Vasopressin Receptor Expression Reveals Role of Endogenous Vasopressin in Ameliorating Acute Lung Injury in Pig Models of Pulmonary Hypertension

Abstract

Acute lung injury (ALI) that evolves into acute respiratory distress syndrome (ARDS) is a critical care management challenge with 30–40% mortality. Despite the beneficial ability of pharmacological doses of vasopressin (VP)to elevate blood pressure without worsening pulmonary hypertension (PHN) in severe septic shock ARDS, circulating VP levels (not necessarily indicative of local tissue VP action) remain relatively low and it is unclear whether VP has a physiological role in maintaining pulmonary blood flow and oxygenation in ARDS. We hypothesized that if endogenous VP has an important role in ameliorating ALI, vascular VP receptor mRNA expression will increase within hours after initial ALI insult in order to replenish spent receptors that are degraded when activated by endogenous VP.Anesthetized Yorkshire cross pigs(n=36, 7.9 ± 0.2 kg body weight) were used to examine pulmonary hemodynamics in ALI without the confounding effects of systemic hypotension. PHN was induced by either disrupting the lung alveolar‐capillary interface with oleic acid (OA; 0.1 ml/kg iv, n=14) or by causing endothelial dysfunction with endotoxin (ETX; up to 35,000 units iv, n=16). ALI pigs had elevated pulmonary to systemic vascular resistance ratios (PVR/SVR: OA = 0.48 ± 0.07 and ETX = 0.48 ±0.04) compared to controls (0.20 ± 0.01, n=6). Mean arterial pressure was constant (60±4 mm Hg in all groups). ALI was managed with supplemental oxygen with or without mesenchymal stem cells to facilitate lung tissue repair. Within 2 hours after treatment, PVR/SVR began to return towards baseline in the ETX group but remained elevated in the OA group. This provided a range of pulmonary vasoconstriction states to compare against changes in plasma VP, pituitary VP content, and the mRNA expression of VP, V1aR, V1bR, and V2R receptors in pulmonary, carotid, renal, celiac, and mesenteric arteries, and aorta collected12 to 16 hours after initial ALI. Stepwise multiple regression revealed that PVR/SVR at 2–4 hours of established lung injury was positively correlated with V1aR expression in the aorta and mesenteric artery and V2R expression in the pulmonary and renal arteries, and negatively correlated with V2R expression in the aorta and celiac arteries (r2=0.88, p<0.0001). Results are consistent with endogenous VP responding to pulmonary hypertension in ALI via a pulmonary V2R mediated vasodilatory counter effect, in the face of V1aR mediated vasoconstriction in other vascular beds, to maintain pulmonary blood flow and improve blood oxygenation.Support or Funding InformationThis project was supported by the US Army Medical Command. The views expressed in this abstract are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. GovernmentThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.