Growth factors in idiopathic pulmonary fibrosis: relative roles

Abstract

Treatment of idiopathic pulmonary fibrosis patients has evolved very slowly; the fundamental approach of corticosteroids alone or in combination with other immunosuppressive agents has had little impact on long-term survival. The continued use of corticosteroids is justified because of the lack of a more effective alternative. Current research indicates that the mechanisms driving idiopathic pulmonary fibrosis reflect abnormal, dysregulated wound healing within the lung, involving increased activity and possibly exaggerated responses by a spectrum of profibrogenic growth factors. An understanding of the roles of these growth factors, and the way in which they modulate events at cellular level, could lead to more targeted therapeutic strategies, improving patients' quality of life and survival.

Figure 1

Abnormal wound-healing model of idiopathic pulmonary fibrosis pathogenesis. In the model proposed by Selman et al. [10], microinjuries damage the epithelium and cause the release of profibrogenic growth factors and the development of an antifibrinolytic microenvironment that promotes wound clot formation. Proliferating and differentiating fibroblasts migrate through a disrupted basement membrane, secreting extracellular matrix (ECM) proteins and angiogenic factors. An imbalance in matrix-degrading and matrix-enhancing enzymes favours increased deposition of ECM. Myofibroblasts are not removed and they release growth factors that promote epithelial cell apoptosis.

Figure 2

Failure of endogenous regulation of wound-healing in idiopathic pulmonary fibrosis (IPF). Injuries to alveolar epithelial cells (AECs) result in upregulation of growth factor production, including tumour necrosis factor-alpha (TNF-α). Binding of TNF-α to TNF-α receptor (TNF-αR) activates the cyclooxygenase-2 (COX-2) pathway and induces synthesis of prostaglandins including prostaglandin E₂ (PGE₂) and 6-keto-prostaglandin F_1α (PGF_1α). Prostaglandins exert negative feedback control of AEC TNF-α expression and autocrine inhibition, through raised intracellular cAMP levels, of the connective tissue growth factor (CTGF) response to transforming growth factor-β. This results in limited and healthy wound healing, and prevents further progression to fibrosis. In IPF, however, myofibroblasts exhibit marked deficiencies in TNF-α receptor expression and COX-2 induction that result in reduced synthesis of prostaglandins, and a failure in the normal self-limiting wound-healing response (broken arrows), ultimately leading to fibrosis. PRs, prostaglandin receptors.

Figure 3

Potential growth factor-mediated antifibrotic strategies. A universal cell (fibroblast, epithelial cell or inflammatory cell) is depicted with growth factor-processing pathways highlighted (solid arrows). Growth factors may exert autocrine and/or paracrine effects. In idiopathic pulmonary fibrosis, growth factor functions may be diminished or enhanced and reversing these effects could offer potential therapeutic benefits. Various growth factor-specific strategies are depicted (broken arrows) that could be selected to either enhance (+) or inhibit (-) the chosen growth factor function. ECM, extracellular matrix.