Mechanisms of imporvement following functional inhibition of nitrosative stress after brun and smoke-induced acute lung injury

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Title: Mechanisms of imporvement following functional inhibition of nitrosative stress after brun and smoke-induced acute lung injury
Author: Aimalohi Esechie
Abstract: Severe trauma , caused by flame burn and smoke (B + S ) inhalation induces acute lung injury (ALI ) and results in the loss of pulmonary function . A cascade of molecular and cellular events initiates the formation of reactive oxygen /nitrogen species (ROS /RNS ) that in turn drives an inflammatory response and consequently cell death through hyper -activation of poly (ADP -ribose ) polymerase (PARP -1 ) . The purpose of this study was to investigate and counteract pulmonary dysfunction associated with nitrosative stress generated after B + S inhalation injury in an ovine and murine model of ALI . \r \nIn our time course experiment , sheep were sacrificed at 4 , 8 , 12 , 18 and 24 hours post B + S injury . From 4 through 24 hours , there was a progressive increase in airway obstruction and lung edema formation . Furthermore , injury was associated with increased ROS /RNS generation , pro -inflammatory cytokine expression and neutrophil accumulation . Additionally , PARP -1 enzymatic activity increased in parallel with Hoechst 3324 nuclear staining in sheep lung sections . \r \nTreatment after ALI with a hydrogen sulfide (H2S ) donor compound , a peroxynitrite scavenger , was tested to determine the effect on mortality , pulmonary shunt fraction and gas exchange . The H2S donor increased animal survival . Additionally the rapid decline in PaO2 /FiO2 , reduced the pulmonary shunt fraction and elevated airway pressures were improved . Likewise , the lung histological assessment demonstrated marked increase in aerated areas in lung sections . \r \nBurn and smoke injury generates reactive oxygen species and nitrogen species and influences inflammatory cytokine expression . Pro - and anti -inflammatory cytokine protein levels were measured in the lung parenchyma as well as 3 -nitrotyrosine and protein carbonyl formation (indices of RNS and ROS generation , respectively ) . In our murine study , treatment with the H2S donor significantly reduced the pro - inflammatory cytokine level and increased the anti -inflammatory cytokine concentration in the lung . Additionally , ROS and RNS generation were significantly lowered . \r \nThese results demonstrate the effectiveness of inhibiting nitrosative stress after burn and smoke injury using a H2S donor and a possible mechanism for improved outcomes may be the altered the expression pattern of pro - and anti -inflammatory cytokines and ROS generation which may contribute to dysfunctional outcomes after B+ S inhalation injury . \r \n \r \n
URI: http : / /hdl .handle .net /2152 .3 /222
Date: 2008-07-28

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Mechanisms of imporvement following functional inhibition of nitrosative stress after brun and smoke-induced acute lung injury. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /222 .

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