Pathogenesis of chronic obstructive pulmonary disease

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Adres do korespondencji:

Adres do korespondencji: prof. Steven I. Renard M.D., University of Nebrasca Medical Center, Omaha, NE, e-mail: srennard@unma.edu Praca wpłynęła do Redakcji: 6.12.2010 r.

Stephen I. Rennard

University of Nebraska Medical Center, Omaha, NE

Pathogenesis of chronic obstructive pulmonary disease

Patogeneza przewlekłej obturacyjnej choroby płuc

Abstract

Current concepts suggest that COPD largely results from tissue injury, most commonly consequent to an exposure, the most important of which is cigarette smoke. This injury is mediated by a complex network of inflammatory cells and mediators, and it is likely that heterogeneity in the inflammatory response accounts for some of the variable susceptibility to develop COPD and for the some of the clinical heterogeneity of the disease. Mechanisms that can prevent tissue injury are also diverse and are inhibited to varying degrees among individuals with COPD. Finally, the alterations in tissue structure that compromise function depend not only on tissue injury, but also on tissue repair, which can either mitigate or exacerbate lung function loss depending on whether repair processes are effective or disruptive.

Pneumonol. Alergol. Pol. 2011; 79, 2: 132–138

Streszczenie

Współczesne poglądy na patogenezę POChP sugerują, że choroba jest spowodowana uszkodzeniem płuc najczęściej spowodowanym przez dym tytoniowy. Uszkodzenie płuc następuje w wyniku złożonego współdziałania komórek zapalnych i mediatorów zapalenia. Jest prawdopodobne, że różnorodność odpowiedzi zapalnej na dym tytoniowy jest odpowiedzialna za zmienną podatność na rozwój choroby a także różnorodność obrazu klinicznego. Mechanizmy chroniące płuca przed uszkodzeniem są też różnorodne i są w różnym stopniu zahamowane u indywidualnych chorych. Ostatecznie, anatomiczne uszkodzenie płuc, które upośledza czynność płuc zależy nie tylko od procesów niszczenia lecz także od procesów naprawczych w płucach, które mogą chronić czynność płuc lub nasilać zaburzenia, w zależności czy procesy naprawcze są skuteczne czy nasilające uszkodzenie.

Pneumonol. Alergol. Pol. 2011; 79, 2: 132–138

Introduction

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide [1]. The most important cause is cigarette smoking, and studies over the last sixty years have outlined the mechanisms by which smoke exposure can lead to disease [2]. COPD is also recognized as being markedly heterogeneous [3, 4], and it is likely that this is due to multiple pathogenetic mechanisms having different roles in individual patients [2]. It is hoped that understanding the pathogenesis of COPD will lead to novel

therapies and that understanding the mechanisms important in individual patients will allow these therapies to be used selectively [3, 4]. This review will provide an overview of COPD pathogenesis with some emphasis on the newer concepts that altered tissue repair can play a key role.

Historical concepts

Historical concepts of COPD pathogenesis were centered on physiological mechanisms.

COPD is defined by airflow limitation, but this can result from disease of either the airways or the

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macrophages that are resident in the lung, smoke can initiate the release of a variety of chemokines.

These, in turn, can mediate the recruitment and activation of inflammatory cells. Lung cells can also release growth factors that act on bone mar- row to increase the production of inflammatory cells. A number of factors capable of mediating the recruitment of neutrophils, monocyte/macrophages and lymphocytes have all been reported in this regard. In addition, mediators capable of recruiting inflammatory cells can also be generated from de- gradation products of extracellular matrix. This suggests that inflammation, by inducing tissue damage, could initiate a persistent “vicious circle.”

The relative importance of the various factors that can recruit inflammatory cells is not established. Interleukin (IL)-8, which is induced by smoke and increased in the lungs of smokers and COPD patients, has attracted considerable attention [2, 11, 12]. A pilot clinical trial with an anti-IL-8 antibody, however, improved dyspnea, but did not al- ter lung function. The lack of a dramatic effect supports the concept that multiple mediators may modulate inflammatory cell recruitment and im- plies that therapies targeting a specific mediator may not be effective, although this trial did not directly assess inflammation.

In addition to activating cellular inflammatory responses, cigarette smoke can also activate humoral inflammation mediated by complement.

Smoke activates complement [13] and leads to the generation of C5a, a potent chemotactic factor [14]. The activity of C5a is greatly potentiated by a co-factor, Gc-globlulin, also known as vitamin D binding protein [15]. This, in turn, is blocked by the protein chemotactic factor inhibitor (CFI).

