Idiopathic Pulmonary Fibrosis: Prevailing and Evolving Hypotheses about Its Pathogenesis and Implications for Therapy

Idiopathic pulmonary fibrosis is a specific form of chronic fibrosing interstitial pneumonia limited to the lung. Although its cause remains unknown, advances in cellular and molecular biology have greatly expanded our understanding of the biological processes involved in its initiation and progression. Recently, an international consensus statement defining the diagnosis, evaluation, and treatment of patients with idiopathic pulmonary fibrosis was produced as a collaborative effort by the American Thoracic Society, the European Respiratory Society, and the American College of Chest Physicians (1). The purpose of the consensus statement was to assist clinicians in the diagnosis and management of idiopathic pulmonary fibrosis. We provide a focused update of the pathogenesis of this disease and discuss the therapeutic implications of these findings. In particular, we examine the hypothesis that idiopathic pulmonary fibrosis is a fibrotic rather than an inflammatory disease. Methods We reviewed the epidemiologic characteristics, clinical behavior, pathogenesis, experimental models, and treatment of idiopathic pulmonary fibrosis. By searching MEDLINE, we identified articles published from 1965 to 2000. The following search terms were used: idiopathic pulmonary fibrosis, alone and with epidemiology, computed tomography, HRCT, bronchoalveolar lavage, prognosis, prognostic factors, pathogenesis, fibroblasts, myofibroblasts, epithelial cells, macrophages, neutrophils, eosinophils, coagulation, collagen, collagenase, metalloproteinases, TIMP, basement membrane, therapy, treatment, review. Pulmonary fibrosis was used alone, with the same mentioned key words, and with transgenic mice, experimental models, bleomycin, and silica. Other terms were usual interstitial pneumonia, nonspecific interstitial pneumonia, BOOP, organizing pneumonia, desquamative interstitial pneumonia, and idiopathic interstitial pneumonias. The reference lists of identified articles and additional sources, such as textbook chapters and meeting abstracts, were reviewed for relevant publications. All of the included papers were peer-reviewed. Data were also extracted from results of unpublished studies conducted by the National Institute of Respiratory Diseases, Mexico; the Faculty of Sciences, National Autonomous University of Mexico; and the National Jewish Medical and Research Center, Denver, Colorado. Epidemiologic and Clinical Characteristics Patients with idiopathic pulmonary fibrosis are usually between 50 to 70 years of age at presentation; two thirds are older than 60 years of age (2). The estimated annual incidence is 7 cases per 100 000 for women and 10 cases per 100 000 for men (3). The incidence, prevalence, and death rate increase with age (3-5). Cigarette smoking has been identified as a potential risk factor for this disease (6). Although other risk factors have been suggested, the studies attempting to define them have often examined unconfirmed cases of idiopathic pulmonary fibrosis (7-13). Several viruses have been implicated in pathogenesis, but no clear evidence points to a viral cause (14-24). In general, evidence of predisposing or etiologic factors is weak, and most patients do not have any obvious risk factors. Familial cases of pulmonary fibrosis provide compelling evidence for participation of genetic factors, but no specific genetic abnormality has been identified (25-38). Most patients have symptoms for more than 6 months before diagnosis (average duration, 24 months). The clinical manifestations include dyspnea on exertion, nonproductive cough, and inspiratory crackles, with or without digital clubbing noted on physical examination. Chest radiography and high-resolution computed tomography typically show patchy, predominantly peripheral, subpleural, lower lung zone reticular opacities (1, 39). High-resolution computed tomography also shows variable but limited ground-glass opacity (usually associated with traction bronchiectasis) and subpleural honeycombing. Confluent alveolar opacities, evidence of pleural disease, or lymphadenopathy suggest another diagnosis (39-43). Pulmonary function tests reveal restrictive impairment, reduced diffusing capacity for carbon monoxide, and arterial hypoxemia exaggerated or elicited by exercise (44-49). The definite diagnosis of idiopathic pulmonary fibrosis requires a compatible clinical history, the exclusion of other known causes of interstitial lung disease (such as drug injuries, environmental exposures, or collagen vascular disease), and a surgical lung biopsy showing usual interstitial pneumonia (1). Previously, pathologists included several histopathologic patterns among the cases labeled as usual interstitial pneumonia, especially desquamative interstitial pneumonia, nonspecific interstitial pneumonia, and bronchiolitis obliterans organizing pneumonia. However, the histopathologic definition for usual interstitial