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Activation of hypoxia-inducible factor-1? in type 2 alveolar epithelial cell is a major driver of acute inflammation following lung contusion.

ABSTRACT: OBJECTIVE:Lung contusion is a major risk factor for the development of acute respiratory distress syndrome. Hypoxia-inducible factor-1? is the primary transcription factor that is responsible for regulating the cellular response to changes in oxygen tension. We set to determine if hypoxia-inducible factor-1? plays a role in the pathogenesis of acute inflammatory response and injury in lung contusion. DESIGN:Nonlethal closed-chest unilateral lung contusion was induced in a hypoxia reporter mouse model and type 2 cell-specific hypoxia-inducible factor-1? conditional knockout mice. The mice were killed at 5-, 24-, 48-, and 72-hour time points, and the extent of systemic and tissue hypoxia was assessed. In addition, injury and inflammation were assessed by measuring bronchoalveolar lavage cells (flow cytometry and cytospin), albumin (permeability injury), and cytokines (inflammation). Isolated type 2 cells from the hypoxia-inducible factor-1? conditional knockout mice were isolated and evaluated for proinflammatory cytokines following lung contusion. Finally, the role of nuclear factor-?B and interleukin-1? as intermediates in this interaction was studied. RESULTS:Lung contusion induced profound global hypoxia rapidly. Increased expression of hypoxia-inducible factor-1? from lung samples was observed as early as 60 minutes, following the insult. The extent of lung injury following lung contusion was significantly reduced in conditional knockout mice at all the time points, when compared with the wild-type littermate mice. Release of proinflammatory cytokines, such as interleukin-1?, interleukin-6, macrophage inflammatory protein-2, and keratinocyte chemoattractant, was significantly lower in conditional knockout mice. These actions are in part mediated through nuclear factor-?B. Hypoxia-inducible factor-1? in lung epithelial cells was shown to regulate interleukin-1? promoter activity. CONCLUSION:Activation of hypoxia-inducible factor-1? in type 2 cell is a major driver of acute inflammation following lung contusion.

SUBMITTER: Suresh MV

PROVIDER: S-EPMC4245055 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Activation of hypoxia-inducible factor-1α in type 2 alveolar epithelial cell is a major driver of acute inflammation following lung contusion.

Suresh Madathilparambil V MV Ramakrishnan Sadeesh Kumar SK Thomas Bivin B Machado-Aranda David D Bi Yu Y Talarico Nicholas N Anderson Erik E Yatrik Shah M SM Raghavendran Krishnan K

Critical care medicine 20141001 10

<h4>Objective</h4>Lung contusion is a major risk factor for the development of acute respiratory distress syndrome. Hypoxia-inducible factor-1α is the primary transcription factor that is responsible for regulating the cellular response to changes in oxygen tension. We set to determine if hypoxia-inducible factor-1α plays a role in the pathogenesis of acute inflammatory response and injury in lung contusion.<h4>Design</h4>Nonlethal closed-chest unilateral lung contusion was induced in a hypoxia ...[more]

PMID: 25014067

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Project description:Alveolar type II (ATII) cells remain differentiated and express surfactant proteins when cultured at an air-liquid (A/L) interface. When cultured under submerged conditions, ATII cells dedifferentiate and change their gene expression profile. We have previously shown that gene expression under submerged conditions is regulated by hypoxia inducible factor (HIF) signaling due to focal hypoxia resulting from ATII cell metabolism. Herein, we sought to further define gene expression changes in ATII cells cultured under submerged conditions. We performed a genome wide microarray on RNA extracted from rat ATII cells cultured under submerged conditions for 24-48h after switching from an A/L interface. We found significant alterations in gene expression, including upregulation of the HIF target genes stanniocalcin-1 (STC1), tyrosine hydroxylase (Th), enolase (Eno) 2, and matrix metalloproteinase (MMP) 13, and we verified upregulation of these genes by RT-PCR. Because STC1, a highly evolutionarily conserved glycoprotein with anti-inflammatory, anti-apoptotic, anti-oxidant, and wound healing properties, is widely expressed in the lung, we further explored the potential functions of STC1 in the alveolar epithelium. We found that STC1 was induced by hypoxia and HIF in rat ATII cells, and this induction occurred rapidly and reversibly. We also showed that recombinant human STC1 (rhSTC1) enhanced cell motility with extended lamellipodia formation in alveolar epithelial cell (AEC) monolayers but did not inhibit the oxidative damage induced by LPS. We also confirmed that STC1 was upregulated by hypoxia and HIF in human lung epithelial cells. In this study, we have found that several HIF target genes including STC1 are upregulated in AECs by a submerged condition, that STC1 is regulated by hypoxia and HIF, that this regulation is rapidly and reversibly, and that STC1 enhances wound healing moderately in AEC monolayers. However, STC1 did not inhibit oxidative damage in rat AECs stimulated by LPS in vitro. Therefore, alterations in gene expression by ATII cells under submerged conditions including STC1 were largely induced by hypoxia and HIF, which may be relevant to our understanding of the pathogenesis of various lung diseases in which the alveolar epithelium is exposed to relative hypoxia.

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Activation of hypoxia-inducible factor-1? in type 2 alveolar epithelial cell is a major driver of acute inflammation following lung contusion.

Publications

Activation of hypoxia-inducible factor-1α in type 2 alveolar epithelial cell is a major driver of acute inflammation following lung contusion.

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