Open access peer-reviewed chapter

Chronic Pseudomonas aeruginosa Infection as the Pathogenesis of Chronic Obstructive Pulmonary Disease

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Takemasa Matsumoto and Masaki Fujita

Submitted: October 6th, 2017 Reviewed: February 28th, 2018 Published: March 30th, 2018

DOI: 10.5772/intechopen.76058

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Chronic obstructive pulmonary disease (COPD), resulted from tobacco smoking, has an extremely poor prognosis and is a major cause of chronic morbidity and mortality worldwide. In this chapter, we review the role of bacterial infection on the pathogenesis of COPD, with a particular focus on Pseudomonas aeruginosa. Chronic infection with P. aeruginosa has been shown to contribute to COPD pathogenesis under certain conditions. In addition, P. aeruginosa is a major factor influencing severe symptoms, acute exacerbation, and the progression of COPD. Treatment for chronic P. aeruginosa infection may become a new strategy for addressing COPD.


  • chronic inflammation
  • emphysema
  • acute exacerbation
  • bronchiectasis
  • microorganism
  • pathogenesis

1. Introduction

Chronic obstructive pulmonary disease (COPD) is induced by mainly tobacco smoking. The patients of COPD complained of cough, sputa, or exertional dyspnea. Compared to the patients with bronchial asthma, COPD has an extremely poor prognosis. Approximately 3,200,000 COPD patients died worldwide in 2015 [1]. The mortality is estimated to be ≥8-fold that of bronchial asthma. In this chapter, we review the role of bacterial infection on the pathogenesis of COPD, with a particular focus on Pseudomonas aeruginosa.


2. Chronic obstructive lung disease (COPD)

COPD is a relatively common disease characterized by respiratory symptoms and airflow limitation, usually caused by smoking. A mixture of small airway disease and parenchymal destruction caused airflow limitation. COPD patients complained of cough, dyspnea, and sputum production. Acute exacerbation frequently occurs after an acute respiratory infection. The acute exacerbation leads to more severe airflow limitation [2]. Sometimes, COPD patients are accompanied with bronchiectasis. These patients caused more frequent acute exacerbations and severe airway obstruction. Also, these patients demonstrated pathogenic microorganisms and mortality [3]. At present, there is no universally effective treatment for COPD. Some treatments just relieve the symptoms, while others could slow the progression of the disease. The most effective treatment is stopping smoking. Bronchodilators are the mainstay of available treatment options for COPD. There are several types of bronchodilators. Long-acting beta agonist (LABA), long-acting muscarinic antagonist (LAMA), or a combination of these agents is used for COPD patients, since long-acting medication is preferred. For the patients complicated with bronchial asthma, known as asthma-COPD overlap (ACO), inhaled glucocorticoids (ICSs) can be used. Also, ICSs can be used for patients with frequent COPD exacerbation. Short-acting beta agonists (SABAs) and short-acting muscarinic anticholinergics (SAMAs) are used to relieve symptoms, such as exertional dyspnea. Since theophylline can be given orally, it can be used for patients who cannot inhale medications. Advanced COPD patients with hypoxemia are administered with long-term oxygen therapy (LTOT). Rehabilitation programs are also important. They can be effective; however, they do not improve the outcome. Lung volume reduction surgery is performed in select patients with COPD; however, the candidate patients are limited. Also, lung transplantation is rarely done because of lack of donors [4]. Antioxidants, mucolytics, antiproteases, and antifibrotics are sometimes used; however, these drugs are not a mainstay for COPD. Anti-inflammatory drugs such as phosphodiesterase 4 inhibitors are used to reduce airway inflammation. Also, kinase inhibitors, chemokine receptor antagonists, innate immune mechanism inhibitors, and statins are developing [5]. However, these new treatments are still insufficient to demonstrate the evidence for caring COPD. As such, a novel therapy for COPD is required.


3. Pseudomonas aeruginosa

P. aeruginosais a glucose non-fermenting Gram-negative bacillus. The size of P. aeruginosais 0.7 × 2 μm. P. aeruginosais localized in the natural environment such as in soil and freshwater. P. aeruginosadoes not show usually pathogenicity in healthy individuals but, however, causes infection mainly in immunocompromised patients [6]. P. aeruginosais well known to cause chronic infection in bronchiectasis as well as COPD. Biofilm formation is important for chronic infection. A biofilm is a self-produced polymer matrix consisting of polysaccharides, protein, and DNA. Bacteria are embedded in biofilm. The polysaccharide alginate is the major components of the P. aeruginosabiofilm matrix. P. aeruginosaescapes from host immunity and antibacterial drugs using biofilms [7, 8].


