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Cortactin Heterozygous Mice with Sickle Cell Disease are Protected Against Hemin-Induced Acute Lung Injury
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A4199 - Cortactin Heterozygous Mice with Sickle Cell Disease are Protected Against Hemin-Induced Acute Lung Injury
Author Block: N. M. Jones1, J. Sysol2, S. Singla2, H. Wang2, S. M. Dudek2, R. F. Machado1; 1Division of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Indiana University School of Medicine, Indianapolis, IN, United States, 2Division of Pulmonary, Critical Care, Sleep, and Allergy, University of Illinois at Chicago, Chicago, IL, United States.
Introduction: In 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 shown to lead to endothelial cell activation and subsequent ALI and ACS in vitro and animal studies. Here, we examined the role of cortactin (Cttn), a cytoskeletal protein that regulates endothelial cell barrier function, in response to hemin-induced ALI and ACS.
Methods: Cortactin heterozygous (Cttn+/-) mice (n=8) and their wild type siblings (n=8) were irradiated and subsequently received bone marrow cells (BMC) extruded from the femurs of SCD mice. Each Cttn or wild type recipient mouse received approximately 1 x 107 cells from the one time transplant. Following hemoglobin electrophoretic proof of BMC transplantation 10 weeks later, the mice received 35 µmol/kg of hemin. Within 24 hours surviving mice were sacrificed and bronchoalveolar (BAL) and lung samples were analyzed.
Results and Conclusion: When compared with wild type littermates the mortality for Cttn+/- mice was lower (Cttn+/- =87.5%, Cttn WT= 62.5%, P value =0.2278) after hemin infusion. Analysis of BAL showed that protein concentrations in BAL fluid of Cttn WT mice were nearly 50% higher than in Cttn+/- mice (Cttn+/- = 496.0 µg/mL ml, Cttn WT= 934.2 µg/mL, n=8, p=0.0041). We also found that cell infiltration in the lungs of Cttn WT mice was greater than the amount found in Cttn+/- mice (Cttn WT= 1.318 x 107 cells/ml, Cttn+/- =0.7728 x 107 cells/ml, n=8, p=0.0078). Histological analysis demonstrated a higher degree of hemin-induced injury in the lungs of the Cttn WT mice compared with the lungs of the Cttn+/- mice. Our results show that reduction of cortactin expression appears to protect against hemin-induced ACS in SCD. Studies are currently underway to understand the mechanisms associated with this effect.
Author Block: N. M. Jones1, J. Sysol2, S. Singla2, H. Wang2, S. M. Dudek2, R. F. Machado1; 1Division of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Indiana University School of Medicine, Indianapolis, IN, United States, 2Division of Pulmonary, Critical Care, Sleep, and Allergy, University of Illinois at Chicago, Chicago, IL, United States.
Introduction: In 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 shown to lead to endothelial cell activation and subsequent ALI and ACS in vitro and animal studies. Here, we examined the role of cortactin (Cttn), a cytoskeletal protein that regulates endothelial cell barrier function, in response to hemin-induced ALI and ACS.
Methods: Cortactin heterozygous (Cttn+/-) mice (n=8) and their wild type siblings (n=8) were irradiated and subsequently received bone marrow cells (BMC) extruded from the femurs of SCD mice. Each Cttn or wild type recipient mouse received approximately 1 x 107 cells from the one time transplant. Following hemoglobin electrophoretic proof of BMC transplantation 10 weeks later, the mice received 35 µmol/kg of hemin. Within 24 hours surviving mice were sacrificed and bronchoalveolar (BAL) and lung samples were analyzed.
Results and Conclusion: When compared with wild type littermates the mortality for Cttn+/- mice was lower (Cttn+/- =87.5%, Cttn WT= 62.5%, P value =0.2278) after hemin infusion. Analysis of BAL showed that protein concentrations in BAL fluid of Cttn WT mice were nearly 50% higher than in Cttn+/- mice (Cttn+/- = 496.0 µg/mL ml, Cttn WT= 934.2 µg/mL, n=8, p=0.0041). We also found that cell infiltration in the lungs of Cttn WT mice was greater than the amount found in Cttn+/- mice (Cttn WT= 1.318 x 107 cells/ml, Cttn+/- =0.7728 x 107 cells/ml, n=8, p=0.0078). Histological analysis demonstrated a higher degree of hemin-induced injury in the lungs of the Cttn WT mice compared with the lungs of the Cttn+/- mice. Our results show that reduction of cortactin expression appears to protect against hemin-induced ACS in SCD. Studies are currently underway to understand the mechanisms associated with this effect.
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