Accelerated Variant of Idiopathic Pulmonary Fibrosis: Clinical Behavior and Gene Expression Pattern

Abstract

BackgroundIdiopathic pulmonary fibrosis (IPF) is characterized by the insidious onset of dyspnea or cough. However, a subset of patients has a short duration of symptoms with rapid progression to end-stage disease. In this study, we evaluated clinical and molecular features of “rapid” and “slow” progressors with IPF.Methods and Findings26 patients with <6 months of symptoms before first presentation [rapid progressors] and 88 patients with >24 months of symptoms [slow progressors] were studied. Survival was analyzed by the Kaplan-Meyer method and proportional hazard's model. Lung microarrays and tissue proteins were measured in a subset of patients. No differences were found in age, physiologic impairment and bronchoalveolar lavage (BAL) cellular profile. There were more males (OR = 6.5; CI:1.4-29.5; p = 0.006) and smokers (OR = 3.04; CI:1.1-8.3; p = 0.04) in the rapid progressors group. Survival from the beginning of symptoms was significantly reduced in rapid progressors (HR = 9.0; CI:4.48-18.3; p<0.0001) and there was a tendency for decreased survival from the time of diagnosis (HR = 1.5; CI:0.81-2.87; p = 0.18). We identified 437 differentially expressed genes. Lungs of rapid progressors overexpressed genes involved in morphogenesis, oxidative stress, migration/proliferation, and genes from fibroblasts/smooth muscle cells. Upregulation of two of these genes, adenosine-2B receptor and prominin-1/CD133, was validated by immunohistochemistry and were expressed by alveolar epithelial cells. BAL from rapid progressors showed a >2-fold increase of active matrix metalloproteinase-9, and induced a higher fibroblast migration compared with slow progressors and controls [238±98% versus 123±29% (p<0.05) and 30±17% (p<0.01)].Conclusions/SignificanceA subgroup of IPF patients, predominantly smoking males, display an accelerated clinical course and have a gene expression pattern that is different from those with slower progression and longer survival. These findings highlight the variability in the progression of IPF, and may explain, in part, the difficulty in obtaining significant and reproducible results in studies of therapeutic interventions in patients with IPF.

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

“…end products, as potential regulators of lung fibrosis (6)(7)(8)(9)(10)(11)(12). Additionally, we and others have identified gene expression patterns that distinguish IPF from hypersensitivity pneumonitis, variants of disease that characterize distinct patterns of progression and characterize patients with pulmonary hypertension (9,(13)(14)(15)(16).…”

“…Additionally, we and others have identified gene expression patterns that distinguish IPF from hypersensitivity pneumonitis, variants of disease that characterize distinct patterns of progression and characterize patients with pulmonary hypertension (9,(13)(14)(15)(16). A common limitation to all of these studies was the starting material used for analysis, since the IPF lung is known for its variable involvement and temporal heterogeneity (1).…”

Interstitial lung disease: new challenges and evolving phenotypes

“…Many of the genes with increased expression in IPF encode proteins associated with extracellular matrix formation, cell proliferation, migration, invasion and cell morphology, and proteins expressed in smooth muscle cells [17], reminiscent of that observed in cancer biology [11]. This observation holds true in studies on lungs obtained from patients with the accelerated variant of IPF [18] or acute exacerbation of IPF [19]. It is not clear whether activation of inflammation pathways is not key to the pathogenesis of IPF, or if published genomic studies reflected prominent remodelling in the fibrotic lung while failing to catch more subtle deregulation of other pathways involved in the interplay between injured pneumocytes and myofibroblasts.…”

Idiopathic Pulmonary Fibrosis: Clinical Behavior, Pathogenic Mechanisms and Therapeutic Approach

“…Most patients progress slowly or even remain stable for some time, but some patients deteriorate rapidly, showing an accelerated course of the disease 2,4 . In addition, around 10% of patients present unexpected deterioration with a sudden and acute worsening of symptoms and lung function 5 .…”