
      or lack of synthetic substances. The activity of neutrophil elastase, MMPs, and proteolytic enzymes particularly augmented by constituents of cigarette smoke (nitrites and oxidants) subsequently affects surfactant function.
      • Pison U.
      • Tam E.K.
      • Caughey G.H.
      • Hawgood S.
      Proteolytic inactivation of dog lung surfactant-associated proteins by neutrophil elastase.
      • Putman E.
      • Van Golde L.M.G.
      • Haagsman H.P.
      Toxic oxidant species and their impact on the pulmonary surfactant system.
      Oxidative stress from an oxidant/antioxidant imbalance leads to surfactant lipid peroxidation and directly damages surfactant homeostasis.
      • Anseth J.W.
      • Goffin A.J.
      • Fuller G.G.
      • et al.
      Lung surfactant gelation induced by epithelial cells exposed to air pollution or oxidative stress.
      • Starosta V.
      • Griese M.
      Oxidative damage to surfactant protein D in pulmonary diseases.
      There is an evidence of increased oxidative stress in the airways of patients with COPD.
      • Joppa P.
      • Petrásová D.
      • Stancák B.
      • et al.
      Oxidative stress in patients with COPD and pulmonary hypertension.
      Host defense may be impaired due to the oxidative damage to functional capacity of surfactant protein D to agglutinate bacteria
      • Starosta V.
      • Griese M.
      Oxidative damage to surfactant protein D in pulmonary diseases.
      (Fig. 2).
      Figure thumbnail gr2
      Figure 2Possible role of surfactant dysfunction in the pathogenesis of COPD.
      Biochemical and biophysical dysfunction of pulmonary surfactant have been reported in various diseases, such as the acute respiratory distress syndrome, asthma, pneumonia, mechanically-ventilated lung injury and COPD.
      • Cochrane C.G.
      Pulmonary surfactant in allergic inflammation: new insights into the molecular mechanisms of surfactant function.
      • Calkovská A.
      Pulmonary surfactant in the respiratory tract.
      Lusuardi et al. found an increased ratio of phosphatidylglycerol/cardiolipin and decreased concentrations of total phospholipids in BAL of 20 smoking, nonasthmatic COPD patients compared to 5 nonsmoking healthy controls.
      • Lusuardi M.
      • Capelli A.
      • Carli S.
      • et al.
      Role of surfactant in chronic obstructive pulmonary disease: therapeutic implications.
      It was also reported that total phospholipid and surface activity decreased in BAL fluid in smokers.
      • Schmekel B.
      • Bos J.A.
      • Khan A.R.
      • Wohlfart B.
      • Lachmann B.
      • Wollmer P.
      Integrity of the alveolar-capillary barrier and alveolar surfactant system in smokers.
      Type II pneumocytes exposed directly to cigarette smoke in culture decreased secretion of PC.
      • Wirtz H.R.
      • Schmidt M.
      Acute influence of cigarette smoke on secretion of pulmonary surfactant in rat alveolar type II cells in culture.
      Analysis of SP-A, SP-B and SP-D genes in patients with COPD revealed a correlation with the severity of the disease.
      • GuoX Lin H.M.
      • Lin Z.
      • Montaño M.
      • Sansores R.
      • Wang G.
      • et al.
      Surfactant protein gene A, B, and D marker alleles in chronic obstructive pulmonary disease of a Mexican population.
      • Hu R.C.
      • Xu Y.J.
      • Zhang J.X.
      Surfactant protein B 1580 polymorphism is associated with susceptibility to chronic obstructive pulmonary disease in Chinese Han population.
      Smokers with COPD had significantly lower SP-D levels than healthy smokers in a cross-sectional study.
      • Sims M.W.
      • Tal-Singer R.M.
      • Kierstein S.
      • Musani A.I.
      • Beers M.F.
      • Panettieri R.A.
      • et al.
      Chronic obstructive pulmonary disease and inhaled steroids alter surfactant protein D (SP-D) levels: a cross-sectional study.
