Direkte Thrombininhibitoren können die negativen Effekte von Heparin auf Lungenwachstum und -funktion nach linksseitiger Pneumonektomie bei Mäusen nicht aufheben

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.

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In einem Mausmodell kompensatorischen Lungenwachstums nach linksseitiger Pneumonektomie und an Lungenendothelzellen wurde geprüft, ob Bivalirudin und Argatroban die negativen Effekte subtherapeutischen Heparins aufheben. In vitro senkte Heparin die Endothelzellproliferation und steigerte die Apoptose; die Inhibitoren hoben nur den Proliferationseffekt auf. In vivo senkte niedrig dosiertes Heparin das Lungenvolumen; in allen Heparin-Gruppen sanken Lungenfunktion und Belastbarkeit. Laut den Autoren deuten die Daten darauf hin, dass die Inhibitoren die heparinbedingte Hemmung von Lungenwachstum und -funktion nicht aufheben; klinische Studien seien gerechtfertigt.

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