| First Author | Jones NM | Year | 2022 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 322 |
| Issue | 6 | Pages | L890-L897 |
| PubMed ID | 35503995 | Mgi Jnum | J:325670 |
| Mgi Id | MGI:7281006 | Doi | 10.1152/ajplung.00274.2021 |
| Citation | Jones NM, et al. (2022) Cortactin Loss Protects Against Hemin-Induced Acute Lung Injury in Sickle Cell Disease. Am J Physiol Lung Cell Mol Physiol |
| abstractText | In 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 micromol/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-induced injury in HMLVECs, by decreasing protein expression of p38/HSP27, and improving cell barrier function and decreasing the production of ROS. Further studies examining the role of CTTN in ACS are warranted, and may open a new avenue of potential treatment for this devastating disease. |