      Experimental study on lung injury showed that the susceptibility to ozone-induced airway inflammation was associated with decreased levels of surfactant protein D.
      • Kierstein S.
      • Poulain F.R.
      • Cao Y.
      • Grous M.
      • Mathias R.
      • Kierstein G.
      • et al.
      Susceptibility to ozone-induced airway inflammation is associated with decreased levels of surfactant protein D.
      SP deficient mice had an abnormal pulmonary phenotype characterized by activated alveolar macrophages, increased levels of MMPs and emphysematous changes in the lung parenchyma.
      • Wert S.E.
      • Yoshida M.
      • LeVine A.M.
      • et al.
      Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice.
      • Yoshida M.
      • Whitsett J.A.
      Alveolar macrophages and emphysema in surfactant protein-D-deficient mice.
      • Haque R.
      • Umstead T.M.
      • Ponnuru P.
      • et al.
      Role of surfactant protein-A (SP-A) in lung injury in response to acute ozone exposure of SP-A deficient mice.
      Increased SP-D level in smoking-induced mouse emphysema could be interpreted as a protective role in the development of smoking-induced emphysema.
      • Hirama N.
      • Shibata Y.
      • Otake K.
      • et al.
      Increased surfactant protein-D and foamy macrophages in smoking-induced mouse emphysema.
      The ability to maintain free airflow in narrow conducting airways of rats was dependent on the quality of surfactant.
      • Enhorning G.
      • Duffy L.C.
      • Welliver R.C.
      Pulmonary surfactant maintains patency of conducting airways in the rat.
      Airway surfactant dysfunction, at least in part, contributes to increased airway resistance (Fig. 2). Moreover, surfactant dysfunction could increase pressure gradient across the alveolar wall resulting in the rupture of the alveolar wall and the development of emphysema, as extracellular matrix components of the alveolar wall may be partially damaged in COPD It was found that surfactant had an unexpected anti-inflammatory effects.
      • Kerecman J.
      • Mustafa S.B.
      • Vasquez M.M.
      • et al.
      Immunosuppressive properties of surfactant in alveolar macrophage NR8383.
      SP-D could suppress NF-kB activation and MMP production in alveolar macrophages,
      Surfactant protein D regulates NF-kB and matrix metalloproteinase production in alveolar macrophages via oxidant-sensitive pathways
      although the precise role of pulmonary surfactant in the pathogenesis of airway inflammation remains unclear. There is limited information on the value of exogenous surfactant treatment of patients with COPD. Patients with stable chronic bronchitis who received aerosolized surfactant improved pulmonary function and sputum transport by cilia in a dose-related pattern.
      • Anzueto A.
      • Jubran A.
      • Ohar J.A.
      • et al.
      Effects ofaerosolized surfactant in patients with stable chronic bronchitis: a prospective randomized controlled trial.
      The exogenous surfactant was used to treat the patients with severe exacerbation of COPD requiring mechanical ventilation.
      • Wirtz H.
      • Habscheid W.
      • Ertl G.
      • et al.
      Exogenous surfactant application in respiratory failure due to chronic obstructive pulmonary disease.

      Granzymes in type II pneumocytes and COPD

      Numerous studies showed altered balance of the CD4+/CD8 + T lymphocyte ratio, especially CD8 + T lymphocytes,
      • Chrysofakis G.
      • Tzanakis N.
      • Kyriakoy D.
      • et al.
      Perforin expression and cytotoxic activity of sputum CD8+ lymphocytes in patients with COPD.
      infiltrating in the airways and lung parenchyma. The serine proteases Granzyme A (GrA) and B (GrB) together with perforin are major effector molecules of CD8 + T lymphocytes and natural killer cells. Increased GrA and GrB expression was found in the sputum and/or lung speciments of patients with COPD. The expression of GA was significantly higher in type II Pneumocytes of patients with COPD versus control subjects.
      • Vernooy J.H.
