Cortactin Loss Protects Against Hemin-Induced Acute Lung Injury in Sickle Cell Disease

Am J Physiol Lung Cell Mol Physiol. 2022 May 3. doi: 10.1152/ajplung.00274.2021. Online ahead of print.ABSTRACTIn patients with sickle cell disease (SCD), acute chest syndrome (ACS) is a major cause of morbidity and mortality. The pathophysiology of ACS is complex and hemin, the prosthetic moiety of hemoglobin, has been implicated in endothelial cell (EC) activation and subsequent ALI and ACS in vitro and in animal studies. Here, we examined the role of cortactin (CTTN), a cytoskeletal protein that regulates EC function, in response to hemin-induced ALI and ACS. Cortactin heterozygous (Cttn+/-) mice and their wild type siblings were irradiated and subsequently received bone marrow cells (BMC) from SCD mice (SS) to generate SS Cttn+/- and SS CttnWT chimeras. Following hemoglobin electrophoretic proof of BMC transplantation, the mice received 35 µmol/kg of hemin. Within 24 hours surviving mice were sacrificed, and bronchoalveolar fluid (BAL) and lung samples were analyzed. For in vitro studies, human lung microvascular endothelial cells (HLMVECs) were used to determine hemin-induced changes in gene expression and reactive oxygen species (ROS) generation in cortactin deficiency and control conditions. When compared with wild type littermates, the mortality for SS Cttn+/- mice trended to be lower after hemin infusion and these mice exhibited less severe lung injury and less necroptotic cell death. In vitrostudies confirmed that cortactin deficiency is protective against hemin-in...
Source: American Journal of Physiology. Lung Cellular and Molecular Physiology - Category: Cytology Authors: Source Type: research