Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
Pharmacol Res. 2019 Sep;147:104364. doi: 10.1016/j.phrs.2019.104364. Epub 2019 Jul 31.
Wound healing responses are physiological reactions to injuries and share common characteristics and phases independently of the injured organ or tissue. A major hallmark of wound healing responses is the formation of extra-cellular matrix (ECM), mainly consisting of collagen fibers, to restore the initial organ architecture and function. Overshooting wound healing responses result in unphysiological accumulation of ECM and collagen deposition, a process called fibrosis. Importantly, hypoxia (oxygen demand exceeds supply) plays a significant role during wound healing responses and fibrotic diseases. Under hypoxic conditions, cells activate a gene program, including the stabilization of hypoxia-inducible factors (HIFs), which induces the expression of HIF target genes counteracting hypoxia. In contrast, in normoxia, so-called HIF-prolyl hydroxylases (PHDs) oxygen-dependently hydroxylate HIF-α, which marks it for proteasomal degradation. Importantly, PHDs can be pharmacologically inhibited (PHI) by so-called PHD inhibitors. There is mounting evidence that the HIF-pathway is continuously up-regulated during the development of tissue fibrosis, and that pharmacological (HIFI) or genetic inhibition of HIF can prevent organ fibrosis. By contrast, initial (short-term) activation of the HIF pathway via PHI during wound healing seems to be beneficial in several models of inflammation or acute organ injury. Thus, timing and duration of PHI and HIFI treatment seem to be crucial. In this review, we will highlight the role of hypoxia-adaptive pathways during wound healing responses and development of fibrotic disease. Moreover, we will discuss whether PHI and HIFI might be a promising treatment option in fibrotic disease, and consider putative pitfalls that might result from this approach.
伤口愈合反应是对损伤的生理反应，具有共同的特征和阶段，与受伤的器官或组织无关。伤口愈合反应的一个主要标志是细胞外基质（ECM）的形成，主要由胶原纤维组成，以恢复初始器官结构和功能。过度的伤口愈合反应导致 ECM 和胶原沉积的非生理积累，这一过程称为纤维化。重要的是，缺氧（氧需求超过供应）在伤口愈合反应和纤维化疾病中起着重要作用。在缺氧条件下，细胞激活一个基因程序，包括缺氧诱导因子（HIFs）的稳定化，这诱导了 HIF 靶基因的表达，以对抗缺氧。相比之下，在常氧条件下，所谓的 HIF-脯氨酰羟化酶（PHD）氧依赖性地羟化 HIF-α，使其标记为蛋白酶体降解。重要的是，PHD 可以被所谓的 PHD 抑制剂药理学抑制（PHI）。越来越多的证据表明，HIF 通路在组织纤维化的发展过程中持续上调，并且 HIF 的药理学（HIFI）或遗传抑制可以预防器官纤维化。相比之下，在伤口愈合过程中通过 PHI 早期（短期）激活 HIF 途径似乎在几种炎症或急性器官损伤模型中是有益的。因此，PHI 和 HIFI 的时间和持续时间似乎是至关重要的。在这篇综述中，我们将强调缺氧适应途径在伤口愈合反应和纤维化疾病发展中的作用。此外，我们将讨论 PHI 和 HIFI 是否可能是纤维化疾病的一种有前途的治疗选择，并考虑由此方法可能产生的潜在陷阱。
