Transforming Growth Factor-β: Master Regulator of the Respiratory System in Health and Disease

Abstract

In this article, we review the biology and physiological importance of transforming growth factor-β (TGF-β) to homeostasis in the respiratory system, its importance to innate and adaptive immune responses in the lung, and its pathophysiological role in various chronic pulmonary diseases including pulmonary arterial hypertension, chronic obstructive pulmonary disease, asthma, and pulmonary fibrosis. The TGF-β family is responsible for initiation of the intracellular signaling pathways that direct numerous cellular activities including proliferation, differentiation, extracellular matrix synthesis, and apoptosis. When TGF-β signaling is dysregulated or essential control mechanisms are unbalanced, the consequences of organ and tissue dysfunction can be profound. The complexities and myriad checkpoints built into the TGF-β signaling pathways provide attractive targets for the treatment of these disease states, many of which are currently being investigated. This review focuses on those aspects of TGF-β biology that are most relevant to pulmonary diseases and that hold promise as novel therapeutic targets.

Keywords: COPD; asthma; fibroblast; pulmonary arterial hypertension; pulmonary fibrosis.

Figure 1.

Canonical transforming growth factor-β (TGF-β) signaling cascade. TGF-β is secreted in an inactive form noncovalently bound to the LAP and covalently bound to LTBPs. TGF-β can be activated by release from this complex by a variety of mechanisms including acidification, oxidation, proteolytic cleavage, and physical force exerted through integrins such as α_vβ₆. Active TGF-β ligand binds TGF-β receptor (TβR) II, initiating formation of heterotetrameric complexes with TβRI. R-Smads are phosphorylated by TβRI, and with help from anchor proteins such as SARA, combine with co-Smad4 and translocate to the nucleus, where they can direct gene transcription in diverse cell types. Signal attenuation is exerted at the level of the receptor complex and by dephosphorylation of phosphorylated Smads by Smad phosphatases. AT, alveolar type; co-Smad, common-mediator SMAD; ECM, extracellular matrix; LAP, latency-associated peptide; LTBP, latent TGF-β binding protein; MMP, matrix metalloproteinase; R-Smad, receptor Smad; SARA, Smad anchor for receptor activation

Figure 2.

Downstream pathological effects of the TGF-β signaling cascade in selected lung diseases. (A) TGF-β influences development of pulmonary fibrosis by promoting differentiation of fibroblasts to myofibroblasts, elaboration of ECM components, epithelial to mesenchymal transition of ATII cells to fibroblasts, and ATII cell apoptosis. (B) Effects of TGF-β in the pathogenesis of pulmonary arterial hypertension include ECM deposition, fibroblast proliferation, and pulmonary artery muscularization. (C) Asthma pathogenesis is driven by TGF-β–dependent processes, including ECM deposition, airway smooth muscle cell proliferation, and mucus production. (D) TGF-β can influence the development of COPD via mechanisms including up-regulation of MMPs, leading to alveolar tissue loss, elaboration of ECM components, and ATII cell growth inhibition. COPD, chronic obstructive pulmonary disease; EMT, epithelial to mesenchymal transition.