Multiple organ dysfunction is a life threatening syndrome that affects a considerable proportion of patients after resuscitation from hemorrhagic shock (HS). Lung is a critical target in this insidious process. Histopathologic and physiologic studies have shown that structural and functional changes in the pulmonary endothelium contribute significantly to the pathogenesis of post-HS lung injury. Injury to lung appears to be secondary to systemic events including delivery to the pulmonary circulation of activated neutrophils, cytokines and bacteria (and their toxins) via translocation from ischemic gut and/or liver. The molecular mechanisms responsible for pulmonary damage in post HS lung injury remain unclear but a role for an imbalance between free radicals and cellular defense mechanisms is apparent. We propose that the molecular determinants for enhanced sensitivity of the lung to pro-inflammatory stimuli during resuscitation arise early in the course of HS within resident cells of the alveolar capillary barrier. We theorize that adaptive responses to HS, including increased intrapulmonary synthesis of NO, result in endothelial cell metabolic changes thereby initiating a sequence of events including apoptosis. These compensatory responses may initially be critical components of pulmonary defense, but in the transition to more severe HS, they become maladaptive. The molecular events leading to apoptosis become unbalanced due to excessive production of iNOS-derived NO in the presence of oxidative stress (enhanced superoxide anion production and decreased intracellular thiols). Accordingly, SPECIFIC AIMS are to determine: I. a protective role for metallothionein (MT) in modifying pulmonary endothelial cell injury after resuscitation from HS or hepatic ischemia/reperfusion (I/R) in MT knockout and transgenic mice; II. a contributory role for iNOS-derived NO in post-HS and IR lung injury in iNOS knockout mice; III. the molecular mechanism and intracellular signaling pathways in which NO causes endothelial cell damage and apoptosis during oxidative stress in cultured murine lung endothelial cells(MLEC); and IV. effects of NO on novel gene expression in lung tissue and MLEC during oxidative stress by RT-PCR-differential display.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
1P50GM053789-01A1
Application #
6240646
Study Section
Project Start
1997-06-01
Project End
1998-05-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Schimunek, Lukas; Namas, Rami A; Yin, Jinling et al. (2018) An Enrichment Strategy Yields Seven Novel Single Nucleotide Polymorphisms Associated With Mortality and Altered Th17 Responses Following Blunt Trauma. Shock 49:259-268
Zettel, Kent; Korff, Sebastian; Zamora, Ruben et al. (2017) Toll-Like Receptor 4 on both Myeloid Cells and Dendritic Cells Is Required for Systemic Inflammation and Organ Damage after Hemorrhagic Shock with Tissue Trauma in Mice. Front Immunol 8:1672
Sun, Qian; Loughran, Patricia; Shapiro, Richard et al. (2017) Redox-dependent regulation of hepatocyte absent in melanoma 2 inflammasome activation in sterile liver injury in mice. Hepatology 65:253-268
Zettel, Kent R; Dyer, Mitchell; Raval, Jay S et al. (2017) Aged Human Stored Red Blood Cell Supernatant Inhibits Macrophage Phagocytosis in an HMGB1 Dependent Manner After Trauma in a Murine Model. Shock 47:217-224
Moore, Frederick A; Moore, Ernest E; Billiar, Timothy R et al. (2017) The role of NIGMS P50 sponsored team science in our understanding of multiple organ failure. J Trauma Acute Care Surg 83:520-531
Yang, Yong; Zhang, Peng; Zhao, Yanfeng et al. (2016) Decreased MicroRNA-26a expression causes cisplatin resistance in human non-small cell lung cancer. Cancer Biol Ther 17:515-25
Yang, Weng-Lang; Sharma, Archna; Wang, Zhimin et al. (2016) Cold-inducible RNA-binding protein causes endothelial dysfunction via activation of Nlrp3 inflammasome. Sci Rep 6:26571
Vodovotz, Yoram (2016) Reverse Engineering the Inflammatory ""Clock"": From Computational Modeling to Rational Resetting. Drug Discov Today Dis Models 22:57-63
Yang, Jie; Zhao, Yanfeng; Zhang, Peng et al. (2016) Hemorrhagic shock primes for lung vascular endothelial cell pyroptosis: role in pulmonary inflammation following LPS. Cell Death Dis 7:e2363
Namas, Rami A; Almahmoud, Khalid; Mi, Qi et al. (2016) Individual-specific principal component analysis of circulating inflammatory mediators predicts early organ dysfunction in trauma patients. J Crit Care 36:146-153

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