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Browsing by Subject "Necroptosis"
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Item Cortactin loss protects against hemin-induced acute lung injury in sickle cell disease(American Physiological Society, 2022) Jones, Nicole M.; Sysol, Justin R.; Singla, Sunit; Smith, Patricia; Sandusky, George E.; Wang, Huashan; Natarajan, Viswanathan; Dudek, Steven M.; Machado, Roberto F.; Medicine, School of MedicineIn patients with sickle cell disease (SCD), acute chest syndrome (ACS) is a common form of acute lung injury and 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 acute lung injury (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 (n = 8) and their wild-type siblings (n = 8) were irradiated and subsequently received bone marrow cells (BMCs) extruded from the femurs of 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 h, surviving mice were euthanized, 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 vitro studies confirmed that cortactin deficiency is protective against hemin-induced injury in HMLVECs, by decreasing protein expression of p38/HSP27, 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.Item Necroptosis is SARMful to your health(Rockefeller University Press, 2020-08-03) Pierchala, Brian A.; Anatomy and Cell Biology, School of MedicineNecroptosis is a cell death pathway involved in inflammation and disease. In this issue, Ko et al. (2020. J. Cell Biol.https://doi.org/10.1083/jcb.201912047) link SARM1, the executioner of Wallerian degeneration of axons, to necroptosis, revealing a unique form of axonal disassembly likely involved in neurodegenerative disorders.Item A surfactant polymer wound dressing protects human keratinocytes from inducible necroptosis(Springer Nature, 2021-02-23) Khandelwal, Puneet; Das, Amitava; Sen, Chandan K.; Srinivas, Sangly P.; Roy, Sashwati; Khanna, Savita; Surgery, School of MedicineChronic wounds show necroptosis from which keratinocytes must be protected to enable appropriate wound re-epithelialization and closure. Poloxamers, a class of synthetic triblock copolymers, are known to be effective against plasma membrane damage (PMD). The purpose of this study is to evaluate the efficacy of a specific poloxamer, surfactant polymer dressing (SPD), which is currently used clinically as wound care dressing, against PMD in keratinocytes. Triton X-100 (TX100) at sub-lytic concentrations caused PMD as demonstrated by the efflux of calcein and by the influx of propidium iodide and FM1-43. TX100, an inducer of necroptosis, led to mitochondrial fragmentation, depletion of nuclear HMGB1, and activation of signaling complex associated with necroptosis (i.e., activation of RIP3 and phosphorylation of MLKL). All responses following exposure of human keratinocytes to TX100 were attenuated by pre- or co-treatment with SPD (100 mg/ml). The activation and translocation of phospho-MLKL to the plasma membrane, taken together with depletion of nuclear HMGB1, characterized the observed cell death as necroptosis. Thus, our findings show that TX100-induced plasma membrane damage and death by necroptosis were both attenuated by SPD, allowing keratinocyte survival. The significance of such protective effects of SPD on keratinocytes in wound re-epithelialization and closure warrant further studies.