Transforming growth factor beta 1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis.

Abstract

Idiopathic pulmonary fibrosis is an inexorably fatal disorder characterized by connective tissue deposition within the terminal air spaces resulting in loss of lung function and eventual respiratory failure. Previously, we demonstrated that foci of activated fibroblasts expressing high levels of fibronectin, procollagen, and smooth muscle actin and thus resembling those found in healing wounds are responsible for the connective tissue deposition and scarring in idiopathic pulmonary fibrosis. Using in situ hybridization and immunohistochemistry, we now demonstrate the presence of transforming growth factor beta 1 (TGF-beta 1), a potent profibrotic cytokine, in the foci containing these activated fibroblasts. These results suggest that matrix-associated TGF-beta 1 may serve as a stimulus for the persistent expression of connective tissue genes. One potential source of the TGF-beta 1 is the alveolar macrophage, and we demonstrate the expression of abundant TGF-beta 1 mRNA in alveolar macrophages in lung tissue from patients with idiopathic pulmonary fibrosis.

Release of transforming growth factor-beta (TGF-β) and fibronectin by alveolar macrophages in airway diseases

“…TGF-is a growth factor involved in fibrosis, since it induces the deposition of ECM by simultaneously stimulating cells to increase the synthesis of most ECM proteins, decreasing the production of ECM-degrading proteases and increasing the production of protease inhibitors (TIMPs) [26]. In patients with fibrotic lung diseases, increased TGF-production co-localized with areas of increased fibrotic ECM protein deposition has been demonstrated in biopsies [27] as well as in BAL cells. These findings suggest that expression of this growth factor results in an enhanced ECM synthesis and deposition in the disease process.…”

Dermal Melanocortin Receptor Rebound in Diffuse Systemic Sclerosis after Anti‐TGFβ1 Antibody Therapy

“…Fibroblasts synthesize increased amounts of transforming growth factor beta (TGFb), leading to upregulated procollagen mRNA levels [3], and the release of huge amounts of extracellular matrix (ECM) macromolecules [4]. Likewise, increased TGFb mRNa and protein is present in affected areas in ILD in SSc [5]. A TGFb responsive gene signature may also be found in the skin of dSSc patients with severe disease [6].…”

“…Only two patients were included in Sweden, one at our clinic having recent onset dSSc, and one from the Lund region. Considering the role of the melanocortin system reviewed above, we investigated our patient for expression of MC [1][2][3]5 Rs, POMC, TGFb and TNFa mRNAs in skin biopsies taken before and after treatment with the recombinant human anti-TGFb1 antibody, and compared to biopsies from 3 healthy controls.…”

“…There are five subtypes of melanocortin receptors (MCRs), MC [1][2][3][4][5] R, which are responsive to the natural agonist ligands, a-, b-, c-melanocyte stimulating hormone (MSHs) and adrenocorticotropin (ACTH). These are peptides, which (along with other peptides such as the endorphins) are derived from the pro-opio-melanocortin (POMC) precursor protein, by virtue of the prohormone convertases (PCs) 1 and 2 [8].…”

“…The MC [1][2][3]5 R were shown to be upregulated by their own ligands, a-MSH and ACTH, while they were down-regulated by TGFb in various tissues and cell types [20][21][22]. Moreover, TGFb and the pro-inflammatory cytokine TNFa seem to induce opposing effects on the regulation of POMC gene expression, as TGFb down-regulates basal POMC gene expression in fibroblasts and keratinocytes, and this effect was partially reversed by TNFa [11]).…”