Alveolar Type 1 Epithelial Cell Deficiency in Pulmonary Hypertension

Abstract

Rationale: Pulmonary Arterial Hypertension (PAH) is a severe health condition that involvesan ongoing process of pulmonary vascular resistance and vascular remodeling. These changes can eventually cause right heart failure (RHF) and in severe cases and can eventually result in death. AT1 cells mediate gas exchange in the lung. However, the connection between AT1 cell dysfunction and the onset of pulmonary hypertension (PH) is still not well-understood. A better understanding of the mechanisms could help the improvement of treatment for PAH. Objectives: To investigate the role and underlying mechanisms of AT1 cell deficiency in the pathogenesis of PAH. Methods: To determine whether AT1 cells are deficient in the development of PAH, lung sections from idiopathic PAH (IPAH) and control donors, as well as lung tissues from PH mice model Egln1Tie2cre (CKO) mice and wild-type (WT) mice, were evaluated for the expression of AT1 cell markers. Reverse Transcription-quantitative PCR (RT-qPCR) was performed in mice samples, to determine the expression levels of AT1 cells markers (Ager, Aqp5, Hopx, Rtkn2) using lung tissues from CKO and WT mice. Western blot analysis was then performed to quantitatively evaluate AT1 cell marker protein levels (Ager, Hopx) in lungs from CKO and WT mice. Immunofluorescence staining was applied using HOPX in both mice lungs and human IPAH lungs. Additionally, the expression of VEGFA, AT1 derived factor, was determined using the RNAscope technique on human IPAH and control lungs. Results: The findings of this study showed the mRNA levels of AT1 markers including Hopx and Rtkn2 were downregulated in CKO mice. The expression levels of AT1 markers Ager but not Hopx was downregulated in CKO mice by Western Blot. A decrease of AT1 cells assessed by quantification of HOPX in the IPAH human samples and CKO mice was observed in Immunofluorescent staining. Lastly, upregulated VEGFA expression in IPAH human samples were recorded as revealed by the RNA scope. Conclusion: The findings of this study demonstrated that there is a deficiency of AT1 cells in PAH patients and PH mice. Deficient AT1 cells might lead to impaired regeneration of the pulmonary vasculature and the development of PAH. Our study might provide a novel concept to treat PAH patient via studying the AT1 cells and their underlying signaling.