A rat model of smoke inhalation injury: influence of combustion smoke on gene expression in the brain.
Acute smoke inhalation causes death and injury in victims of home and industrial fires as well as victims of combat situations. The lethal factors in combustion smoke inhalation are toxic gases and oxygen deficiency, with carbon monoxide (CO) as a primary cause of death. In survivors, inhalation of smoke can result in severe immediate and delayed neuropathologies. To gain insight into the progression of molecular events contributing to smoke inhalation sequelae in the brain, we developed a smoke inhalation rat model and conducted a genome-wide analysis of gene expression. Microarray analysis revealed a modified brain transcriptome with changes peaking at 24 h and subsiding within 7 days post-smoke. Overall, smoke inhalation down regulated genes associated with synaptic function, neurotransmission, and neurotrophic support, and upregulated genes associated with stress responses, including nitric oxide synthesis, antioxidant defenses, proteolysis, inflammatory response, and glial activation. Notably, among the affected genes, many have been previously implicated in other types of brain injury, demonstrating the usefulness of microarrays for analysis of changes in gene expression in complex insults. In accord with previously described modulations of nitric oxide homeostasis in CO poisoning, microarray analysis revealed increased brain expression of nitric oxide synthase (NOS) and NOS ligand after inhalation of smoke. Furthermore, immunostaining showed significant elevations in perivascular NOS and in protein nitration, corroborating the involvement of nitric oxide perturbations in post-smoke sequelae in the brain. Thus, the new rat model, in combination with microarray analyses, affords insight into the complex molecular pathophysiology of smoke inhalation in the brain.
Lee
Heung M
HM
Shriners Hospital for Children, 815 Market Street, Galveston, TX 77550, USA; Department of Surgery, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.
Greeley
George H
GH
Herndon
David N
DN
Sinha
Mala
M
Luxon
Bruce A
BA
Englander
Ella W
EW
D000818:Animals; D001784:Blood Gas Analysis / Q000379:methods; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D002263:Carboxyhemoglobin / Q000032:analysis / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods*; D007120:Immunochemistry / Q000379:methods; D007928:Lethal Dose 50; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012906:Smoke / Q000009:adverse effects*; D015208:Smoke Inhalation Injury / Q000139:chemically induced* / Q000401:mortality; D013997:Time Factors; D036401:Toxicity Tests, Chronic / Q000379:methods; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
D012906:Smoke; D002263:Carboxyhemoglobin