Early Activation of Liver Apoptotic Signaling Pathways during Heat Stroke Recovery in Mice

Abstract

The inflammatory response to heat stroke (HS) often culminates in multi‐organ failure and death. Liver damage is a long‐term HS response but the early signaling events leading to damage are unknown. This study examined liver apoptotic pathway activation during early HS recovery in mice. Liver expression of 15 signaling phosphoproteins (Multiplex; p‐Akt, p‐c‐Jun, p‐CREB, p‐ERK, p‐GSK3, p‐HSP27, p‐IkBα, p‐IRS1, p‐JNK, p‐MEK1, p‐p38MAPK, p‐p53, p‐p70S6K, p‐p90RSK, p‐STAT3) were measured in B6129F2 mice (n=9/gp) at baseline, maximum core temperature (42.4°C), ~1h and ~3h of HS recovery and compared to non‐heated controls. Liver p‐Akt (833.2±112.8 vs. 1611.1±174.0 mean fluorescence intensity [MFI]) and p‐p38 MAPK (6.6±1.4 vs. 16.6±3.1 MFI) were decreased in HS compared to control mice at all time points (ANOVA, P<0.05). Conversely, p‐JNK was increased above controls through ~1h (79.2±17.7 vs. 21.7±3.3 MFI) and p‐c‐Jun was increased at all time points with a peak at hypothermia (2733.6±616.9 vs.153.8±8.2 MFI; ANOVA, P<0.05). p‐STAT3 was elevated in HS mice at ~1h with a peak at ~3h. HS minimally affected all other proteins. Phosphorylation of c‐Jun and JNK with concomitant Akt and p38 MAPK dephosphorylation suggests liver apoptosis is initiated during early HS recovery. STAT3 activation may be a compensatory response to limit liver damage. Research supported by MRMC. Author views not official US Army or DOD policy.