Transforming growth factor-beta 1 modulates type II cell fibronectin and surfactant protein C expression

Maniscalco, William M.; Sinkin, Robert A.; Watkins, Richard H.; Campbell, M. H.

doi:10.1152/ajplung.1994.267.5.l569

Cited by 28 publications

(20 citation statements)

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“…In the present study and in previous work (Zhou et al, 1996a), TGF-␤1 did not significantly alter branching morphogenesis in lungs of the SP-C-TGF-␤1 transgenic mice, perhaps due to the low level of the transgene expression driven by SP-C promoter before E15. However, TGF-␤1 inhibited events later in lung morphogenesis, including lung sacculation and epithelial cell differentiation, consistent with the previous findings that the exogenous TGF-␤1 inhibited SP-C (Maniscalco et al, 1994), SP-A (Whitsett et al, 1987) and surfactant phospholipid synthesis in embryonic lung explant cultured in vitro.…”

Section: Discussionsupporting

confidence: 90%

TGF‐β1 perturbs vascular development and inhibits epithelial differentiation in fetal lung in vivo

Zeng

Gray

Stahlman

et al. 2001

Developmental Dynamics

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Members of the transforming growth factor ␤ (TGF-␤) family of polypeptides have been implicated in morphogenesis and differentiation in numerous tissues, including the lung. In order to further define effects of TGF-␤ signaling in lung morphogenesis, a constitutively active form of TGF-␤1 was expressed in respiratory epithelial cells of the fetal mouse lung in vivo. Expression of TGF-␤1 arrested lung morphogenesis in the pseudoglandular stage of development, inhibiting synthesis of differentiation-dependent proteins, SP-B, SP-C, and CCSP, and maintaining embryonic patterns of staining for thyroid transcription factor-1 (TTF-1) and hepatocyte nuclear factor-3␤ (HNF-3␤). The pulmonary mesenchyme was thickened and vascular density was increased by TGF-␤1. TGF-␤1 decreased expression of vascular endothelial growth factor-A (VEGF-A) mRNA and protein, and the abundance of Flk-1 mRNA in the lung mesenchyme. Distribution of platelet-endothelial cell adhesion molecule (PECAM)-1, a marker of pulmonary blood vessels, was altered, and ultrastructural studies demonstrated that TGF-␤1 inhibited vascular development in the fetal lung. TGF-␤1 perturbed both epithelial cell differentiation and formation of the pulmonary vasculature, supporting the concept that precise control of signaling via the TGF-␤ receptor pathway is critical for normal lung morphogenesis.

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Section: Discussionsupporting

confidence: 90%

TGF‐β1 perturbs vascular development and inhibits epithelial differentiation in fetal lung in vivo

Zeng

Gray

Stahlman

et al. 2001

Developmental Dynamics

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“…However, previous studies by this research group have demonstrated that chronic ethanol ingestion increases oxidant stress in type II cells (Brown et al, 2001a;Brown et al, 2001b) as well as TGF-β (Bechara et al, 2004). Both oxidant stress (Maniscalco et al, 1998) and TGF-β (Maniscalco et al, 1994) have been shown to increase fibronectin synthesis by type II cells; therefore, this might explain the observed increase in susceptibility to acute lung injury in the setting of chronic ethanol exposure. Thus, chronic ethanol ingestion altered matrix formation by alveolar epithelial type II cells to include enhanced synthesis and incorporation of fibronectin into the extracellular matrix.…”

Section: Discussionmentioning

confidence: 81%

Alveolar type II cells from ethanol-fed rats produce a fibronectin-enriched extracellular matrix that promotes monocyte activation

