Sympathetic Spleen Denervation Attenuate Pulmonary Hypertension by Decreasing Lung Infiltration of Hematopoietic Stem Cells And Neuroinflammation
Authors: Oliveira Aline , Alves Mathew , Pham Ann , Ebrahimi Elnaz , He Jacky , Patel Harsh , Fu Chunhua , de Kloet Annette , Krause Eric , Bryant Andrew 
Published: May 2023

Background: Pulmonary Hypertension (PH) is a severe disease characterized by increased pulmonary arterial pressure that ultimately leads to right heart failure. Previous studies have indicated PH as a disease that affects several other organ systems in addition to the lungs. Of particular interest has been the brain and its contribution to the pathogenesis of PH. Neural control of immunity and inflammation is well-established in the literature, whereby sympathetic-mediated emergency granulopoiesis from the spleen is a critical source for the inflammatory process in different diseases. Aim: Investigate the hypothesis of a feedforward loop involving increased sympathetic activity and hematopoietic stem cells (HSCs). In this hypothesis, infiltration of HSC to the brain contributes to neuroinflammation, maladaptive neuroplasticity in preautonomic neurons, and consequently, autonomic disbalance, which contributes to increased inflammatory response and severity of PH. Method: Sympathetic denervation of spleen was performed in C57BL6-J mice (n=40) using absolute ethanol/saline repeatedly applied in the splenic hilum. Following completion of either splenic denervation or sham surgery, animals were allowed to recover for 6 weeks before exposure to either Chronic Hypoxia (CH-PH; FIO2 10%) or normoxia (room air, FIO2 21%) for 4 weeks. Then, right ventricular systolic pressure (RVSP) was recorded, followed by harvest of tissues. Alpha-smooth muscle actin (αSMC) and Masson trichrome staining in the lungs was used for characterization of pulmonary hypertension. Immune cell profile in the lung, spleen and brain was performed by flow cytometry. Iba1 staining was used to label microglia/macrophage cells. Together, histological and flow data were used to evaluate whether the neuroinflammation observed in CH-PH is dependent/independent of sympathetic-mediated infiltration of myeloid precursors from the circulation to preautonomic nuclei such as the paraventricular nucleus of the hypothalamus (PVN). TH staining was performed in the spleen of all animals to confirm the spleen denervation. Result: Sympathetic spleen denervation attenuated the increase of RVSP, Iba1+ cells within the PVN and proliferation of αSMC and collagen in the lungs induced by CH. Furthermore, sympathetic denervation also blunted the changes in the catecholamine metabolism in PMN-MDSC cells within the lung and altered TREM2+ microglia cells’ response to CH. Conclusion: Our previous experiments demonstrated that the exposure of chimeric mice with GFP bone marrow cells to chronic hypoxia illustrates the translocation of these cells into the brain of PH animals. Current experiments show that sympathetic spleen denervation attenuates the infiltration of hematopoietic cells to the PVN and PH development. Together, these results indicate that hematopoietic cells may contribute directly to lung inflammation as well as to the dysfunctional neuro-immune axis observed in PH.

NIH grant HL102033, HL110170, HL142776; AHA 20POST35210516

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.