Alec Judd

Introduction: Pulmonary arterial hypertension (PAH) is defined as increased blood pressure in the cardiovascular system between the right ventricle and left atrium; normal values are <25 mmHg.¹ Pulmonary arterial blood pressure is influenced by a myriad of factors including diet, exercise, and stress levels, and can be secondary to many other conditions, including diabetes, nephropathies, and hormonal imbalances. Toll-like receptors are proteins found on sentinel cells, such as macrophages and dendritic cells, that are responsible for recognizing PAMPs/DAMPs and activating various parts of the innate immune system,² including the release of various cytokines, like TNFα, IL‐1β, IL‐6 and IL‐12. TLR4, while traditionally known to recognize LPS, can also recognize DAMPs such as HMGB1.^{3, 4} Methods: Model organisms were generated by exposure to extended periods of hypoxia, resulting in PAH. Plasma levels and platelet levels of test subjects’ inflammatory factors HMGB1, IL-1β, IL-6, and TNF-α were measured by ELISA.⁵ Morphological changes in test subjects’ pulmonary arteries were observed using HE and immunohistochemistry, including vessel wall thickness and collagen deposition to measure levels of fibrosis. Levels of BMPR2 and its downstream constituents (phosphorylated Smad1/5/8, Id1/Id3) were also measured by ELISA.⁴ Results: Levels of HMGB1, TLR4, and multiple inflammatory markers are increased, and levels of BMPR2 are decreased in PAH model rats.⁶ Exogenous HMBG1 inhibits downstream products of the BMPR2 pathway, including Id1 and Id2. ELISA and in vitro cell assays displayed migration of pulmonary arterial smooth muscle cells to the extracellular milieu during conditions of hypoxia.⁴ Conclusions: The TLR4/HMGB1 pathway inhibits BMPR2 and its pathway constituents, which leads to pulmonary arterial smooth muscle cell migration, resulting in pulmonary vasculature remodeling, and subsequent development of PAH. TLR4/HMGB1 and pathway constituents are potential targets for the treatment, diagnosis, and prognosis of PAH.

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