Smoke can inhibit the activity of CFI, thus leading to unopposed Gc-globulin potentiated C5a chemotaxis [16].

Inflammatory mediators and tissue damage The concept that neutrophil elastase mediates tissue damage has been greatly expanded [2].

The neutrophil produces two serine proteases in addition to elastase, and all three can cause emphysema in model systems. In addition, neutrophils produce several mediators in the other major classes: matrix metalloproteases (MMPs) and cystein proteases, and these can also result in tissue damage and emphysema. Other inflammatory cells produce their own sets of secreted proteases and, as a result, there is a large number of proteases likely present in the lower respiratory tract of smokers and COPD patients that can cause tissue damage. In addition, proteases likely contribute to pulmonary parenchyma [5]. The degree to which

these different sites are involved can vary markedly from patient to patient. Disease of the large airways results in chronic cough with sputum production and disease of the small airways causes airflow limitation [2]. Disease of the pulmonary parenchyma that results in loss of alveolar tissue with enlargement of airspaces, i.e. emphysema, may or may not be associated with airflow limitation [5].

Orie and colleagues from the Netherlands pro- posed the idea that asthma, through the chronic effects of airways hyper-reactivity, could lead to fixed narrowing of the airways and airflow obstruction [6]. This concept was contrasted with the idea that airways infection leads to mucus hypersecretion, which, over time, leads to airflow obstruction [7]. Both concepts have become more complex over time, and current data suggests that both “pathways” contribute to airflow limitation [2].

Laurell and Erickson described that emphysema occurs among individuals deficient in the cir- culating serine protease inhibitor alpha 1 anti-trypsin [8]. This led to the concept that imbalance between protease production and anti-protease protection leads to tissue destruction. About the same time, Liebow suggested that failure to maintain an adequate pulmonary capillary bed should lead to loss of alveolar wall and the development of emphysema [9]. A large body of data now supports the general concept of an imbalance between mediators that damage tissue and defense mechanisms that provide protection, and a growing body of evidence supports the concept that failure of tissue maintenance and repair also contribute to emphysema.

Importantly, current concepts, which are ba- sed on the cellular and biochemical pathways involved, suggest that shared mechanisms contribute to disease pathogenesis at different sites and help explain the overlap among the historical hy- potheses.

Cigarette smoke and inflammation Cellular recruitment and activation

The concept that elastase released from neutrophils exceeded the protective effect of alpha 1 anti-trypsin and resulted in tissue damage led to many studies of inflammation and inflammatory mediators in the lungs of COPD patients and in response to cigarette smoke. Smoke, which contains as many as 6,000 molecular entities, can initiate an inflammatory response in a number of ways [2, 10]. By interacting with the epithelial cells that line the airways and alveoli as well as the

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COPD pathogenesis by activating cells. Neutrophil elastase, for example, is an extremely potent stimulus for mucus release and induces goblet cell metaplasia in the airways [17–19]. Thus, proteases may play a pathogenetic role in airways disease as well as emphysema.

In addition to the release of proteases, inflammatory cells can induce tissue damage through the release of both active oxidants and toxic peptides [2]. The oxidative stress induced by smoke, in particular, has been shown in a number of model systems to lead to changes that resemble COPD. In addition, the lower respiratory tract of patients with COPD shows signs of oxidative stress [20].

Treatment with anti-oxidants, however, has had limited success [21]. As with proteases, the lung contains a number of endogenous anti-oxidants.

How the balance among the various oxidant and anti-oxidant species present in the lung contribu- tes to the pathogenesis of COPD is an area of active research.

Inflammatory cells also produce peptides that can damage lung cells. These include peptides that have non-specific toxicity such as defensins and granzyme B [22] as well as small molecules such as ceramide [23] that can induce cellular apoptosis. By inducing cell damage, these mediators may lead to the development of emphysema.

In addition to stimulating the recruitment and activation of inflammatory cells, smoke can also shift the protease burden of the lung by inactiva- ting anti-proteases and anti-oxidants. Alpha 1 anti- trypsin, which also inhibits the activity of defensins, for example, is inactivated by cigarette smoke [2, 24]. Neutrophil elastase can degrade TIMP- 1, a major inhibitor of MMPs [2]. Thus smoke, by inactivation of alpha 1 anti-trypsin, could cause excess elastase burden that, in turn, will reduce levels of MMP1, which will result in less inhibi- tion of MMP activity. Because of the multiple in- teractions among the various protease cascades, cigarette smoke can lead to a variety of proteolytic activities.

