by McDowell, Susan Ann

Abstract (Summary)
Acute lung injury is a common, severe respiratory syndrome that can develop from indirect and direct insults to the lung. Despite extensive research since the initial description of acute lung injury over 30 years ago, questions remain about the basic pathogenic mechanisms and their relationship to therapeutic strategies. Microarray analysis during the progression of nickel-induced acute lung injury revealed an overall pattern of gene expression consistent with several pathogenic processes, including oxidative stress. NO can generate oxidative stress, either alone or by the formation of other reactive nitrogen species with reactive oxygen species. NO synthesis can be inhibited by binding of hepatocyte growth factor-like protein to the receptor tyrosine kinase Ron. Mice with a targeted deletion of the tyrosine kinase domain of Ron (Ron tk-/-) overproduce NO in response to endotoxin, therefore, these mice were used to examine whether the overproduction of NO would increase susceptibility to nickel-induced acute lung injury. In response to nickel, Ron tk-/- mice displayed decreased survival time, accelerated cytokine expression, augmented serum nitrite levels, and earlier onset of perivascular edema. To examine whether inhibiting NO would increase resistance to nickel-induced acute lung injury, NO synthesis was inhibited using NG-nitro-L-arginine methyl ester (L-NAME). Sixty-percent of L-NAME treated mice survived nickel-induced acute lung injury versus 5% of saline-treated mice. L-NAME treatment attenuated cytokine expression, polymorphonuclear cell infiltration and protein levels in lavage, and restored cyclin dependent kinase like 2 (Cdkl2) and surfactant gene expression. Restoration of surfactant gene expression is consistent with enhanced survival and attenuation of cytokine expression. These findings indicate that Ron is a key regulator of NO during nickel-induced acute lung injury and that NO inhibition may be protective by restoration of surfactant gene expression.
Bibliographical Information:


School:University of Cincinnati

School Location:USA - Ohio

Source Type:Master's Thesis

Keywords:nickel acute lung injury ron cdna microarray


Date of Publication:01/01/2001

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