4. P. aeruginosaand lung diseases other than chronic obstructive pulmonary disease

P. aeruginosais often detected in ventilator-associated pneumonia and nosocomial pneumonia. Moreover, bronchiectasis is easily colonized by P. aeruginosa[9]. P. aeruginosainfection is a risk factor for mortality and morbidity in cystic fibrosis patients [10]. P. aeruginosasometimes produces mucinous materials, so-called mucoid P. aeruginosa. Gibson et al. reported that mucoid P. aeruginosacontributes to the progression of cystic fibrosis compared to non-mucoid P. aeruginosa[11]. P. aeruginosainfection in non-cystic fibrosis bronchiectasis patients induces more severe impairment of the pulmonary function, although the rate of decline in the pulmonary function is not affected [12].


5. P. aeruginosaand chronic obstructive pulmonary disease

5.1. Steady status of COPD and P. aeruginosa

Numerous studies have characterized the lung microbiome of healthy adult subjects using BAL samples. The most common phyla consistently observed have been Bacteroides, Firmicutes, and Proteobacteriain the phylum level. Prominent genera among healthy controls are Prevotella, Veillonella, Streptococcus, and Pseudomonas. Tobacco smoking alters the microbial constitution of the upper airways [13]. Erb-Downward et al. reported that Pseudomonas, Streptococcus, Prevotella, Fusobacterium, Haemophilus, Veillonella, and Porphyromonaswere observed in COPD lungs [14]. P. aeruginosais often observed in the sputum of patients with COPD. Rosel et al. reported that P. aeruginosawas colonized in one-quarter of patients with COPD during steady status [15]. P. aeruginosawas detected in 4–34.7% of sputum samples from COPD patients [16, 17, 18, 19, 20]. P. aeruginosacauses chronic infections in COPD [21], and especially COPD patients accompanied with bronchiectasis are easily colonized with P. aeruginosa. COPD patients with P. aeruginosacolonization have a worse disease activity than COPD patients without P. aeruginosacolonization. Desai et al. conducted a longitudinal prospective observational study of COPD. They found that the average of breathlessness, cough, and sputum scale (BCSS) score was higher during the periods of colonization compared to periods without colonization. Colonization was associated with a clinically significant worsening of daily symptoms, even in the absence of clinical exacerbation [22]. These findings suggest that novel therapies that decrease the bacterial colonization may be able to improve the daily symptoms and quality of life in COPD patients.

5.2. Acute exacerbation of COPD and P. aeruginosa

Acute exacerbation of COPD is defined as a worsening of the respiratory condition, such as coughing, sputum production, and dyspnea, beyond daily physiological fluctuations and requiring additional treatment. COPD patients with acute exacerbation document a worse quality of life as well as decrease of pulmonary function. Finally, COPD patients with acute exacerbation result in lower mortality [9]. Acute exacerbation mainly occurs due to airway infections. The relationship between COPD and P. aeruginosainfection in acute exacerbation of COPD has already been reported [23, 24, 25, 26]. However, bacteria other than P. aeruginosacan also cause acute exacerbation of COPD. Indeed, infection with a new strain of Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniaeis strongly associated with the occurrence of exacerbation. H. influenza(20–30%), S. pneumoniae(10–15%), and M. catarrhalis(10–15%) were causative bacteria for acute exacerbation. P. aeruginosaaccounted for only 5–10% of causative bacteria. Infection of respiratory viruses has also been shown to cause exacerbations. However, it is difficult to identify the specific respiratory viruses because of technical problems. P. aeruginosais less frequently detected from the sputum in COPD patients with acute exacerbation than in those without exacerbation. However, acute exacerbation caused by P. aeruginosagenerally produces a more severe clinical condition than that caused by other pathogens [26].

5.3. Progression of COPD and P. aeruginosa

The relationship between disease progression and P. aeruginosainfection in COPD patients is not fully understood. Bronchiectasis, a percentage of forced expiratory volume in 1 s (%FEV1) of <35%, systemic steroid use, and antibiotic therapy within the preceding 3 months increased the risk of P. aeruginosacolonization [13, 23, 24]. The detection rates of H. influenzaand P. aeruginosawere reported not to be associated with the severity of emphysematous changes [26, 27]. However, chronic P. aeruginosainfection was recently reported to be associated with severe obstruction in COPD patients [28]. Hospitalized COPD patients with acute exacerbation by P. aeruginosademonstrated worse lung function, greater dyspnea, and more hospitalizations over the previous year. Therefore, P. aeruginosainfection is commonly observed in COPD patients and has been found to cause severe symptoms of COPD, the development of severe acute exacerbation, disease progression, and a poor prognosis.


