Impaired induction of IL-10 expression in the lung following hemorrhagic shock

• Published in: Shock (Augusta, Ga.) Vol. 22; no. 4; p. 333
• Main Authors: Khadaroo, Rachel G, Fan, Jie, Powers, Kinga A, Fann, Brand, Kapus, Andras, Rotstein, Ori D
• Format: Journal Article
• Language: English
• Published: United States 01.10.2004
• Subjects: Animals; Blotting, Western; Bronchoalveolar Lavage Fluid - cytology; Chemokines, CXC - metabolism; DNA-Binding Proteins; Intercellular Signaling Peptides and Proteins - metabolism; Interleukin-10 - administration & dosage; Interleukin-10 - metabolism; Lipopolysaccharides - pharmacology; Lung - metabolism; Macrophages, Alveolar - drug effects; Macrophages, Alveolar - metabolism; Male; Neutrophils - drug effects; Rats; Rats, Sprague-Dawley; Resuscitation; RNA, Messenger - metabolism; Shock, Hemorrhagic - metabolism; Sp1 Transcription Factor; Sp3 Transcription Factor; STAT3 Transcription Factor; Trans-Activators; Transcription Factors; Transcription, Genetic - drug effects; Up-Regulation - physiology
• ISSN: 1073-2322
• DOI: 10.1097/01.shk.0000136095.96306.08

The balance between pro- and anti-inflammatory cytokines is considered to be an important determinant of the magnitude of inflammation in a number of disease states. We previously showed that resuscitated hemorrhagic shock augmented LPS-induced release of proinflammatory molecules by alveolar macrophages (AM). In the present studies, we evaluated the expression and regulation of the counter inflammatory cytokine IL-10 in the lung using this model. We hypothesized that impaired up-regulation of IL-10 in shock/resuscitated animals might serve as a mechanism contributing to accentuated lung inflammation. In a rodent model, animals exposed to LPS alone exhibited enhanced IL-10 mRNA levels in lung tissue as well as in AM, but antecedent shock/resuscitation delayed and attenuated the LPS-induced IL-10 mRNA levels. The ability of shock to attenuate LPS-stimulated IL-10 was also seen in the protein levels. This effect correlated with an augmented expression of cytokine-induced neutrophil chemoattractant (CINC) mRNA. Shock/resuscitated animals given exogenous IL-10 had reduced proinflammatory response, as shown by decreased expression of CINC mRNA and decreased neutrophil sequestration in the lung. Shock/resuscitation plus LPS markedly reduced the transcription rate of IL-10 mRNA compared to LPS alone but did not affect IL-10 mRNA stability. Reduced IL-10 transcription was not caused solely by impaired nuclear translocation of STAT3 and Sp1/Sp3 transcription factors because LPS-induced nuclear translocation of these factors was augmented by antecedent shock. Considered together, these findings show that shock/resuscitation suppresses LPS-induced IL-10 expression by AM in the lung by inhibiting IL-10 gene transcription. Failed up-regulation of counter inflammatory cytokines may contribute to augmented organ dysfunction in trauma patients.