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
- acute exacerbation
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 . 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
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 . 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 . 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 . 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 . However, these new treatments are still insufficient to demonstrate the evidence for caring COPD. As such, a novel therapy for COPD is required.
P. aeruginosaand lung diseases other than chronic obstructive pulmonary disease
P. aeruginosaand chronic obstructive pulmonary disease
5.1. Steady status of COPD and
Numerous studies have characterized the lung microbiome of healthy adult subjects using BAL samples. The most common phyla consistently observed have been
5.2. Acute exacerbation of COPD and
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 . Acute exacerbation mainly occurs due to airway infections. The relationship between COPD and
5.3. Progression of COPD and
The relationship between disease progression and
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 . 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 . 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 . Potential mechanisms include high concentrations of reactive oxygen species (ROS) , oxidative stress , and matrix metalloproteinase (MMP)-12 [39, 40]. Inhaled stimuli, such as sulfur dioxide [41, 42], nitrogen dioxide , and oxidant , 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 , and interstitial fibrosis with enlargement of the airspaces . 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 . Apoptosis in the alveoli resulted in airspace enlargement was also attained by a block of vascular endothelial cell growth factor (VEGF) receptor-2 . 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 . 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 , and beige mice  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 , 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 , fibroblast growth factor (FGF) receptor (FGFR)-3, and FGFR-4-double knockout mice . Mice lacking the surfactant protein D (SP-D) gene  and the tissue inhibitor of metalloproteinase-3 (TIMP-3) gene  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.
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 . 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.
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 . 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
8. Conclusion and future directions
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).