6. Pathogenesis of chronic obstructive pulmonary disease

The pathogenesis of COPD is considered to be chronic airflow limitation results from an abnormal inflammatory response to the inhaled particles and gasses in the lung in susceptible smokers. There is a famous hypothesis that a protease-antiprotease imbalance leads to the progression of the destruction of alveoli [2]. Alveolar cell loss through apoptosis might contribute to the pathogenesis [29, 30, 31]. There are many animal models for COPD, including elastase, cigarette, inhaled gasses, and gene-targeted models. As COPD models, administration of papain or porcine pancreatic elastase model is well known [32]. Neutrophil elastase and proteinase-3, but not non-elastolytic enzymes, such as bacterial collagenase, caused COPD-like changes [33, 34, 35]. Cigarette smoking is a major factor inducing the development of COPD. Long-term cigarette smoking caused macrophage-predominant inflammation and airspace enlargement in animal models similar to those found in humans [36]. Potential mechanisms include high concentrations of reactive oxygen species (ROS) [37], oxidative stress [38], and matrix metalloproteinase (MMP)-12 [39, 40]. Inhaled stimuli, such as sulfur dioxide [4142], nitrogen dioxide [43], and oxidant [44], have been shown to induce COPD-like lesions in animal models. Ultrafine particles, such as silica, coal dust, diesel exhaust particles, and cadmium, induced focal emphysema [45, 46], chronic airway inflammation [47], and interstitial fibrosis with enlargement of the airspaces [48]. Alveolar wall apoptosis without the accumulation of inflammatory cells, resulting in emphysematous changes, was attained by active caspase-3 [31, 49]. Prednisolone also causes emphysematous changes through apoptosis [50]. Apoptosis in the alveoli resulted in airspace enlargement was also attained by a block of vascular endothelial cell growth factor (VEGF) receptor-2 [51]. Ceramide production, as the second messenger lipid, was induced by apoptosis. Ceramide played a role in induction of inflammation by the blockade of apoptosis by a VEGF receptor antibody. Since ceramide administration provoked the expression of MMP-12, it was considered to be a link between excessive apoptosis and inflammation [52]. Several gene-targeted models demonstrated COPD-like changed; however, the changes were developmental abnormalities rather than the destruction of mature lung tissue. Tight-skin mice [53, 54], pallid mice [55], and beige mice [56] were reported to be models. COPD mimic models by genetically altered techniques have been reported such as the overexpression of collagenase in the lung of transgenic mice [57], the deficiency of the microfibrillar component fibulin-5 and the deficiency of platelet-derived growth factor A (PDGF-A) [58, 59], epithelial restricted integrin αvβ6 knockout mice [60], fibroblast growth factor (FGF) receptor (FGFR)-3, and FGFR-4-double knockout mice [61]. Mice lacking the surfactant protein D (SP-D) gene [62] and the tissue inhibitor of metalloproteinase-3 (TIMP-3) gene [63] showed COPD-like lesions. These gene-targeted mice provided useful information for understanding the pathogenesis of COPD. However, none of these mice showed the same pathologic changes as those seen with human COPD.


7. Pseudomonas aeruginosaas the pathogenesis for chronic obstructive pulmonary disease

Chronic inflammation also plays a pivotal role in its development. Administration of lipopolysaccharide (LPS) to the lungs induced severe inflammation and resulted in airspace enlargement [64, 65]. COPD-like changes, such as goblet cell metaplasia in the larger airways, thickening of the airway walls, and irreversible alveolar enlargement, were attained by repeated administration of LPS [66, 67]. Tumor necrosis factor (TNF)-alpha is a proinflammatory cytokine induced by stimuli such as LPS. We reported that TNF-alpha overexpression mice in the lungs demonstrated pulmonary emphysema-like changes [68, 69]. MMP activation induced alveolar enlargement [68]. Chronic inflammation by TNF-alpha overexpression is considered to play an important role in the development of COPD. Several reports have found that the overexpression of inflammatory cytokines, such as IL-13 and IFN-gamma, resulted in pathologic changes mimicking human COPD [70, 71, 72]. These reports also supported the hypothesis that chronic inflammation in the lungs leads to lung tissue destruction, a hallmark of pulmonary emphysema, and chronic bronchitis.

We therefore investigated the role of chronic inflammation in the pathogenesis of COPD. P. aeruginosainduced chronic inflammation as previously described. We hypothesized that chronic inflammation, specifically that induced by P. aeruginosa, contributed to the pathogenesis of COPD. To test this hypothesis, pathophysiological changes due to chronic P. aeruginosainfection in club cell secretory protein (CCSP)-deficient mice were investigated [73]. The nonciliary bronchial epithelium as well as the uterine and urethral ducts expresses CCSP proteins [74]. The anti-inflammatory response could be speculated as the role of CCSP [75]. Therefore, we consider CCSP-deficient mice to be a model susceptible to chronic infection. CCSP-deficient mice with single administration of P. aeruginosademonstrated similar result to wild-type mice [76]. We used P. aeruginosa-colonized catheter methods [73]. This chronic status of P. aeruginosainfection continued for more than 5 weeks. As a result, these deficient mice showed more severe inflammation in response to chronic P. aeruginosainfection than wild-type (WT) mice, and their bronchi were markedly stenotic (Figure 1). The mean linear intercept, destruction index, and lung compliance in the CCSP-deficient mice were significantly higher than those in the wild-type mice (Figure 2). Severe inflammation leads to the destruction of the alveolar wall, and bronchial stenosis leads to air trapping (Figure 3). Chronic infection of P. aeruginosain CCSP-deficient mice demonstrated COPD-like changes [73]. Recent studies attempting to characterize COPD have shown that CCSP is strongly related to COPD progression [77, 78]. CCSP has been reported to play a role in the modulation of pulmonary inflammation during the infection and recovery phases. Our study revealed the important role of CCSP in the chronic infection phase. Chronic P. aeruginosainfection might play a distinctive role in the pathogenesis of COPD. However, several limitations exist. Mice have less airway branching than humans and lack respiratory bronchioles. Major species differences between murine and human lung morphogenesis and discrepancies in both the innate and adaptive immunity between the human and murine immune systems exist [79, 80]. We should consider the limitations carefully.