pneumonia has narrowed and excludes these patterns (1, 50, 51). The histologic hallmark of usual interstitial pneumonia is a heterogeneous appearance at low magnification with alternating areas of normal lung, interstitial inflammation, fibroblastic foci, dense fibrosis, and honeycomb change. These histopathologic changes affect the peripheral subpleural parenchyma most severely. Prevailing Hypothesis: Inflammation Leads To Fibrosis It has been widely held that a common pathogenetic sequence underlies all fibrotic lung diseases, regardless of cause. This inflammatory fibrosis hypothesis asserts that chronic inflammation injures the lung and modulates fibrogenesis, leading to the end-stage fibrotic scar (52). Several of the key concepts that formed the basis for this hypothesis no longer seem valid. Inflammation Is Not a Prominent Histopathologic Finding in Usual Interstitial Pneumonia A major driving force sustaining the inflammatory fibrosis theory for usual interstitial pneumonia was the commonly held view that desquamative interstitial pneumonia, a predominately intra-alveolar macrophage accumulation (that is, alveolitis), was the earliest lesion in this disorder (52, 53). However, desquamative interstitial pneumonia is a nonspecific response to cigarette smoke (54, 55). Alveolar septa may be thickened by a sparse inflammatory infiltrate; however, this lesion rarely contains fibroblastic foci or the extensive fibrotic pattern common in usual interstitial pneumonia. Consequently, given that most patients with idiopathic pulmonary fibrosis are current or former cigarette smokers, intra-alveolar macrophage accumulation is to be expected and probably does not play a key role in pathogenesis. Most important, little evidence supports the concept that inflammation is more prominent in early stages of usual interstitial pneumonia. Careful review of larger numbers of better defined cases shows that the inflammatory component is usually mild, occurs mainly in areas of collagen deposition or honeycomb change, and rarely involves otherwise unaltered alveolar septa (50). Finally, interstitial lung diseases in which inflammation is a prominent feature of early diseasefor example, hypersensitivity pneumonitisoften do not progress to end-stage fibrosis. Inflammation Is Not Required for the Development of a Fibrotic Response Some evidence, primarily from transgenic animals, shows that it is possible to dissociate the inflammatory response from the fibrotic response. Interleukin-10deficient mice instilled with silica showed greater lung inflammation but less fibrotic response than wild-type mice (56). Munger and colleagues (57) demonstrated in bleomycin lung injury that mice deficient in the integrin v6 (6/), a ligand that binds and activates transforming growth factor-, developed exaggerated inflammation but were protected from pulmonary fibrosis. Both the 6/ and 6+/+ mice showed similar levels of total transforming growth factor- protein. Sime and coworkers (58), using two replication-deficient adenoviruses expressing active and latent transforming growth factor- 1, showed that overexpression of both transgenes provoked transient inflammation. However, only the active form induced fibroblast proliferation and progressive extracellular matrix accumulation (58). Adamson and colleagues (59) were able to induce a lung fibrotic response in a blood-free environment. Mice were exposed to 95% hyperoxia, and lung explants were cultured at various stages of hyperoxic injury. As epithelial alveolar damage increased, epithelial cell proliferation in the explants was retarded while fibroblast growth became predominant mainly at areas of epithelial necrosis. Collagen production also increased. It is important to note that these explants had few macrophages and no blood components. Thus, epithelial injury in the absence of ongoing inflammation is adequate to stimulate the development of fibrosis. Clinical Measurements of Inflammation Fail To Correlate with Stage or Outcome in Idiopathic Pulmonary Fibrosis Because alveolitis was presumed to have a central role in the pathogenesis of fibrotic lung diseases, it was believed that methods to determine its character and intensity had to be identified in order to stage and treat patients. However, most markers of inflammation failed to correlate with disease stage or outcome in idiopathic pulmonary fibrosis. Thus, it has been proven that cellular constituents of bronchoalveolar lavage, gallium-67 lung scan and tissue, and circulating immune complexes have rather limited clinical value in staging or monitoring idiopathic pulmonary fibrosis (60-73). High-resolution computed tomography lung scanning has been proposed as a technique to determine the activity of idiopathic pulmonary fibrosis, since it has been shown that the extent and severity of ground-glass opacities correlate with alveolitis in several diffuse infiltrative lung disorders (74). However, in idiopathic pulmonary fibrosis, ground-glass opacities do not show a relationship with the inflammat