The pathogenesis of lung emphysema: lessons learned from murine models

Abstract

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality throughout the world and is defined by the Global initiative in Obstructive Lung Disease (GOLD) as: “a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases”. COPD involves two spectra of clinical or pathological conditions, chronic bronchitis and lung emphysema and is associated with the accumulation and activation of several types of inflammatory cells in the lung tissue and bronchoalveolar lavage fluid (BALF). These activated inflammatory cells, but also structural cells in the respiratory tract release many inflammatory mediators, which are probably involved in the development of COPD. Cigarette smoking is by far the most important risk factor for COPD in more than 90% of the COPD patients. The experiments described in this thesis were performed to gain more knowledge about the mechanisms underlying cigarette smoke-induced lung emphysema and to search new compounds with a potential therapeutic activity. Several murine models of lung emphysema were used to mimic the pathological changes that are observed in COPD patients. The cascade of events leading to the development of lung emphysema will start with cigarette smoke exposure. Cigarette smoke exposure can stimulate epithelial cells, alveolar macrophages, neutrophils and B cells to release inflammatory mediators, including interleukin-8 (IL-8, CXCL8), adenosine-5'-triphosphate (ATP) and immunoglobulin free light chains (IgLC). These mediators have the capacity to attract and/or activate neutrophils. Subsequently, activated neutrophils release CXCL8 and different proteases, such as matrix metalloproteinase (MMP)-8 and MMP-9, which can proteolytically cleave collagen to smaller fragments resulting in an optimal substrate for the enzyme prolyl endopeptidase (PE). Various cell types, like neutrophils, macrophages and epithelial cells, express PE. These collagen fragments are then further cleaved to Proline-Glycine-Proline (PGP) by PE. Besides CXCL8, the generated PGP is also chemotactic for neutrophils and this results in an environment of chronic inflammation with proteolytic damage and ongoing PGP formation. Finally, this will lead to alveolar wall destruction (emphysema) and mucus hypersecretion (chronic bronchitis). Different possible treatment interventions were found to tackle the ongoing inflammation observed in COPD patients. First, a significantly decreased neutrophil influx in the BALF of smoke-exposed mice was observed after treatment with the IgLC antagonist, F991, the PE inhibitor, valproic acid (VPA) and the PGP antagonist, L-arginine-threonine-arginine (RTR). Secondly, the increased release of CXCL8 and elastase by ATP- or cigarette smoke extract-stimulated human neutrophils was inhibited by treatment with apyrase and suramin. Thirdly, CXCR2 antagonists inhibited the growth-related oncogene (GRO)-alpha (CXCL1)- and PGP-induced neutrophilic inflammation in the murine BALF and lung tissue. Although smoking cessation should be the first step in reducing the progression of lung emphysema, additional medication could be provided to tackle the sustained airway inflammation.