Figure 1.

Histology of lungs after chronicP. aeruginosainfection. Inflammatory cells infiltrated around the bronchioles and the alveoli septa. The CCSP-deficient model (CCSP−/−) showed bronchial constriction and alveolar enlargement compared to the wild-type model.

Figure 2.

Pulmonary physiology after chronicP. aeruginosainfection. (A) ChronicP. aeruginosainfection in CCSP-deficient mice (CCSP−/−) resulted in an increase in the mean linear intercept compared to that in wild-type (WT) mice. Furthermore, the CCSP-deficient mice demonstrated a severe destructive index (B). (C) CCSP(−/−) induced elevated pulmonary compliance compared with WT mice. These results indicate that chronicP. aeruginosainfection in CCSP-deficient mice induced COPD-like changes.

Figure 3.

Schematic illustrations of COPD-like changes induced by chronicP. aeruginosainfection. (A) WhenP. aeruginosainfected the bronchus, CCSP was secreted from club cells to suppress the inflammation. (B) Since CCSP-deficient mice could not suppress the inflammation through CCSP secretion, serious inflammation occurred. (C) As a result, the bronchus became stenotic, and air trapping occurred. Air trapping progressed, and the alveoli were destroyed. (D) Alveolar destruction due to inflammation also occurred. Finally, the CCSP-deficient mice demonstrated COPD-like changes.

Recently, macrolide treatment has been reported to protect against acute exacerbation. Among some subjects with COPD, taking azithromycin daily for 1 year, when added to the usual treatment regimen, reduced the frequency of exacerbations and improved the quality of life [81]. Macrolides are known to modulate the inflammation, the so-called immunomodulatory effect, besides antimicrobial effects. In Japan, macrolides are used to treat chronic infection with P. aeruginosa, such as diffuse panbronchiolitis (DPB). These agents might therefore modulate the chronic inflammation induced by P. aeruginosa. Further studies are needed to clarify the pathogenesis of COPD. We should seek out direct evidence that chronic P. aeruginosainfection is related to the pathogenesis of COPD.


8. Conclusion and future directions

P. aeruginosainfection had never been reported as the pathogenesis of COPD. However, we showed that chronic infection of P. aeruginosacontributed to COPD pathogenesis. P. aeruginosais also a major factor influencing the severity of symptoms, acute exacerbation, and progression of COPD. Treating chronic P. aeruginosainfection may become a new strategy for treating COPD.



We appreciate the assistance of Dr. Brian Quinn for editing the English usage.


Conflict of interest

The authors declare that they have no conflicts of interest (COI).


