Smad3 Signaling Involved in Pulmonary Fibrosis and Emphysema

Abstract

The incidence of finding evidence of both emphysema and pulmonary fibrosis in the same patient has received increased attention. Several investigators have found on biopsy the presence of emphysema of the upper zones and diffuse parenchymal disease with fibrosis of the lower zones of the lung, especially associated with current or previous heavy smokers. Believed previously to be two different disease mechanisms, there are now data to implicate some common pathways of cell and molecular activation leading to the different morphologic and physiologic outcomes. According to a current view, emphysema may originate from a protease/antiprotease imbalance, whereas a role for antiproteases has been proposed in the modulation of fibrosis. Overexpression of transforming growth factor ␤ (TGF-␤) in experimental rodent models leads to progressive pulmonary fibrosis, accompanied with marked upregulation of protease inhibitors, such as tissue inhibitor of metalloproteinases (TIMP) and plasminogen activator inhibitor-1 (PAI-1) genes, along with excessive matrix accumulation. It may be that a "matrix degrading" pulmonary microenvironment, one in which metalloproteinase activities prevail, favors the development of emphysema, whereas a "matrix nondegrading" microenvironment, with enhanced presence of TIMPs, would lead to matrix accumulation and fibrosis. Surprisingly, although Smad3 null mice, deficient in TGF-␤ signal transmission, are resistant to bleomycin-and TGF-␤-mediated fibrosis, they develop spontaneous age-related airspace enlargement, consistent with emphysema, with a lack of ability to repair tissue damage appropriately. A common element is tissue damage and repair, with TGF-␤ and the Smad signaling pathway playing prominent molecular roles. Both changes can be followed in experimental models with noninvasive imaging and physiologic measurements.

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

“…Smad3 activation contributes to the induction of gene expression and the promotion of fibrosis. 24,29,30,74,75,77 Some data suggest that Smad3 can be activated by H 2 O 2 . 78,79 (v) It has been clearly demonstrated that the action of TGF-b is induced through the activation of NF-kB.…”

“…[24][25][26][27][28] Specifically, the Smad3 protein emerges as a pro-fibrotic member of the Smad protein family because its phosphorylation promotes the progression of fibrosis. 29,30 It has been reported that oxidative stress induces the EMT. Human epidermal keratinocytes exposed to H 2 O 2 showed protein expression that was consistent with the EMT, 31 and similar results were founded in renal tubular epithelial cells.…”

Regulation of TGF-β1-driven Differentiation of Human Lung Fibroblasts

“…Abnormal Smad signaling (i.e. overexpression of Smads 2/3) increases the production of collagens, which hence promotes deposition of extracellular matrix proteins (49). Once phosphorylated, Smads 2 and 3 that act downstream of the TGF-␤1 receptor form a complex with Co-Smad 4, which translocates to the nucleus to specifically regulate gene transcription (50).…”

Disruption of Plasminogen Activator Inhibitor-1 Gene Enhances Spontaneous Enlargement of Mouse Airspace with Increasing Age

“…PAI-1 binds to fibrin and forms covalent complexes with t-PA or u-PA, eliminating plasminogen activation and fibrinolysis (Hertig and Rondeau 2004). Although some studies found that PAI-1 expression changed in emphysema models (Bonniaud et al 2004;Gauldie et al 2006), prior to the current report, the role of PAI-1 in the development of emphysema was not well understood.…”

“…It was found that Smad3 gene knockout mice showed age-related emphysema-like changes, and had a lower PAI-1 gene expression compared with wild-type mice (Bonniaud et al 2004). Overexpression of TGF-β in experimental rodent models led to upregulation of protease inhibitors, including PAI-1 (Gauldie et al 2006). However, a direct relationship between PAI-1 and change of lung structure with increasing age has not yet been found.…”