Interleukin-6 production in hemorrhagic shock is accompanied by neutrophil recruitment and lung injury.
Hemorrhagic shock (HS) initiates an inflammatory cascade that includes the production of cytokines and recruitment of neutrophils (PMN) and may progress to organ failure, inducing acute respiratory distress syndrome (ARDS). To examine the hypothesis that interleukin-6 (IL-6) contributes to PMN infiltration and lung damage in HS, we examined the lungs of rats subjected to unresuscitated and resuscitated HS for the production of IL-6 and activation of Stat3. Using semiquantitative RT-PCR, we found a striking increase in IL-6 mRNA levels only in resuscitated HS, with peak levels observed 1 h after initiation of resuscitation. Increased IL-6 protein expression was localized to bronchial and alveolar cells. Electrophoretic mobility shift assay of protein extracts from shock lungs exhibited an increase in Stat3 activation with kinetics similar to IL-6 mRNA. In situ DNA binding assay determined Stat3 activation predominantly within alveoli. Intratracheal instillation of IL-6 alone into normal rats resulted in PMN infiltration into lung interstitium and alveoli, marked elevation of bronchoalveolar lavage cellularity, and increased wet-to-dry ratio. These findings indicate that IL-6 production and Stat3 activation occur early in HS and may contribute to PMN-mediated lung injury, including ARDS after HS.
Hierholzer
C
C
Department of Surgery, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA.
Kalff
J C
JC
Omert
L
L
Tsukada
K
K
Loeffert
J E
JE
Watkins
S C
SC
Billiar
T R
TR
Tweardy
D J
DJ
D000818:Animals; D001980:Bronchi / Q000276:immunology / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007322:Instillation, Drug; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology; D008168:Lung / Q000276:immunology / Q000473:pathology*; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D009195:Peroxidase / Q000032:analysis; D016133:Polymerase Chain Reaction; D011650:Pulmonary Alveoli / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D012151:Resuscitation; D050796:STAT3 Transcription Factor; D012771:Shock, Hemorrhagic / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D015850:Interleukin-6; D012333:RNA, Messenger; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494088:Stat3 protein, rat; D015534:Trans-Activators; D009195:Peroxidase