IDIOPATHIC PULMONARY FIBROSIS: NEW CONCEPTS IN PATHOGENESIS AND IMPLICATIONS FOR DRUG THERAPY

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal pulmonary disease for which there are no proven or approved drug therapies. Anti-inflammatory and immunosuppressive agents have been largely ineffective. The precise relationship of IPF to other idiopathic interstitial pneumonias (IIPs) is not known, despite the observation that different histopathological patterns of IIP may co-exist in the same patient. We propose that these different histopathological “reaction” patterns may be determined by complex interactions between host and environmental factors that alter the local alveolar milieu. Recent paradigms in IPF pathogenesis have focused on dysregulated epithelial-mesenchymal interactions, an imbalance in TH1/TH2 cytokines and potential roles for aberrant angiogenesis. In this review, we discuss these evolving concepts in disease pathogenesis and emerging therapies designed to target pro-fibrogenic pathways in IPF. CLINICAL EVALUATION AND DIAGNOSTIC APPROACH TO IPF Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive parenchymal lung disease with a median survival of less than three years following diagnosis, although the clinical course can be highly variable (1,2). No pharmacologic therapies have proven effective for this disorder (3). IPF is the most common of the idiopathic interstitial pneumonias (IIPs, Figure 1) with a prevalence of 13−20 per 100,000 people in the general population (3,4). It is more common in men than women and its prevalence increases with age (3,4). Predictors of a worse outcome include progressive dyspnea, oxygen desaturation during the 6-minute walk (5), worsening pulmonary function and gas-exchange (6,7), the presence and extent of honeycombing on highresolution computed tomography (HRCT) (8), and the presence of pulmonary hypertension (2,9). The diagnosis of IPF is based on clinical, radiographic and histopathologic evaluations (3). Common clinical features consist of progressive dyspnea, dry cough and the presence of basilar “velcro-like” rales on examination. Digital clubbing and clinical signs of cor-pulmonale may be present. Extrapulmonary signs/symptoms are usually absent, while constitutional symptoms such as fatigue and malaise may be noted. Secondary causes of pulmonary fibrosis such as collagen-vascular disease, chronic hypersensitivity pneumonitis, adverse drug reactions, granulomatous diseases and pneumoconiosis must be excluded. More recently, HRCT has taken a more prominent role in the diagnosis of IPF and can help distinguish IPF from other IIPs (10). A patchy pattern of peripheral, subpleural and predominantly lower lobe reticular opacities combined with honeycombing, traction bronchiectasis and the absence of significant ground glass opacities together constitute the classic radiographic features of IPF. The presence of these features on HRCT, when reported by an experienced chest radiologist, correlates well *Address correspondence to: Victor J. Thannickal, M.D. Division of Pulmonary and Critical Care Medicine University of Michigan Medical Center 6301 MSRB III 1150 W. Medical Center Dr. Ann Arbor, Michigan 48109 United States of America Phone: 734−936 −9371 Fax: 734−764−4556 e-mail: vjt@umich.edu. NIH Public Access Author Manuscript Treat Respir Med. Author manuscript; available in PMC 2008 February 6. Published in final edited form as: Treat Respir Med. 2006 ; 5(5): 325–342. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript with the histologic pattern of usual interstitial pneumonia (UIP) on surgical lung biopsy (11, 12). Thus, classic radiographic findings in the context of an appropriate clinical presentation may abrogate the need for a surgical lung biopsy; however, a bronchoscopy with transbronchial biopsy may be advisable in this setting, primarily to exclude infection and malignancy. In the absence of typical clinical and radiographic features, a surgical lung biopsy is recommended for the definitive diagnosis of IPF. Diagnostic accuracy may be improved if biopsies are obtained from multiple lobes, as recent studies have shown that several distinct histopathologic patterns may co-exist in the same patient and the presence of UIP on any biopsy confer a worse prognosis (13). Histopathologic features of UIP include patchy areas of fibrosis in association with areas of normal lung architecture, the so-called “temporal” heterogeneity of UIP. Mild inflammatory cell infiltration may be present in UIP, but is not a prominent feature. Fibroblastic foci, consisting of aggregates of myofibroblasts underlying “injured,” reparative epithelium, are key histologic features of IPF (14). The presence and extent of fibroblastic foci, while not pathognomonic, are of prognostic value in IPF as the profusion of these lesions correlates with a worse prognosis (15).