      • Möller G.M.
      • van Suylen R.J.
      • et al.
      Increased granzyme A expression in type II pneumocytes of patients with severe chronic obstructive pulmonary disease.
      GrA is known to stimulate the production of IL-6 and IL-8 which increased in the lungs of patients with COPD.
      • Sower L.E.
      • Klimpel G.R.
      • Hanna W.
      • Froelich C.J.
      Extracellular activities of human granzymes. Granzyme A induces IL-6 and IL-8 production in fibroblast and epithelial cell lines.
      GrA and GrB exert the proteolytic action on extracellular matrix and may play a role in airway remodeling and tissue destruction in COPD.
      • Buzza M.S.
      • Zamurs L.
      • Sun J.
      • et al.
      Extracellular matrix remodeling by human granzyme B via cleavage of vitronectin, fibronectin, and laminin.
      In adition, perforin-dependent cell apoptosis initiated by GrA and GrB could target the development of tissue destruction.
      • Lieberman J.
      • Fan Z.
      Nuclear war: the granzyme A-bomb.
      • Trapani J.A.
      • Sutton V.R.
      • Granzyme B.
      Pro-apoptotic, antiviral and antitumor functions.
      It is possible that GrA and GrB are involved in alveolar cell apoptosis, responsible for the loss of alveolar structures in COPD.
      It is also possible that type II Pneumocytes are involve in the pathogenesis of COPD through the over-expression and activation of GrA and GrB. There is still no direct evidence to confirm the precise role of type II pneumocytes in the COPD. The further study should clarify if type II pneumocytes act as the primary or secondary role in the pathogenesis of COPD. There is a great need to define the valid strategies clarify type II pneumocyte dysfunctions in COPD and the potential as the targeting cell for therapy and.

      Acknowledgements

      The work was supported by Shanghai Leading Academic Discipline Project (Project Number: B115), Fudan University (Distinguished Professor Grant), and Shanghai Science & Technology Committee ( 08PJ1402900, 9540702600, 08DZ2293104 ).

      Conflict of interest

      We declare that we do not have conflict claim.

      References

        • Cazzola M.
        • Donner C.F.
        • Hanania N.A.
        One hundred years of chronic obstructive pulmonary disease (COPD).
        Respir Med. 2007; 101: 1049-1065
        • Devendra G.
        • Spragg R.G.
        Lung surfactant in subacute pulmonary disease.
        Respir Res. 2002; 3: 19
        • Demedts I.K.
        • Demoor T.
        • Bracke K.R.
        • Joos G.F.
        • Brusselle G.G.
        Role of apoptosis in the pathogenesis of COPD and pulmonary emphysema.
        Respir Res. 2006; 30: 53
        • Hogg J.C.
        • Chu F.
        • Utokaparch S.
        • et al.
        The nature of small-airway obstruction in chronic obstructive pulmonary disease.
        N Engl J Med. 2004; 350: 2645-2653
        • Tetley T.D.
        Inflammatory cells and chronic obstructive pulmonary disease.
        Curr Drug Targets Inflamm Allergy. 2005 Dec; 4: 607-618
        • Zhao M.Q.
        • Amir M.K.
        • Rice W.R.
        • Enelow R.I.
        Type II pneumocyte-CD8 + T-cell interactions: relationship between target cell cytotoxicity and activation.
        Am J Respir Cell Mol Biol. 2001; 25: 362-369
        • Barnes P.J.
        Chronic obstructive pulmonary disease.
        N Engl J Med. 2000; 343: 269-280
        • Serrano-Mollar A.
        • Nacher M.
        • Gay-Jordi G.
        Intratracheal transplantation of alveolar type II cells reverses bleomycin-induced lung fibrosis.
        Am J Respir Crit Care Med. 2007; 176: 1261-1268
        • Devendra G.
        • Spragg R.G.
        Lung surfactant in subacute pulmonary disease.
        Respir Res. 2002; 3: 19
        • Xue Y.