  1. 1. GBD 2015 Chronic Respiratory Disease Collaborators. Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015. The Lancet Respiratory Medicine. 2017;5:691-706. DOI: 10.1016/S2213-2600(17)30293-X
  2. 2. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Global Initiative for Chronic Obstructive Lung Disease. Available from:
  3. 3. Du Q, Jin J, Liu X, Sun Y. Bronchiectasis as a comorbidity of chronic obstructive pulmonary disease: A systematic review and meta-analysis. PLoS One. 2016;11:e0150532. DOI: 10.1371/journal.pone.0150532
  4. 4. Ferguson GT, Make B. Management of stable chronic obstructive pulmonary disease. In: Stoller JK, editor. Waltham, MA: UpToDate Inc.;[Accessed: November 15, 2017]
  5. 5. Ross CL, Hansel TT. New drug therapies for COPD. Clinics in Chest Medicine. 2014;35:219-239. DOI: 10.1016/j.ccm.2013.10.003
  6. 6. Williams BJ, Dehnbostel J, Blackwell TS.Pseudomonas aeruginosa: Host defence in lung diseases. Respirology. 2010;15:1037-1056. DOI: 10.1111/j.1440-1843.2010.01819.x
  7. 7. Ono T, Murakami K, Miyake Y. Regulatory networks for antibiotic tolerance and biofilm formation inPseudomonas aeruginosa. Nippon Saikingaku Zasshi. 2012;67:227-243
  8. 8. Høiby N, Ciofu O, Bjarnsholt T.Pseudomonas aeruginosabiofilms in cystic fibrosis. Future Microbiology. 2010;5:1663-1674. DOI: 10.2217/fmb.10.125
  9. 9. Angrill J, Agustí C, de Celis R, Rañó A, Gonzalez J, Solé T, Xaubet A, Rodriguez-Roisin R, Torres A. Bacterial colonisation in patients with bronchiectasis: Microbiological pattern and risk factors. Thorax. 2002;57:15-19
  10. 10. Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson RL.Pseudomonas aeruginosaand other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatric Pulmonology. 2002;34:91-100
  11. 11. Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. American Journal of Respiratory and Critical Care Medicine. 2003;168:918-951
  12. 12. Chalmers JD, Smith MP, McHugh BJ, Doherty C, Govan JR, Hill AT. Short- and long-term antibiotic treatment reduces airway and systemic inflammation in non-cystic fibrosis bronchiectasis. American Journal of Respiratory and Critical Care Medicine. 2012;186:657-665. DOI: 10.1164/rccm.201203-0487OC
  13. 13. Dickson RP, Erb-Downward JR, Huffnagle GB. The role of the bacterial microbiome in lung disease. Expert Review of Respiratory Medicine. 2013;7:245-257. DOI: 10.1586/ers.13.24
  14. 14. Erb-Downward JR, Thompson DL, Han MK, Freeman CM, McCloskey L, Schmidt LA, Young VB, Toews GB, Curtis JL, Sundaram B, Martinez FJ, Huffnagle GB. Analysis of the lung microbiome in the “healthy” smoker and in COPD. PLoS One. 2011;6:e16384. DOI: 10.1371/journal.pone.0016384
  15. 15. Rosell A, Monsó E, Soler N, Torres F, Angrill J, Riise G, Zalacaín R, Morera J, Torres A. Microbiologic determinants of exacerbation in chronic obstructive pulmonary disease. Archives of Internal Medicine. 2005;165:891-897
  16. 16. Gallego M, Pomares X, Espasa M, Castañer E, Solé M, Suárez D, Monsó E, Montón C.Pseudomonas aeruginosaisolates in severe chronic obstructive pulmonary disease: Characterization and risk factors. BMC Pulmonary Medicine. 2014;14:103. DOI: 10.1186/1471-2466-14-103
  17. 17. Papi A, Bellettato CM, Braccioni F, Romagnoli M, Casolari P, Caramori G, Fabbri LM, Johnston SL. Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. American Journal of Respiratory and Critical Care Medicine. 2006;173:1114-1121
  18. 18. Sethi S, Evans N, Grant BJB, Murphy TF. New strains of bacteria and exacerbations of chronic obstructive pulmonary disease. The New England Journal of Medicine. 2002;347:465-471
  19. 19. Monsó E, Ruiz J, Rosell A, Manterola J, Fiz J, Morera J, Ausina V. Bacterial infection in chronic obstructive pulmonary disease. A study of stable and exacerbated outpatients using the protected specimen brush. American Journal of Respiratory and Critical Care Medicine. 1995;152:1316-1320
  20. 20. Nouira S, Marghli S, Belghith M, Besbes L, Elatrous S, Abroug F. Once daily oral ofloxacin in chronic obstructive pulmonary disease exacerbation requiring mechanical ventilation: A randomised placebo-controlled trial. Lancet. 2001;358:2020-2025
  21. 21. Martı’nez-Solano L, Macia M’a D, Fajardo A, Oliver A, Martinez JL. ChronicPseudomonas aeruginosainfection in chronic obstructive pulmonary disease. Clinical Infectious Diseases. 2008;47:1526-1533. DOI: 10.1086/593186
  22. 22. Desai H, Eschberger K, Wrona C, Grove L, Agrawal A, Grant B, Yin J, Parameswaran GI, Murphy T, Sethi S. Bacterial colonization increases daily symptoms in patients with chronic obstructive pulmonary disease. Annals of the American Thoracic Society. 2013;11:303-309. DOI: 10.1513/AnnalsATS.201310-350OC
