RICERCA ITALIANA     

Pathogenetic mechanisms and clinical manifestations of chronic obstructive pulmonary disease

Università degli Studi di Padova

Abstract

In industrialised countries, chronic obstructive pulmonary disease (COPD) is one of the most important causes of invalidity and mortality and its prevalence is increasing as compared to cardiovascular diseases and cancer. Epidemiological data estimates that by 2020, COPD will rank among the five most common causes of disability worldwide with consequent social and economic impact. COPD is defined as a disease state characterised by not fully reversible airflow limitation that is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, in particular to cigarette smoke. Indeed, cigarette smoke is the major risk factor for the development of COPD. However, only a minority of smokers develop COPD suggesting that additional factors related to the individual or to the environment might be involved in determining individual’s susceptibility to develop the disease. Despite the numerous studies which have endeavored to identify these factors, the pathogenetic mechanisms of COPD are still unknown.
The aim of this project is to identify specific etiopathogenetic factors which may influence the clinical course of COPD (in patients exposed to the same risk factors). Further aims are to investigate the cellular and molecular mechanisms involved in the pathogenesis and in the progression of chronic airflow limitation, focussing in particular on those involved in the parenchymal destruction that characterizes emphyesema. Finally, the correlations between cellular changes and clinical and functional parameters will be analysed in the different clinical phenotypes of the disease: “predominant emphysema”, “predominant bronchitis”, in different stages of severity and in severe COPD requiring lung transplantation. A better understanding of the pathogenetic mechanisms of COPD and the identification of biological markers able to detect among smokers those at risk of developing COPD, will provide a rational basis for monitoring and early treatment in order to prevent or at least slow down the evolution towards chronic respiratory insufficiency.
Given the interdisciplinarity of this project, 4 Research Units have been recruited. Each Unit will focus their research on one specific field. However, the value of this project is the opportunity to share different skills. For example, only with this kind of collaboration could we have the opportunity to unite the collection of precious biological samples such as those from patients undergoing lung transplantation for severe COPD with the skill of advanced molecular technologies. It is important to underline that some Units have been working together for several years as can be inferred from several publications in peer review journals. <<<

Principal Investigator

Marina Saetta Università degli Studi di PADOVA

Research Objectives

COPD is a progressive disease that may become extremely serious and disabling. Presently, in fact, COPD is one of most important causes of invalidity and mortality, and its prevalence is increasing as compared to cardiovascular diseases and cancer. COPD is not a disease entity, but rather a complex of conditions that include emphysema and chronic bronchitis. Even if cigarette smoking is the most important risk factor for the development of COPD, only 15 % of heavy smokers develop the disease, suggesting the presence of factors predisposing to the "susceptibility" to COPD. The pathogenetic mechanisms of the airflow limitation that characterizes COPD are still unknown, even if they have been the object of several studies in recent years. The aim of this project is to identify morphologic alterations and specific etiopathogenetic factors which may influence the clinical course of COPD (in patients exposed to the same risk factors). Further aims are to investigate the cellular and molecular mechanisms involved in the pathogenesis and in the progression of chronic airflow limitation, focussing in particular on those involved in the parenchymal destruction that characterizes emphysema. Finally, the correlations between cellular changes and clinical and functional parameters will be analysed in the different clinical phenotypes of the disease: “predominant emphysema”, “predominant bronchitis”, in different stages of severity and, in particular, severe COPD requiring lung transplantation. A better understanding of the pathogenetic mechanisms of COPD and the identification of biological markers able to detect among smokers those at risk of developing COPD, will provide a rational basis for monitoring and early treatment in order to prevent or at least slow down the evolution towards chronic respiratory insufficiency. <<<

