Pulmonary fibrosis: patterns and perpetrators

Abstract

Pulmonary fibrosis occurs in a variety of clinical settings, constitutes a major cause of morbidity and mortality, and represents an enormous unmet medical need. However, the disease is heterogeneous, and the failure to accurately discern between forms of fibrosing lung diseases leads to inaccurate treatments. Pulmonary fibrosis occurring in the context of connective tissue diseases is often characterized by a distinct pattern of tissue pathology and may be amenable to immunosuppressive therapies. In contrast, idiopathic pulmonary fibrosis (IPF) is a progressive and lethal form of fibrosing lung disease that is recalcitrant to therapies that target the immune system. Although animal models of fibrosis imperfectly recapitulate IPF, they have yielded numerous targets for therapeutic intervention. Understanding the heterogeneity of these diseases and elucidating the final common pathways of fibrogenesis are critical for the development of efficacious therapies for severe fibrosing lung diseases.

Figure 1. Fibrotic NSIP.

(A) Chest CAT scan from a 60-year-old woman with 6 months of cough, exertional breathlessness, and fatigue. (B) Surgical lung biopsy shows a homogenous pattern of fibrosis and chronic inflammation with a paucity of normal lung. Magnification, ×40. (C) Chest CAT after treatment with a combination of prednisone and mycophenolate mofetil.

Figure 2. Classic usual interstitial pneumonia.

(A) Chest CAT scan demonstrating the cardinal radiographic features of IPF: subpleural honeycombing, traction bronchiectasis, and thickened interlobular septae. (B) Lung biopsy demonstrating the cardinal pathologic manifestations of UIP: a variegated pattern of chronic interstitial fibrosis, subpleural accentuation, and fibroblastic foci. (C) Lung biopsy demonstrating a fibroblast focus without accompanying inflammation. (B and C) Magnification, ×40.

Figure 3. A UIP pattern in the absence of IPF.

(A) Chest CAT scan from a 68-year-old man who presented with cough and exertional breathlessness that demonstrates subpleural reticular opacities but without definitive honeycombing. (B) Surgical lung biopsy revealed a variegated pattern of chronic interstitial fibrosis without microscopic honeycombing but with fibroblastic foci and areas of mononuclear inflammation. Magnification in B, ×40; C is a higher-magnification view of boxed area in B.

Figure 4. Model of the relationship between ER stress and lung fibrosis.

Genetic predisposition such as mutations in surfactant protein genes renders AEC2s vulnerable to environmental insults such as viral infections and cigarette smoking. These insults may result in the accumulation of misfolded proteins in the ER. Persistent injury may lead to ER stress and eventually to epithelial cell apoptosis. However, ER stress leading directly to pulmonary fibrosis in the absence of injury remains to be demonstrated.

Figure 5. Proposed mechanisms of severe lung fibrosis.

Injured AEC2s attempting to repair damage release growth factors, cytokines, coagulants, and other substances. These factors promote mesenchymal expansion and activation, leading to the accumulation of matrix-producing and invasive fibroblasts/myofibroblasts. Figure adapted with permission from the American Journal of Respiratory Cell and Molecular Biology (2).