  23. 23. Lode H, Allewelt M, Balk S, De Roux A, Mauch H, Niederman M, Schmidt-Ioanas M. A prediction model for bacterial etiology in acute exacerbations of COPD. Infection. 2007;35:143-149
  24. 24. Garcia-Vidal C, Almagro P, Romaní V, Rodríguez-Carballeira M, Cuchi E, Canales L, Blasco D, Heredia JL, Garau J.Pseudomonas aeruginosain patients hospitalised for COPD exacerbation: A prospective study. The European Respiratory Journal. 2009;34:1072-1078. DOI: 10.1183/09031936.00003309
  25. 25. Murphy TF, Brauer AL, Eschberger K, Lobbins P, Grove L, Cai X, Sethi S.Pseudomonas aeruginosain chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine. 2006;177:853-860. DOI: 10.1164/rccm.200709-1413OC
  26. 26. Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. The New England Journal of Medicine. 2008;359:2355-2365. DOI: 10.1056/NEJMra0800353
  27. 27. Naito K, Yamasaki K, Yatera K, Akata K, Noguchi S, Kawanami T, Fukuda K, Kido T, Ishimoto H, Mukae H. Bacteriological incidence in pneumonia patients with pulmonary emphysema: A bacterial floral analysis using the 16S ribosomal RNA gene in bronchoalveolar lavage fluid. International Journal of Chronic Obstructive Pulmonary Disease. 2017;12:2111-2120. DOI: 10.2147/COPD.S140901
  28. 28. Boixeda R, Almagro P, Díez-Manglano J, Cabrera FJ, Recio J, Martin-Garrido I, Soriano JB. Bacterial flora in the sputum and comorbidity in patients with acute exacerbations of COPD. International Journal of Chronic Obstructive Pulmonary Disease. 2015;10:2581-2591. DOI: 10.2147/COPD.S88702
  29. 29. Tuder RM, Petrache I, Elias JA, Voelkel NF, Henson PM. Apoptosis and emphysema: The missing link. American Journal of Respiratory Cell and Molecular Biology. 2003;28:551-554
  30. 30. Kasahara Y, Tuder RM, Cool CD, Lynch DA, Flores SC, Voelkel NF. Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. American Journal of Respiratory and Critical Care Medicine. 2001;163:737-744
  31. 31. Imai K, Mercer BA, Schulman LL, Sonett JR, D’Armiento JM. Correlation of lung surface area to apoptosis and proliferation in human emphysema. The European Respiratory Journal. 2005;25:250-258
  32. 32. Gross P, Pfitzer EA, Tokker E, Babyak MA, Kaschak M. Experimental emphysema: Its production with papain in normal and silicotic rats. Archives of Environmental Health. 1965;11:50-58
  33. 33. Janoff A, Sloan B, Weinbaum G, Damiano V, Sandhaus RA, Elias J, Kimbel P. Experimental emphysema induced with purified human neutrophil elastase: Tissue localization of the instilled protease. The American Review of Respiratory Disease. 1977;115:461-478
  34. 34. Senior RM, Tegner H, Kuhn C, Ohlsson K, Starcher BC, Pierce JA. The induction of pulmonary emphysema with human leukocyte elastase. The American Review of Respiratory Disease. 1977;116:469-475
  35. 35. Rom WN, Basset P, Fells GA, Nukiwa T, Trapnell BC, Crysal RG. Alveolar macrophages release an insulin-like growth factor I-type molecule. The Journal of Clinical Investigation. 1988;82:1685-1693
  36. 36. Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science. 1997;277:2002-2004
  37. 37. MacNee W. Oxidative stress and lung inflammation in airways disease. European Journal of Pharmacology. 2001;429:195-207
  38. 38. Bowler RP, Crapo JD. Oxidative stress in airways: Is there a role for extracellular superoxide dismutase? American Journal of Respiratory and Critical Care Medicine. 2002;166:S38-S43
  39. 39. Shipley JM, Wesselschmidt RL, Kobayashi DK, Ley TJ, Shapiro SD. Metalloelastase is required for macrophage-mediated proteolysis and matrix invasion in mice. Proceedings of the National Academy of Sciences of the United States of America. 1996;93(9):3942-3946
  40. 40. Shapiro SD, Goldstein NM, Houghton AM, Kobayashi DK, Kelley D, Belaaouaj A. Neutrophil elastase contributes to cigarette smoke-induced emphysema in mice. The American Journal of Pathology. 2003;163:2329-2335
  41. 41. Shore S, Kobzik L, Long NC, Skornik W, Van Staden CJ, Boulet L, Rodger IW, Pon DJ. Increased airway responsiveness to inhaled methacholine in a rat model of chronic bronchitis. American Journal of Respiratory and Critical Care Medicine. 1995;151:1931-1938
  42. 42. Kodavanti UP, Jackson MC, Ledbetter AD, Starcher BC, Evansky PA, Harewood A, Winsett DW, Costa DL. The combination of elastase and sulfur dioxide exposure causes COPD-like lesions in the rat. Chest. 2000;117:299S-302S