Timescale

24 months

National and international background

According to the most recent guidelines, COPD is defined as a disease state characterised by not fully reversible airflow limitation that is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, in particular to cigarette smoke. Although COPD mainly affects the lungs, it also produces significant systemic consequences (1). Clinically, the principle symptoms of COPD are cough, sputum production and dyspnea. Furthermore, the natural history of the disease is marked by frequent exacerbation associated with infection, which can play an important role in the decline of lung function. The GOLD Guidelines classifies COPD into 5 stages, from 0 to 4, based on the severity of bronchoconstriction (1).
COPD is one of the major causes of invalidity and mortality in industrialised countries and its prevalence is increasing as compared to cardiovascular diseases and cancer. Epidemiological data estimates that by 2020, COPD will rank among the five most common causes of disability worldwide with consequent social and economic impact (2).
Cigarette smoking is the major risk factor for the development of COPD. However, since in a population of heavy smokers, only 15% of subjects develop COPD, it is possible that additional factors might be involved in determining individual's susceptibility to develop airflow limitation. These include genetic predisposition or environmental conditions (viral and bacterial infections). COPD is not a disease entity, but rather a set of conditions that contribute to airflow limitation. These conditions include emphysema, pathologically defined by the destruction of alveolar wall and enlargement of airspaces, and chronic bronchitis clinically defined by symptoms of chronic cough and sputum production (2). As it has been recently emphasized, the current tendency to lump a variety of conditions under the acronym COPD potentially blurs important distinctions that could be useful in clinical practice to improve the understanding of the natural history of the disease and to focus treatment strategies for different COPD phenotypes (3,4).
Laennec gave us the first anatomic description of emphysema in 1826 (5). He also recognized that airflow obstruction and symptoms of chronic bronchitis were the functional and clinical correlates in life of the pathological finding of emphysema at autopsy (5). Within a few years arguments began as to whether airflow limitation was always caused by emphysema or whether disease of the conducting airways without emphysema could also cause airflow obstruction. We are still concerned with this question.
As the flow is the result of a driving pressure (elastic recoil of the lung) and of an opposing resistance (airway obstruction) a reduction in flow may be due both to a reduced elastic recoil of the lung or to an increased resistance. A reduced elastic recoil of the lung is mainly due to parenchymal destruction that characterizes emphysema while an increased resistance is mainly due to peripheral airway inflammation. Therefore, parenchymal destruction and inflammation of the airways are the main alterations responsabile for airflow limitation in COPD (6).
The role of symptoms of chronic bronchitis in the development of chronic airflow limitation is still controversial (7-9). In fact, chronic sputum production has traditionally been considered to be irrelevant to the development of chronic airflow limitation (7,8). However, it has been shown that in patients with airflow limitation, chronic sputum production was significantly associated with an excess of FEV1 decline (8,9). It is therefore possible to hypothesize that chronic sputum production may not be determinant for the development of the disease, but it may play a role in its progression.
Forty years ago, Burrows and colleagues described the distinctive clinical, functional, and pathologic characteristics of the emphysematous and bronchitic types of patients with chronic airway obstruction (10). They found that patients with gross emphysema at autopsy had, in vivo, typical radiographic findings of emphysema, progressive dyspnea, relatively mild bronchitis, and absence of heart failure; PaCO2 could be normal or low at rest, no cyanosis was present, the diffusing capacity was notably impaired, and the total lung capacity could be increased. Patients with relatively minor or absent emphysematous destruction at autopsy, had, in vivo, a long history of chronic productive cough with radiographic changes suggestive of previous inflammatory lung disease. A recent study was undertaken to ascertain whether COPD patients had distinct functional, radiological, and sputum cell characteristics depending on the presence or the absence of emphysema on high resolution computed tomography (HRCT) of the chest (11). The Authors found that in subjects with documented emphysema chest x-ray score of emphysema was higher, chest x-ray score of chronic bronchitis was lower (11), and the number of lymphocytes in induced sputum was increased (12). In recent years, it has been shown that COPD patients with a clinical diagnosis of chronic bronchitis had on HRCT both an increased percentage of