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Gene expression changes during the development of acute lung injury: role of transforming growth factor beta.

ABSTRACT: Acute lung injury can occur from multiple causes, resulting in high mortality. The pathophysiology of nickel-induced acute lung injury in mice is remarkably complex, and the molecular mechanisms are uncertain.To integrate molecular pathways and investigate the role of transforming growth factor beta (TGF-beta) in acute lung injury in mice.cDNA microarray analyses were used to identify lung gene expression changes after nickel exposure. MAPPFinder analysis of the microarray data was used to determine significantly altered molecular pathways. TGF-beta1 protein in bronchoalveolar lavage fluid, as well as the effect of inhibition of TGF-beta, was assessed in nickel-exposed mice. The effect of TGF-beta on surfactant-associated protein B (Sftpb) promoter activity was measured in mouse lung epithelial cells.Genes that decreased the most after nickel exposure play important roles in lung fluid absorption or surfactant and phospholipid synthesis, and genes that increased the most were involved in TGF-beta signaling. MAPPFinder analysis further established TGF-beta signaling to be significantly altered. TGF-beta-inducible genes involved in the regulation of extracellular matrix function and fibrinolysis were significantly increased after nickel exposure, and TGF-beta1 protein was also increased in the lavage fluid. Pharmacologic inhibition of TGF-beta attenuated nickel-induced protein in bronchoalveolar lavage. In addition, treatment with TGF-beta1 dose-dependently repressed Sftpb promoter activity in vitro, and a novel TGF-beta-responsive region in the Sftpb promoter was identified.These data suggest that TGF-beta acts as a central mediator of acute lung injury through the alteration of several different molecular pathways.

SUBMITTER: Wesselkamper SC

PROVIDER: S-EPMC2718437 | biostudies-literature | 2005 Dec

REPOSITORIES: biostudies-literature

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Gene expression changes during the development of acute lung injury: role of transforming growth factor beta.

Wesselkamper Scott C SC Case Lisa M LM Henning Lisa N LN Borchers Michael T MT Tichelaar Jay W JW Mason John M JM Dragin Nadine N Medvedovic Mario M Sartor Maureen A MA Tomlinson Craig R CR Leikauf George D GD

American journal of respiratory and critical care medicine 20050811 11

<h4>Rationale</h4>Acute lung injury can occur from multiple causes, resulting in high mortality. The pathophysiology of nickel-induced acute lung injury in mice is remarkably complex, and the molecular mechanisms are uncertain.<h4>Objectives</h4>To integrate molecular pathways and investigate the role of transforming growth factor beta (TGF-beta) in acute lung injury in mice.<h4>Methods</h4>cDNA microarray analyses were used to identify lung gene expression changes after nickel exposure. MAPPFin ...[more]

PMID: 16100012

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Project description:BACKGROUND: Recently, several members of the transforming growth factor-beta (TGF-beta) superfamily have been shown to be essential for regulating the growth and differentiation of ovarian follicles and thus fertility. METHODS: Ovaries of neonatal and adult sheep were examined for expression of the TGF-betas 1-3 and their receptors (RI and RII) by in situ hybridization using ovine cDNAs. The effects of TGF-beta 1 and 2 on proliferation and differentiation of ovine granulosa cells in vitro were also studied. RESULTS: The expression patterns of TGF-beta 1 and 2 were similar in that both mRNAs were first observed in thecal cells of type 3 (small pre-antral) follicles. Expression of both mRNAs continued to be observed in the theca of larger follicles and was also present in cells within the stroma and associated with the vascular system of the ovary. There was no evidence for expression in granulosa cells or oocytes. Expression of TGF-beta 3 mRNA was limited to cells associated with the vascular system within the ovary. TGFbetaRI mRNA was observed in oocytes from the type 1 (primordial) to type 5 (antral) stages of follicular growth and granulosa and thecal cells expressed this mRNA at the type 3 (small pre-antral) and subsequent stages of development. The TGFbetaRI signal was also observed in the ovarian stroma and vascular cells. In ovarian follicles, mRNA encoding TGFbetaRII was restricted to thecal cells of type 3 (small pre-antral) and larger follicles. In addition, expression was also observed in some cells of the surface epithelium and in some stromal cells. In granulosa cells cultured for 6 days, both TGF-beta 1 and 2 decreased, in a dose dependent manner, both the amount of DNA and concentration of progesterone. CONCLUSION: In summary, mRNA encoding both TGF-beta 1 and 2 were synthesized by ovarian theca, stroma and cells of the vascular system whereas TGF-beta 3 mRNA was synthesized by vascular cells. Luteinizing granulosa cells also responded to both TGF-beta 1 and beta 2 in vitro. These findings in sheep are consistent with TGF-beta potentially being an important autocrine regulator of thecal cell function and possibly a paracrine regulator of ovarian cell function at various development stages.

Project description:Transforming growth factor β (TGFβ) signaling regulates multifaceted reproductive processes via its transmembrane receptor complex-associated machinery. It has been shown that the type 1 receptor of TGFβ (TGFBR1) is indispensable for female reproductive tract development, pregnancy success, and fertility. However, the role of TGFβ signaling in decidual development and function remains poorly defined. Our objective is to determine the impact of uterine-specific deletion of Tgfbr1 on the differentiation of endometrial stromal cells in pregnant mice, with a focus on the cellular and molecular properties of the decidua. An approach combining histological and immunohistochemical analyses, quantitative PCR, western blot, and RNA-sequencing was utilized. Our results show that decidual development is altered in TGFBR1 conditionally depleted uteri, substantiated by downregulation of genes associated with inflammatory response and uterine natural killer cell abundance, reduced presence of non-decidualized fibroblasts in the antimesometrial region, and impaired decidual cell differentiation. Notably, conditional ablation of TGFBR1 results in the formation of decidua containing more abundant alpha smooth muscle actin (ACTA2)-positive cells at the peripheral region of the antimesometrial side versus controls. This finding is corroborated by upregulation of a subset of smooth muscle marker genes in Tgfbr1 conditionally-deleted decidua. The abnormal cell differentiation is accompanied with increased cell proliferation and enhanced decidual ERK1/2 signaling upon decidual regression. In summary, this study has identified an important role of TGFBR1 in decidual cell differentiation by revealing that conditional ablation of TGFBR1 in the uterus profoundly impacts the cellular and molecular properties of the decidua. Our results suggest that TGFBR1 is required for the development of an integral decidua, a transient but crucial structure that supports embryo development.

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Gene expression changes during the development of acute lung injury: role of transforming growth factor beta.

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Gene expression changes during the development of acute lung injury: role of transforming growth factor beta.

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