  43. 43. Holroyd KJ, Eleff SM, Zhang LY, Jakab GJ, Kleeberger SR. Genetic modeling of susceptibility to nitrogen dioxide-induced lung injury in mice. The American Journal of Physiology. 1997;273:L595-L602
  44. 44. Mudway IS, Kelly FJ. Ozone and the lung: A sensitive issue. Molecular Aspects of Medicine. 2000;21:1-48
  45. 45. Albrecht C, Adolf B, Weishaupt C, Höhr D, Zeitträger I, Friemann J, Borm PJ. Clara-cell hyperplasia after quartz and coal-dust instillation in rat lung. Inhalation Toxicology. 2001;13:191-205
  46. 46. Ernst H, Rittinghausen S, Bartsch W, Creutzenberg O, Dasenbrock C, Görlitz BD, Hecht M, Kairies U, Muhle H, Müller M, Heinrich U, Pott F. Pulmonary inflammation in rats after intratracheal instillation of quartz, amorphous SiO2, carbon black, and coal dust and the influence of poly-2-vinylpyridine-N-oxide (PVNO). Experimental and Toxicologic Pathology. 2002;54:109-126
  47. 47. Sydbom A, Blomberg A, Parnia S, Stenfors N, Sandström T, Dahlén SE. Health effects of diesel exhaust emissions. The European Respiratory Journal. 2001;17:733-746
  48. 48. Snider GL, Lucey EC, Faris B, Jung-Legg Y, Stone PJ, Franzblau C. Cadmium-chloride-induced air-space enlargement with interstitial pulmonary fibrosis is not associated with destruction of lung elastin. Implications for the pathogenesis of human emphysema. The American Review of Respiratory Disease. 1988;137:918-923
  49. 49. Aoshiba K, Yokohori N, Nagai A. Alveolar wall apoptosis causes lung destruction and emphysematous changes. American Journal of Respiratory Cell and Molecular Biology. 2003;28:555-562
  50. 50. Choe KH, Taraseviciene SL, Scerbavicius R, Gera L, Tuder RM, Voelkel NF. Methylprednisolone causes matrix metalloproteinase-dependent emphysema in adult rats. American Journal of Respiratory and Critical Care Medicine. 2003;167:1516-1521
  51. 51. Kasahara Y, Tuder RM, Taraseviciene SL, Le Cras TD, Abman S, Hirth PK, Waltenberger J, Voelkel NF. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. The Journal of Clinical Investigation. 2000;106:1311-1319
  52. 52. Petrache I, Natarajan V, Zhen L, Medler TR, Richter AT, Cho C, Hubbard WC, Berdyshev EV, Tuder RM. Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice. Nature Medicine. 2005;11:491-498
  53. 53. Martorana PA, van Even P, Gardi C, Lungarella G. A 16-month study of the development of genetic emphysema in tight-skin mice. The American Review of Respiratory Disease. 1989;139:226-232
  54. 54. Kielty CM, Raghunath M, Siracusa LD, Sherratt MJ, Peters R, Shuttleworth CA, Jimenez SA. The tight skin mouse: Demonstration of mutant fibrillin-1 production and assembly into abnormal microfibrils. The Journal of Cell Biology. 1998;140:1159-1166
  55. 55. Martorana PA, Brand T, Gardi C, van Even P, de Santi MM, Calzoni P, Marcolongo P, Lungarella G. The pallid mouse. A model of genetic alpha 1-antitrypsin deficiency. Laboratory Investigation. 1993;68:233-241
  56. 56. Keil M, Lungarella G, Cavarra E, van Even P, Martorana PA. A scanning electron microscopic investigation of genetic emphysema in tight-skin, pallid, and beige mice, three different C57 BL/6J mutants. Laboratory Investigation. 1996;74:353-362
  57. 57. D’Armiento J, Dalal SS, Okada Y, Berg RA, Chada K. Collagenase expression in the lungs of transgenic mice causes pulmonary emphysema. Cell. 1992;71:955-961
  58. 58. Nakamura T, Lozano PR, Ikeda Y, Iwanaga Y, Hinek A, Minamisawa S, Cheng CF, Kobuke K, Dalton N, Takada Y, Tashiro K, Ross J Jr, Honjo T, Chien KR. Fibulin-5/DANCE is essential for elastogenesis in vivo. Nature. 2002;415:171-175
  59. 59. Boström H, Willetts K, Pekny M, Levéen P, Lindahl P, Hedstrand H, Pekna M, Hellström M, Gebre MS, Schalling M, Nilsson M, Kurland S, Törnell J, Heath JK, Betsholtz C. PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis. Cell. 1996;85:863-873
  60. 60. Morris DG, Huang X, Kaminski N, Wang Y, Shapiro SD, Dolganov G, Glick A, Sheppard D. Loss of integrin alpha(v)beta6-mediated TGF-beta activation causes Mmp12-dependent emphysema. Nature. 2003;422:169-173
  61. 61. Weinstein M, Xu X, Ohyama K, Deng CX. FGFR-3 and FGFR-4 function cooperatively to direct alveogenesis in the murine lung. Development. 1998;125:3615-3623
  62. 62. Yoshida M, Korfhagen TR, Whitsett JA. Surfactant protein D regulates NF-kappa B and matrix metalloproteinase production in alveolar macrophages via oxidant-sensitive pathways. Journal of Immunology. 2001;166:7514-7519
  63. 63. Leco KJ, Waterhouse P, Sanchez OH, Gowing KL, Poole AR, Wakeham A, Mak TW, Khokha R. Spontaneous air space enlargement in the lungs of mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3). The Journal of Clinical Investigation. 2001;108:817-829
