Robust acute-phase response highlights necessity of time-matched sham-operated controls in early liver ischemia/reperfusion injury studies

Most mechanistic studies on hepatic ischemia/reperfusion injury (IRI) are performed in rodent models with 30-60 min of 70% warm ischemia (occlusion of left and median liver lobes), followed by 3-6 (early) or 24-48 hours (late) of reperfusion. These studies frequently demonstrate strong inflammatory responses. However, many investigations rely on a single sham-operated control group, often sacrificed after the longest reperfusion, leaving no controls for early reperfusion time points.

In this study, we compared hepatic IRI with sham-operated counterparts at early reperfusion times (30 min ischemia, 3 h and 5 h reperfusion). Both groups displayed similar robust inductions of pro-inflammatory cytokines (Il6, Osm, Il1b, Cxcl2), acute-phase genes (Saa2, Cd14, Lbp, Hamp1, Icam1), and modulation of cytokine receptor expression (Il6st, Osmr, Lifr). This suggests that much of the acute inflammatory response is triggered by the laparotomy needed for vascular occlusion rather than IRI itself. While most of the inflammatory response declined between 5 h and 7 h of reperfusion, the acute-phase gene Saa2 continued to increase, indicating it may be specifically linked to IRI.

In conclusion, our study underscores the importance of incorporating time-matched sham-operated controls to accurately assess and interpret hepatic IRI mechanisms, as laparotomy alone triggers a potent acute-phase response. Without these controls, it is challenging to distinguish IRI-specific and surgery-induced inflammatory responses during early reperfusion. Similarly, comparisons between wild-type and knock-out models require time-matched sham-operated controls to confirm that observed phenotypic differences are directly attributable to changes in response to hepatic IRI rather than to the general acute-phase reaction.

Publication History

Article published online:
20 January 2025