        • Williams T.L.
        • Li T.
        • et al.
        Type II pneumocytes modulate surfactant production in response to cigarette smoke constituents: restoration by vitamins A and E.
        Toxicol In Vitro. 2005; 19: 1061-1069
        • Wirtz H.R.
        • Schmidt M.
        Acute influence of cigarette smoke on secretion of pulmonary surfactant in rat alveolar type II cells in culture.
        Eur Respir J. 1996 Jan; 9: 24-32
        • Vlachaki E.M.
        • Koutsopoulos A.V.
        • Tzanakis N.
        • et al.
        Altered surfactant protein-A expression in type II pneumocytes in COPD.
        Chest. 2010; 137: 37-45
        • Dwyer T.M.
        Cigarette smoke-induced airway inflammation as sampled by the expired breath condensate.
        Am J Med Sci. 2003 Oct; 326: 174-178
        • Cox R.A.
        • Burke A.S.
        • Jacob S.
        • et al.
        Activated nuclear factor kappa B and airway inflammation after smoke inhalation and burn injury in sheep.
        J Burn Care Res. 2009; 30: 489-498
        • Demkow U.
        The oxidative stress in emphysema and chronic obstructive pulmonary disaease (COPD).
        Cent Eur J Immunol. 2009; 34: 143-146
        • Vernooy J.
        • Drummen N.
        • van Suylen R.J.
        • et al.
        Enhanced pulmonary leptin expression in patients with severe COPD and asymptomatic smokers.
        Thorax. 2009; 64: 26-32
        • McCourtie A.S.
        • Farivar A.S.
        • Woolley S.M.
        • et al.
        Alveolar macrophage secretory products effect type 2 pneumocytes undergoing hypoxia-reoxygenation.
        Ann Thorac Surg. 2008; 86: 1774-1780
        • Maestrelli P.
        • Paska C.
        • Saetta M.
        • et al.
        Decreased haem oxygenase-1 and increased inducible nitric oxide synthase in the lung of severe COPD patients.
        Eur Respir J. 2003; 21: 971-976
        • Hodge S.
        • Hodge G.
        • Holmes M.
        • Reynolds P.N.
        Increased airway epithelial and T-cell apoptosis in COPD remains despite smoking cessation.
        Eur Respir J. 2005; 25: 447-454
        • Vernooy J.H.
        • Dentener M.A.
        • van Suylen R.J.
        • et al.
        Intratracheal instillation of lipopolysaccharide in mice induces apoptosis in bronchial epithelial cells: no role for tumor necrosis factor-alpha and infiltrating neutrophils.
        Am J Respir Cell Mol Biol. 2001; 24: 569-576
        • Cataldo D.D.
        • Gueders M.M.
        • Rocks N.
        • et al.
        Pathogenic role of matrix metalloproteases and their inhibitors in asthma and chronic obstructive pulmonary disease and therapeutic relevance of matrix metalloproteases inhibitors.
        Cell Mol Biol. 2003; 49: 875-884
        • De Boer W.I.
        • van Schadewijk A.
        • Sont J.K.
        • et al.
        Transforming growth factor beta1 and recruitment of macrophages and mast cells in airways in chronic obstructive pulmonary disease.
        Am J Respir Crit Care Med. 1998; 158: 1951-1957
        • Takizawa H.
        • Tanaka M.
        • Takami K.
        • et al.
        Increased expression of transforming growth factor-beta1 in small airway epithelium from tobacco smokers and patients with chronic obstructive pulmonary disease (COPD).
        Am J Respir Crit Care Med. 2001; 163: 1476-1483
        • Serrano-Mollar A.
        • Nacher M.
        • Gay-Jordi G.
        • et al.
        Intratracheal transplantation of alveolar type II cells reverses bleomycin-induced lung fibrosis.
        Am J Resp Crit Care. 2007; 176: 1261-1268
        • Frerking I.
        • Günther A.
        • Seeger W.
        • Pison U.