  64. 64. Wittels EH, Coalson JJ, Welch MH, Guenter CA. Pulmonary intravascular leukocyte sequestration. A potential mechanism of lung injury. The American Review of Respiratory Disease. 1974;109:502-509
  65. 65. Corteling R, Wyss D, Trifilieff A. In vivo models of lung neutrophil activation. Comparison of mice and hamsters. BMC Pharmacology. 2002;2:1
  66. 66. Vernooy JH, Dentener MA, van Suylen RJ, Buurman WA, Wouters EF. Long-term intratracheal lipopolysaccharide exposure in mice results in chronic lung inflammation and persistent pathology. American Journal of Respiratory Cell and Molecular Biology. 2002;26:152-159
  67. 67. Brusselle GG, Bracke KR, Maes T, D’hulst AI, Moerloose KB, Joos GF, Pauwels RA. Murine models of COPD. Pulmonary Pharmacology & Therapeutics. 2005;19:155-165
  68. 68. Fujita M, Shannon JM, Irvin CG, Fagan KA, Cool C, Augustin A, Mason RJ. Overexpression of tumor necrosis factor-a produces an increase in lung volumes and pulmonary hypertension. American Journal of Physiology. Lung Cellular and Molecular Physiology. 2001;280:L39-L49
  69. 69. Fujita M, Mason RJ, Cool C, Shannon JM, Hara N, Fagan KA. Pulmonary hypertension in TNF-alpha-overexpressing mice is associated with decreased VEGF gene expression. Journal of Applied Physiology. 2002;93:2162-2168
  70. 70. Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J, Zhang Y, Elias JA. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. The Journal of Clinical Investigation. 1999;103:779-788
  71. 71. Zheng T, Zhu Z, Wang Z, Homer RJ, Ma B, Riese RJ Jr, Chapman HA Jr, Shapiro SD, Elias JA. Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase- and cathepsin-dependent emphysema. The Journal of Clinical Investigation. 2000;106:1081-1093
  72. 72. Wang Z, Zheng T, Zhu Z, Homer RJ, Riese RJ, Chapman HA Jr, Shapiro SD, Elias JA. Interferon gamma induction of pulmonary emphysema in the adult murine lung. The Journal of Experimental Medicine. 2000;192:1587-1600
  73. 73. Matsumoto T, Fujita M, Hirano R, Uchino J, Tajiri Y, Fukuyama S, Morimoto Y, Watanabe K. ChronicPseudomonas aeruginosainfection-induced chronic bronchitis and emphysematous changes. International Journal of Chronic Obstructive Pulmonary Disease. 2016;11:2321-2327. DOI: 10.2147/COPD.S113707
  74. 74. Bernard A, Marchandise FX, Depelchin S, Lauwerys R, Sibille Y. Clara cell protein in serum and bronchoalveolar lavage. The European Respiratory Journal. 1992;5:1231-1238
  75. 75. Mantile G, Miele L, Cordella-Miele E, Singh G, Katyal SL, Mukherjee AB. Human Clara cell 10-kDa protein is the counterpart of rabbit uteroglobin. The Journal of Biological Chemistry. 1993;268:20343-20351
  76. 76. Watson TM, Reynolds SD, Mango GW, Boe IM, Lund J, Stripp BR. Altered lung gene expression in CCSP-null mice suggests immunoregulatory roles for Clara cells. American Journal of Physiology. Lung Cellular and Molecular Physiology. 2001;281:L1523-L1530
  77. 77. Vestbo J, Edwards LD, Scanlon PD, Yates JC, Agusti A, Bakke P, Calverley PM, Celli B, Coxson HO, Crim C, Lomas DA, MacNee W, Miller BE, Silverman EK, Tal-Singer R, Wouters E, Rennard SI, Investigators ECLIPSE. Changes in forced expiratory volume in 1 second over time in COPD. The New England Journal of Medicine. 2011;365:1184-1192. DOI: 10.1056/NEJMoa1105482
  78. 78. Braido F, Riccio AM, Guerra L, Gamalero C, Zolezzi A, Tarantini F, De Giovanni B, Folli C, Descalzi D, Canonica GW. Clara cell 16 protein in COPD sputum: A marker of small airways damage? Respiratory Medicine. 2007;101:2119-2124. DOI: 10.1016/j.rmed.2007.05.023
  79. 79. Warburton D, Schwarz M, Tefft D, Flores DG, Anderson KD, Cardoso WV. The molecular basis of lung morphogenesis. Mechanisms of Development. 2000;92:55-81
  80. 80. Mestas J, Hughes CC. Of mice and not men: Differences between mouse and human immunology. Journal of Immunology. 2004;172:2731-2738
  81. 81. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA Jr, Criner GJ, Curtis JL, Dransfield MT, Han MK, Lazarus SC, Make B, Marchetti N, Martinez FJ, Madinger NE, McEvoy C, Niewoehner DE, Porsasz J, Price CS, Reilly J, Scanlon PD, Sciurba FC, Scharf SM, Washko GR, Woodruff PG, Anthonisen NR, Clinical Research Network COPD. Azithromycin for prevention of exacerbations of COPD. The New England Journal of Medicine. 2011;365:689-698. DOI: 10.1056/NEJMoa1104623

Written By

Takemasa Matsumoto and Masaki Fujita

Submitted: October 6th, 2017 Reviewed: February 28th, 2018 Published: March 30th, 2018