Effects of Thyroid Hormone on Tissue Hypoxia: Relevance to Sepsis Therapy

Abstract

Tissue hypoxia occurs in various conditions such as myocardial or brain ischemia and infarction, sepsis, and trauma, and induces cellular damage and tissue remodeling with recapitulation of fetal-like reprogramming, which eventually results in organ failure. Analogies seem to exist between the damaged hypoxic and developing organs, indicating that a regulatory network which drives embryonic organ development may control aspects of heart (or tissue) repair. In this context, thyroid hormone (TH), which is a critical regulator of organ maturation, physiologic angiogenesis, and mitochondrial biogenesis during fetal development, may be of important physiological relevance upon stress (hypoxia)-induced fetal reprogramming. TH signaling has been implicated in hypoxic tissue remodeling after myocardial infarction and T3 prevents remodeling of the postinfarcted heart. Similarly, preliminary experimental evidence suggests that T3 can prevent early tissue hypoxia during sepsis with important physiological consequences. Thus, based on common pathways between different paradigms, we propose a possible role of TH in tissue hypoxia after sepsis with the potential to reduce secondary organ failure.

Keywords: HIF-1α; hypoxia; microcirculatory failure; sepsis; thyroid hormone.

Figure 1

Tissue hypoxia has a critical role in the main mechanisms that results in organ failure due to sepsis (the dotted black line represents the hypoxia-independent complex pathophysiological mechanisms, resulting in sepsis immune response, pathological angiogenesis, and metabolic switch; these are not reviewed here). Here, we depict possible sites of TH action (red dotted lines): (1) triiodothyronine (T3) improves tissue hypoxia and inhibits pro-apoptotic kinase signaling activation and (2) affects the other septic mechanisms in a complex way. Eventually, T3 may prevent organ failure.