Other inflammatory etiologies of COPD Cigarette smoking is the most important cau- sative factor for COPD. However, many factors in addition to smoke can also contribute. Other exposures such as environmental or indoor air pollu- tion or a work enviroment with dusts or fumes have been well documented to contribute to COPD [10].

These exposures likely activate similar pathogenetic mechanisms as does cigarette smoke.

It is likely that other risk factors also lead to excess lung inflammation. Asthma, for example,

can progress to fixed airflow limitation even in the absence of smoking [25]. It has been suggested that airway remodeling consequent to the airway inflammation that characterizes asthma is the prime mechanism for this process.

Persistence of inflammation

A major feature of COPD is that, once established, the disease progresses despite removal of the inciting stimulus. Thus, smoking cessation slows the progressive loss of lung function, but the effect is greatest when cessation occurs in the presence of mild disease [26, 27]. Moreover, inflammation in the lower respiratory tract is similar among current and ex-smokers [28]. Among nor- mal smokers, cessation results in a resolution of lower respiratory tract inflammation over a number of months [29, 30]. In contrast, inflammation persists, though the relative distribution of inflammatory cells may change when a patient with COPD quits smoking [31]. This suggests that mechanisms that lead to persistent inflammation are present in COPD. Chemotactic recruitment of inflammatory cells by peptides derived from extracellular matrix, which in turn result from the ac- tion of inflammatory proteases, has been suggested as one mechanism [32–34].

Auto-immune mechanisms may also contribute to COPD. There is an increase in lymphocytes in the lungs of COPD patients, in particular CD8 lymphocytes [35]. In addition, an increased population of lymphocytes that are activated by elastin fragments suggests that there may be sensitization to auto-antigens in COPD [36].

Variable susceptibility

There is marked individual sensitivity to exposures. Thus, only about half of smokers will develop COPD [37]. While the reasons for this individual susceptibility are not established, it is likely that both genetic and environmental factors contribute. In this context, a number of genetic factors have been suggested to be related to COPD through a variety of studies [38]. Interestingly, a large number of these are related to the inflammatory response. This suggests the concept that individual heterogeneity in the inflammatory response can contribute to the heterogeneity in sensitivity to smoke and other exposures.

Diet has also been suggested to contribute to COPD risk, though estimating dietary exposures over the long time frames during which COPD de- velops is difficult. Nevertheless, it is possible that dietary differences also contribute to the varied susceptibility to develop COPD [39].

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Other risk factors

There are several risk factors for COPD in addition to exposure and conditions that are belie- ved to induce lung inflammation. Low birth we- ight, for example, is associated with low lung function and increased risk of COPD in adulthood [40].

In animal models, conditions that lead to abnormal lung development and growth can result in emphysema [2]. This suggests that structural alterations of the lung can also contribute to the development of COPD.

Tissue maintenance and COPD

The concept that inadequate tissue maintenance can lead to the development of COPD was suggested by Liebow [9]. Evidence for this hypothesis was provided by Kasahara and colleagues who demonstrated that antagonism of vascular endothelial growth factor (VEGF), a growth factor for endothelial cells, leads to endothelial cell apoptosis and emphysema in an animal model [41].

Interestingly, this occurs in the absence of obvio- us inflammation. Kasahara and colleagues also demonstrated reduced levels of VEGF and increased apoptosis in the lungs of COPD patients [42].

A number of other investigators have confirmed the presence of apoptotic cells in the lungs of COPD patients [43, 44]. In addition, several groups have shown that induction of apoptosis can cause emphysema. Yoshida and colleagues have provided a link with cigarette smoking by demonstrating that smoke, likely via oxidants, leads to activation of the intracellular stress response protein Rtp801 that, in turn, inhibits a pathway that drives VEGF production in epithelial cells. This suggests a mechanism whereby smoke could lead to inadequate endothelial cell maintenance [45].

Repair

All tissues, including those of the lung, are capable of repair to some degree. The loss of lung tissue that defines emphysema, therefore, repre- sents a balance between tissue injury and tissue repair. In this regard, smoke can inhibit repair processes mediated by both epithelial cells and fibroblasts [46–48].

The parenchymal cells present in the lung in COPD appear to have abnormal repair functions.

