Prevention of trauma/hemorrhagic shock-induced lung apoptosis by IL-6-mediated activation of Stat3.
Acute lung injury (ALI) occurs in up to 37% of patients following trauma/hemorrhagic shock (T/HS) and, in other settings, is due to alveolar epithelial cell (AEC) apoptosis. To determine if AEC apoptosis is a key contributor to ALI following T/HS and whether or not signal transducer and activator of translation (Stat)3 activation can prevent it, rats were pretreated with a Stat3 inhibitor or placebo and subjected to T/HS or sham protocol and resuscitated without or with interleukin (IL)-6. T/HS induced apoptosis in up to 15% of lung cells, 82% of which were AEC. Apoptosis increased with increasing duration of shock and required resuscitation. IL-6 treatment stimulated lung Stat3 activation and prevented AEC apoptosis. Pretreatment of rats with a Stat3 inhibitor blocked the antiapoptotic effect of IL-6. Mice deficient in Stat3 beta, a naturally occurring dominant negative isoform of Stat3, were resistant to T/HS-induced lung apoptosis. T/HS altered the expression of 87% of apoptosis-related genes. IL-6 treatment normalized expression of 75% of the genes altered by T/HS; Stat3 inhibition prevented normalization of 65% of the gene whose expression was normalized by IL-6. Thus, T/HS-induced AEC apoptosis, which depended on the duration of hypotension, required resuscitation and was prevented by IL-6-mediated activation of Stat3, which acted to normalize the apoptosis transcriptome.
Moran
Ana
A
Infectious Diseases Section and Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
Tsimelzon
Anna I
AI
Mastrangelo
Mary-Ann A
MA
Wu
Yong
Y
Yu
Bi
B
Hilsenbeck
Susan G
SG
Poli
Valeria
V
Tweardy
David J
DJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D054856:G-Quadruplexes; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000008:administration & dosage / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000473:pathology*; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D012771:Shock, Hemorrhagic / Q000150:complications*; D014947:Wounds and Injuries / Q000150:complications*
D015850:Interleukin-6; D009838:Oligodeoxyribonucleotides; D050796:STAT3 Transcription Factor