Transforming growth factor beta: a central modulator of pulmonary and airway inflammation and fibrosis

Abstract

The requirement for precise geometric organization of endothelial cells and epithelial cells makes the gas-exchange region of the lung especially vulnerable to the adverse consequences of toxic products released from inflammatory cells. However, as a filter for large volumes of atmospheric gas, the lung is continually exposed to microorganisms and other toxic insults that require robust inflammatory defense. Enhanced production of extracellular matrix proteins is one important mechanism for restricting tissue damage, but excessive matrix production also has serious adverse effects on gas exchange. The amazing ability of the lung to recover from a barrage of environmental insults depends on precisely regulating both inflammation and extracellular matrix production in space and time. Below I review some of the evidence implicating members of the transforming growth factor beta family as critical mediators of this delicate dance and describe examples of how disruption of this balance by alterations in the magnitude of spatially restricted transforming growth factor beta activation can contribute to pathologic consequences of alveolar and airway injury and inflammation.

Figure 1.

Synthesis and organization of latent complexes of transforming growth factor β (TGF-β). All three mammalian isoforms of TGF-β are initially synthesized as a precursor protein that is cleaved in the endoplasmic reticulum into the amino-terminal fragment (called latency associated protein [LAP]) and the shorter carboxy-terminal fragment that is the mature cytokine. These fragments are assembled as a double homodimer called the small latent complex. In virtually all cells this complex is further modified by disulfide linkage to one of a family of proteins called latent TGF-β binding proteins (LTBPs), to form the large latent complex.

Figure 2.

Model of the consequences of αvβ6 integrin-mediated activation of TGF-β by alveolar epithelial cells. Integrin expressed on the luminal surface can present active TGF-β to luminal macrophages, thereby inhibiting protease secretion and maintaining alveolar homeostasis. Integrin on the basal surface can present active TGF-β to fibroblasts, which in excess contributes to the development of pulmonary fibrosis, and to endothelial cells, which regulate pulmonary vascular permeability. Integrin on the lateral surface can present active TGF-β to adjacent epithelial cells, increasing epithelial permeability and decreasing the reabsorption of salt, and therefore water, from the alveolar space.