bronchial wall area and an increased bronchial wall thickness-to-diameter ratio with respect to COPD patients without clinical findings compatible with a diagnosis of chronic bronchitis (13). Patients without a clinical history of chronic bronchitis were more obstructed, hyperinflated, and had lower diffusing capacity than COPD patients with a clinical history of chronic bronchitis (13). A high correlation was found between bronchial wall changes and functional indexes of obstruction in patients with chronic bronchitis, but not in COPD patients who did not have clinical findings compatible with chronic bronchitis (13). These data support the hypothesis that the site of airflow obstruction is mainly in the conductive airways in patients with predominant chronic bronchitis, while it is mainly in the peripheral respiratory airways in patients with predominant emphysema.
The pathogenesis of parenchymal destruction that characterizes emphysema remains enigmatic, although a mechanism involving a protease-antiprotease imbalance is widely supported (14). Proteases, such as neutrophil elastase, are proteolytic enzymes able to degrade lung connective tissue. In physiological conditions, to avoid an excessive destruction in lung tissue, the protease activity is counterbalanced by antiproteases and, in particular, by alpha1-antitripsin. This hypothesis is based on the observation that in some patients, emphysema is associated with deficiency of alpha1-antitripsin, but epidemiological studies have shown that the deficiency of alpha1-antitripsin is present in only 1% of patients with COPD. This observation suggests that other proteases or antiproteases may be involved in parenchymal destruction and metalloproteinases (MMP), in particular, seem to play a crucial role (14).
Metalloproteinases are a large family of proteolytic enzymes that can degrade most of components of the extracellular matrix. They are synthesized in an inactive form and are subsequently activiated by extracelluar proteolysis mediated by other active MMPs or by serine proteases. Once activated, MMPs are inhibited by specific inhibitors called tissue inhibitors of metalloproteinases (TIMP)(15). Recent studies suggest that matrix metalloproteinases are the major proteolytic enzymes involved in the pathogenesis of COPD. Increased levels of MMP-1 and MMP-9 have been detected in bronchoalveolar lavage fluid of patients with emphysema (16-18). In bronchoalveolar lavage fluid of smokers with emphysema, an increase of collagenolytic activity, probably due to elevated levels of MMP-8, is measured (19). Experimental data show that MMP-12 gene deletion in mice protects from the development of emphysema after long term exposure to cigarette smoke (20, 21). These studies show that an increase in the concentration of proteases may have a crucial role in the development of pulmonary emphysema and may lead to an increase of lung tissue degradation products. Recently, the investigation of the protein content of a biological system, i.e. proteomics, has been used for the study of specific diseases, including chronic inflammatory diseases of the lung (22).
The COPD clinical course is progressive and often irreversible, usually unresponsive to medical treatment and lung transplantation remains the only therapeutic option. Small airways and parenchymal epithelium may play an important role in COPD development and progression, and also in its neoplastic evolution. There is evidence in the literature of in vitro and in vivo models where alveolar epithelium is widely damaged also at the end-stage phase of the disease, when the increasing apoptosis is not balanced by increasing proliferation (23). It is not known which cytokines or growth factors are actually involved in the apoptosis/proliferation imblance, even if experimental model have shown the developement of emphysema in animal models with decreased of the receptor of vascular endothelial growth factor (VEGF) (24). The investigation of the molecular substrates which allow the progression towards dysplasia/neoplasia is particularly interesting. Many different factors regulate epithelial proliferation and the balance between proliferation/antiproliferation factors is a key point in cellular homeostasis. Therefore, COPD and lung cancer share tobacco smoking as common risk factor, through which they may also share similar pathogenetic mechanisms. A well defined progression of smoking associated pathological changes occurs in the bronchial epithelium before the development of squamous cell carcinoma. It can be speculated that progression could be facilitated in smokers who develop COPD because of their impaired clearence of carcinogenic substances resulting from chronic airflow limitation. A newly described protein, the Squamous Cell Carcinoma Antigen (SCCA) is a well known tumor-associated protein and it is used as a serum marker for squamous cell carcinoma. SCCA is considered to inhibit tumor necrosis factor (TNF)-alpha (over-expressed in COPD patients) mediated cell death (25). Information on the inhibitory effect of SCCA on the cell death signaling pathway might be useful in developing new terapeuthic strategies for SCCA (26). <<<