Fibroblasts cultured from the lung parenchyma of patients with COPD proliferate more slowly than controls [49, 50] and are more sensitive to inhibi- tion by smoke [51]. Cells from COPD patients are also less robust in chemotactic migration and in contraction of collagenous extracellular matrix [52], which appears to be mediated, at least in part,

by reduced sensitivity to transforming growth factor-b (TGF-b), which generally induces fibroblast- mediated repair functions and by an over production of prostaglandin (PGE), which inhibits fibroblast-mediated repair. Fibroblasts from the lungs of COPD patients also under-produce elastin [53]

and a number of mediators of repair, including hepatocyte growth factor, keratinocyte growth factor [54] and fibronectin [52].

The mechanisms that lead to abnormal repair in the lung are unclear. However, it is of interest that the second largest group of genes associated with COPD are genes that are involved in repair responses (Table 1) [38]. In addition to genetic pre- disposition, an accelerated aging phenomenon has been suggested to play a role [55, 56]. In this context, aging of the lung is associated with an enlargement of airspaces that differs from COPD-associated emphysema and has been termed senile emphysema [57]. Aged animals, however, appear to be particularly susceptible to injury, and this may be a consequence of deficient repair. In this context, increased expression of markers of senescence has been reported in cells obtained from COPD patients, including lung fibroblasts [58, 59].

Fibrosis and COPD

While loss of repair function is a plausible mechanism that can lead to emphysema, COPD is also associated with lung fibrosis [35]. The most important lesion in the small airways associated with loss of airflow is fibrosis and narrowing. This is consistent with other fibrotic tissues where tissue contraction is a regular feature. The production of mediators of fibrosis, including TGF-b and fibronectin, by airway epithelial cells in response to injury has been suggested as a mechanism leading to airway fibrosis [60–62]. In addition, the collagen content of the pulmonary parenchyma is increased in mild emphysema [63]. This suggests the activation of repair mechanisms that may be, to some degree, overly robust.

Increased and decreased repair and cigarette smoke

Fibroblasts cultured from fibrotic tissues, including those of the lung, have been demonstrated to have increased “repair” functions compared to fibroblasts from controls [64, 65]. Interestingly, cigarette smoke exposure is a risk factor not only for COPD, but also for idiopathic pulmonary fibrosis. Kanaji and colleagues (submitted) have recently suggested a mechanism that can account for these disparate effects. Chronic smoke exposure can result in cellular senescence. As noted above,

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cells with increased markers of senescence are present in the lungs of patients with COPD, and the associated loss of function and reduced repair could contribute to the development of emphysema [55, 56]. However, in in vitro experiments, not all cells in a population undergo senescence following smoke exposure [66]. The “resistant” cells remain capable of growth. Interestingly, they grow faster and manifest more robust repair responses than controls, which resembles “fibrosis” cells. This suggests a mechanism: smoke induces senescence, which has been suggested as a protective mechanism to prevent injured cells from replicating and disrupting tissue function. Some cells, and the number may vary among individuals, acquire re- sistance to undergo senescence, and the “escaped”

cells can mediate fibrosis. A variable sensitivity to smoke-induced senescence between airway and alveolar fibroblasts could account for concurrent airway fibrosis and alveolar emphysema.

Therapeutic implications

Understanding the pathogenetic mechanisms that lead to COPD is hoped to lead to novel therapeutic strategies. Early studies identified important mediators such as IL-8 and tumor necrosis factor a (TNF-a). Clinical trials antagonizing these mediators, however, did not show clinical benefits although modest effects antagonizing IL-8 are not exc- luded [67, 68]. As a result, the concept of redun- dant signaling has emerged, which has led to therapeutic strategies that act broadly. These include agents that are in clinical trials including: inhibitors of the kinase P-38, which appears to play a central signaling role for many inflammatory pathways; blockers of the chemokine receptor CXCR2, which mediates the response of neutrophils to many chemotactic signals; and inhibitors

of phosphodiesterase 4, which inhibits the degra- dation of cAMP levels in many inflammatory cells and thereby reduces inflammation. One member of the last family, roflumilast [69, 70] has recently been approved as a therapy for COPD.

Repair of the lung is also a reasonable goal.

Retinoic acid, which stimulates alveolar wall growth in neonatal animals [71], was shown to sti- mulate repair of alveolar wall in emphysema in animal models. Two clinical trials in COPD patients with all-trans retinoic acid were without benefit [72, 73]. However, trials with an agonist selective for the RAR-g receptor, which appears to mediate the repair response, have been initiated.

Similarly, trials with stem cell infusions have been undertaken.

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SERPINA3 SOD3 TGFB1 TIMP2 TVF GSTM1 GSTT ADAM33 TLR4

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