Direct thrombin inhibitors fail to reverse the negative effects of heparin on lung growth and function after murine left pneumonectomy.

Autor:	Tsikis ST; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States.; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States., Hirsch TI; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States.; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States., Klouda T; Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts, United States., Fligor SC; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States.; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States., Pan A; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States.; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States., Joiner MM; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States.; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States., Wang SZ; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States.; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States., Quigley M; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States.; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States., Devietro A; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States.; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States., Mitchell PD; Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, Massachusetts, United States., Kishikawa H; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States., Yuan K; Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts, United States., Puder M; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States.; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States.
Jazyk:	angličtina
Zdroj:	American journal of physiology. Lung cellular and molecular physiology [Am J Physiol Lung Cell Mol Physiol] 2024 Mar 01; Vol. 326 (3), pp. L213-L225. Date of Electronic Publication: 2023 Dec 19.
DOI:	10.1152/ajplung.00096.2023
Abstrakt:	Neonates with congenital diaphragmatic hernia (CDH) frequently require cardiopulmonary bypass and systemic anticoagulation. We previously demonstrated that even subtherapeutic heparin impairs lung growth and function in a murine model of compensatory lung growth (CLG). The direct thrombin inhibitors (DTIs) bivalirudin and argatroban preserved growth in this model. Although DTIs are increasingly used for systemic anticoagulation clinically, patients with CDH may still receive heparin. In this experiment, lung endothelial cell proliferation was assessed following treatment with heparin-alone or mixed with increasing concentrations of bivalirudin or argatroban. The effects of subtherapeutic heparin with or without DTIs in the CLG model were also investigated. C57BL/6J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were preloaded with normal saline, bivalirudin, or argatroban; treated animals received daily intraperitoneal low-dose heparin. In vitro, heparin-alone decreased endothelial cell proliferation and increased apoptosis. The effect of heparin on proliferation, but not apoptosis, was reversed by the addition of bivalirudin and argatroban. In vivo, low-dose heparin decreased lung volume compared with saline-treated controls. All three groups that received heparin demonstrated decreased lung function on pulmonary function testing and impaired exercise performance on treadmill tolerance testing. These findings correlated with decreases in alveolarization, vascularization, angiogenic signaling, and gene expression in the heparin-exposed groups. Together, these data suggest that bivalirudin and argatroban fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of low-dose heparin with DTIs on CDH outcomes are warranted. NEW & NOTEWORTHY Infants with pulmonary hypoplasia frequently require cardiopulmonary bypass and systemic anticoagulation. We investigate the effects of simultaneous exposure to heparin and direct thrombin inhibitors (DTIs) on lung growth and pulmonary function in a murine model of compensatory lung growth (CGL). Our data suggest that DTIs fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of heparin with DTIs on clinical outcomes are thus warranted.
Databáze:	MEDLINE
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