Brown

Ritzenthaler

Guidot

et al. 2007

Alcohol

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Acute lung injury affects close to 200,000 people in the U.S. annually and leads to death in 40-50% of affected patients. Chronic ethanol abuse is thought to contribute to up to 40-50% of subjects who develop acute lung injury. We previously demonstrated in a rat model that chronic ethanol ingestion promoted acute lung injury and associated with chronic oxidant stress, activated matrix metalloproteinases, increased release of transforming growth factor-β, as well as increased expression and deposition of fibronectin, a matrix glycoprotein implicated in lung injury and repair. Since fibronectin can activate monocytes to increase proinflammatory cytokine expression, we hypothesized that generation of fibronectin-enriched matrices during chronic ethanol ingestion might contribute to the development of acute lung injury by stimulating unopposed inflammation. To test this hypothesis, we harvested alveolar type II cells from rats fed the Lieber DiCarli diet (6 wk; 36% of calories from ethanol). After 96 hours of culture, the matrices deposited ex vivo by the type II cells derived from ethanol-fed rats showed increased amounts of fibronectin protein as demonstrated by ELISA. When monocytic U937 cells were plated atop these matrices, there was increased expression of interleukin-1β. This stimulation was inhibited by antibodies against α5β1, a receptor that mediates many of the biological effects of fibronectin. We then tested whether antioxidants ameliorated these effects. Dietary supplements of the antioxidants N-acetylcysteine and Procysteine normalized matrix production by type II cells. Furthermore, the newly derived matrices did not stimulate interleukin-1β expression over control cells. These studies suggest that chronic ethanol exposure induces oxidant stress and activates lung tissue remodeling characterized by increased expression of fibronectin by alveolar type II cells. The newly deposited fibronectin-enriched matrices may stimulate the expression of proinflammatory cytokines in monocytic cells recruited to the lung after injury thereby explaining the priming effects of ethanol.

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“…Iyonaga and colleagues (40) detailed marked changes in cytokeratin expression patterns in AECs from patients with IPF/UIP, and noted that epithelial cells in IPF lung tissues may be fundamentally different in function and nature. AECs exposed to TGF-␤1 down-regulate surfactant protein C production and express extracellular matrix components, such as fibronectin (41). One important study demonstrating Wnt pathway activation in IPF/UIP postulated that some fraction of the abnormal fibroblasts in IPF/UIP could directly derive from epithelial cell precursors at sites of ongoing injury and repair (42).…”

Section: Emt In Lungmentioning

confidence: 99%

Epithelial Origin of Myofibroblasts during Fibrosis in the Lung

Willis

duBois²,

Borok³

2006

Proceedings of the American Thoracic Society

447

348

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An understanding of the mechanisms underlying pulmonary fibrosis remains elusive. Once believed to result primarily from chronic inflammation, it is now clear that inflammation and chronic fibrosis, especially in diseases such as idiopathic pulmonary fibrosis/usual interstitial pneumonia, are often dissociated, and that inflammation is neither necessary nor sufficient to induce fibrosis. The origin of the primary effector cell of fibrosis in the lung, the myofibroblast, is not clearly established. Three potential sources have been hypothesized. Although conversion of resident fibroblasts and differentiation of circulating bone marrow-derived progenitors likely play a role, the possible contribution of alveolar epithelial cells (AECs), through a process termed "epithelial-mesenchymal transition" (EMT), has only recently received consideration. A process by which epithelial cells lose cell-cell attachment, polarity and epithelialspecific markers, undergo cytoskeletal remodeling, and gain a mesenchymal phenotype, EMT plays a prominent role in fibrogenesis in adult tissues such as the kidney. This review summarizes the evidence supporting a central role for EMT in the pathogenesis of lung fibrosis, the potential for EMT in AECs in vitro and in vivo and role of transforming growth factor-␤1 in this process, and the implications of epithelium-driven fibrosis on future research and treatment. Potential pathways involved in EMT are also discussed. It is hoped that a major shift in current paradigms regarding the genesis of pulmonary fibrosis and dissection of the relevant pathways may allow development of targeted interventions that could potentially reverse the process and ameliorate the debilitating effects of abnormal repair and progressive fibrosis.

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Transforming growth factor-beta 1 modulates type II cell fibronectin and surfactant protein C expression

Cited by 28 publications

References 0 publications

TGF‐β1 perturbs vascular development and inhibits epithelial differentiation in fetal lung in vivo

TGF‐β1 perturbs vascular development and inhibits epithelial differentiation in fetal lung in vivo

Alveolar type II cells from ethanol-fed rats produce a fibronectin-enriched extracellular matrix that promotes monocyte activation

Epithelial Origin of Myofibroblasts during Fibrosis in the Lung

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