        Pulmonary surfactant: functions, abnormalities and therapeutic options.
        Intensive Care Med. 2001 Nov; 27: 1699-1717
        • Pastva A.M.
        • Wright J.R.
        • Williams K.L.
        Immunomodulatory roles of surfactant proteins A and D: implications in lung disease.
        Proc Am Thorac Soc. 2007; 4: 252-257
        • Nogee L.M.
        Genetic mechanisms of surfactant deficiency.
        Biol Neonate. 2004; 85: 314-318
        • Devendra G.
        • Spragg R.G.
        Lung surfactant in subacute pulmonary disease.
        Respir Res. 2002; 3: 19
        • Hohlfeld J.
        • Fabel H.
        • Hamm H.
        The role of pulmonary surfactant in obstructive airways disease.
        Eur Respir J. 1997 Feb; 10: 482-491
        • Hamvas A.
        • Nogee L.M.
        • White F.V.
        • et al.
        Progressive lung disease and surfactant dysfunction with a deletion in surfactant protein C gene.
        Am J Respir Cell Mol Biol. 2004; 30: 771-776
        • Pison U.
        • Tam E.K.
        • Caughey G.H.
        • Hawgood S.
        Proteolytic inactivation of dog lung surfactant-associated proteins by neutrophil elastase.
        Biochim Biophys Acta. 1989; 992: 251-257
        • Putman E.
        • Van Golde L.M.G.
        • Haagsman H.P.
        Toxic oxidant species and their impact on the pulmonary surfactant system.
        Lung. 1997; 175: 75-103
        • Anseth J.W.
        • Goffin A.J.
        • Fuller G.G.
        • et al.
        Lung surfactant gelation induced by epithelial cells exposed to air pollution or oxidative stress.
        Am J Respir Cell Mol Biol. 2005; 33: 161-168
        • Starosta V.
        • Griese M.
        Oxidative damage to surfactant protein D in pulmonary diseases.
        Free Radic Res. 2006; 40: 419-425
        • Joppa P.
        • Petrásová D.
        • Stancák B.
        • et al.
        Oxidative stress in patients with COPD and pulmonary hypertension.
        Wien Klin Wochenschr. 2007; 119: 428-434
        • Cochrane C.G.
        Pulmonary surfactant in allergic inflammation: new insights into the molecular mechanisms of surfactant function.
        Am J Physiol Lung Cell Mol Physiol. 2005; 288: L608-L609
        • Calkovská A.
        Pulmonary surfactant in the respiratory tract.
        Cesk Fysiol. 2000; 49: 145-151
        • Lusuardi M.
        • Capelli A.
        • Carli S.
        • et al.
        Role of surfactant in chronic obstructive pulmonary disease: therapeutic implications.
        Respiration. 1992; 59: 28-32
        • Schmekel B.
        • Bos J.A.
        • Khan A.R.
        • Wohlfart B.
        • Lachmann B.
        • Wollmer P.
        Integrity of the alveolar-capillary barrier and alveolar surfactant system in smokers.
        Thorax. 1992; 47: 603-608
        • Wirtz H.R.
        • Schmidt M.
        Acute influence of cigarette smoke on secretion of pulmonary surfactant in rat alveolar type II cells in culture.
        Eur Respir J. 1996; 9: 24-32
        • GuoX Lin H.M.
        • Lin Z.
        • Montaño M.
        • Sansores R.
        • Wang G.
        • et al.
        Surfactant protein gene A, B, and D marker alleles in chronic obstructive pulmonary disease of a Mexican population.
        Eur Respir J. 2001; 18: 482-490
        • Hu R.C.
        • Xu Y.J.
        • Zhang J.X.
        Surfactant protein B 1580 polymorphism is associated with susceptibility to chronic obstructive pulmonary disease in Chinese Han population.
        J Huazhong Univ Sci Technol. 2004; 3 ([English Abstract]): 5
        • Sims M.W.
        • Tal-Singer R.M.
