Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis.
Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis.
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DOI：
10.7554/elife.69348
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发表时间：
2022-02-21
期刊：
影响因子：
7.7
通讯作者：
Jones MG
中科院分区：
文献类型：
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作者：
Brereton CJ;Yao L;Davies ER;Zhou Y;Vukmirovic M;Bell JA;Wang S;Ridley RA;Dean LSN;Andriotis OG;Conforti F;Brewitz L;Mohammed S;Wallis T;Tavassoli A;Ewing RM;Alzetani A;Marshall BG;Fletcher SV;Thurner PJ;Fabre A;Kaminski N;Richeldi L;Bhaskar A;Schofield CJ;Loxham M;Davies DE;Wang Y;Jones MG
细胞外基质（ECM）硬化与下游机械敏感通路的激活密切相关。我们之前报道过，胶原纳米结构的改变是人类纤维化中病理ECM结构-功能的关键决定因素（Jones等，2018）。在这里，通过人体组织、生物信息学和离体研究，我们提供了证据，证明缺氧诱导因子（HIF）途径的激活是这一过程的关键途径，无论氧状态如何（假性缺氧）。虽然TGFβ增加了纤维性胶原的合成速度，但HIF通路的激活需要失调纤维性胶原的翻译后修饰，促进吡啶啉交联，改变胶原纳米结构，增加组织硬度。在体外，抑制HIF活性的因子（FIH）的敲低或氧化应激导致正常成纤维细胞的假性缺氧HIF激活。相比之下，肺纤维化患者成纤维细胞的内源性FIH活性降低，这与常氧HIF通路激活显著增加有关。在人肺纤维化组织中，HIF介导的信号在活跃的纤维生成位点增加，而人肺纤维化间充质细胞亚群的HIF和氧化应激评分均增加。我们的数据表明，氧化应激可以驱动假缺氧HIF通路激活，这是纤维化中致病性胶原结构-功能的关键调节因子。
Extracellular matrix (ECM) stiffening with downstream activation of mechanosensitive pathways is strongly implicated in fibrosis. We previously reported that altered collagen nanoarchitecture is a key determinant of pathogenetic ECM structure-function in human fibrosis (Jones et al., 2018). Here, through human tissue, bioinformatic and ex vivo studies we provide evidence that hypoxia-inducible factor (HIF) pathway activation is a critical pathway for this process regardless of the oxygen status (pseudohypoxia). Whilst TGFβ increased the rate of fibrillar collagen synthesis, HIF pathway activation was required to dysregulate post-translational modification of fibrillar collagen, promoting pyridinoline cross-linking, altering collagen nanostructure, and increasing tissue stiffness. In vitro, knockdown of Factor Inhibiting HIF (FIH), which modulates HIF activity, or oxidative stress caused pseudohypoxic HIF activation in the normal fibroblasts. By contrast, endogenous FIH activity was reduced in fibroblasts from patients with lung fibrosis in association with significantly increased normoxic HIF pathway activation. In human lung fibrosis tissue, HIF-mediated signalling was increased at sites of active fibrogenesis whilst subpopulations of human lung fibrosis mesenchymal cells had increases in both HIF and oxidative stress scores. Our data demonstrate that oxidative stress can drive pseudohypoxic HIF pathway activation which is a critical regulator of pathogenetic collagen structure-function in fibrosis.