        • Kierstein S.
        • Musani A.I.
        • Beers M.F.
        • Panettieri R.A.
        • et al.
        Chronic obstructive pulmonary disease and inhaled steroids alter surfactant protein D (SP-D) levels: a cross-sectional study.
        Respir Res. 2008; 9: 13
        • Kierstein S.
        • Poulain F.R.
        • Cao Y.
        • Grous M.
        • Mathias R.
        • Kierstein G.
        • et al.
        Susceptibility to ozone-induced airway inflammation is associated with decreased levels of surfactant protein D.
        Respir Res. 2006; 7: 85
        • Wert S.E.
        • Yoshida M.
        • LeVine A.M.
        • et al.
        Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice.
        Proc Natl Acad Sci U S A. 2000; 97: 5972-5977
        • Yoshida M.
        • Whitsett J.A.
        Alveolar macrophages and emphysema in surfactant protein-D-deficient mice.
        Respirology. 2006; 11: S37-S40
        • Haque R.
        • Umstead T.M.
        • Ponnuru P.
        • et al.
        Role of surfactant protein-A (SP-A) in lung injury in response to acute ozone exposure of SP-A deficient mice.
        Toxicol Appl Pharmacol. 2007; 220: 72-82
        • Hirama N.
        • Shibata Y.
        • Otake K.
        • et al.
        Increased surfactant protein-D and foamy macrophages in smoking-induced mouse emphysema.
        Respirology. 2007; 12: 191-201
        • Enhorning G.
        • Duffy L.C.
        • Welliver R.C.
        Pulmonary surfactant maintains patency of conducting airways in the rat.
        Am J Respir Crit Care Med. 1995; 151: 554-556
        • Kerecman J.
        • Mustafa S.B.
        • Vasquez M.M.
        • et al.
        Immunosuppressive properties of surfactant in alveolar macrophage NR8383.
        Inflamm Res. 2008; 57: 118-125
      1. Surfactant protein D regulates NF-kB and matrix metalloproteinase production in alveolar macrophages via oxidant-sensitive pathways
        • Anzueto A.
        • Jubran A.
        • Ohar J.A.
        • et al.
        Effects ofaerosolized surfactant in patients with stable chronic bronchitis: a prospective randomized controlled trial.
        JAMA. 1997; 278: 1426-1431
        • Wirtz H.
        • Habscheid W.
        • Ertl G.
        • et al.
        Exogenous surfactant application in respiratory failure due to chronic obstructive pulmonary disease.
        Respiration. 1995; 62: 157-159
        • Chrysofakis G.
        • Tzanakis N.
        • Kyriakoy D.
        • et al.
        Perforin expression and cytotoxic activity of sputum CD8+ lymphocytes in patients with COPD.
        Chest. 2004; 125: 71-76
        • Vernooy J.H.
        • Möller G.M.
        • van Suylen R.J.
        • et al.
        Increased granzyme A expression in type II pneumocytes of patients with severe chronic obstructive pulmonary disease.
        Am J Respir Crit Care Med. 2007; 175: 464-472
        • Sower L.E.
        • Klimpel G.R.
        • Hanna W.
        • Froelich C.J.
        Extracellular activities of human granzymes. Granzyme A induces IL-6 and IL-8 production in fibroblast and epithelial cell lines.
        Cell Immunol. 1996; 171: 159-163
        • Buzza M.S.
        • Zamurs L.
        • Sun J.
        • et al.
        Extracellular matrix remodeling by human granzyme B via cleavage of vitronectin, fibronectin, and laminin.
        J Biol Chem. 2005; 280: 23549-23558
        • Lieberman J.
        • Fan Z.
        Nuclear war: the granzyme A-bomb.
        Curr Opin Immunol. 2003; 15: 553-559
        • Trapani J.A.
        • Sutton V.R.
        • Granzyme B.
        Pro-apoptotic, antiviral and antitumor functions.
        Curr Opin Immunol. 2003; 15: 533-543