Kupffer cells are the resident macrophage population of the liver and have previously been implicated in the pathogenesis of hepatic ischemia-reperfusion injury (IRI). Kupffer cells are the major site of expression of hepatic heme oxygenase-1 (HO-1), which has been shown to have anti-inflammatory actions and to protect animals and cells from oxidative injury. Kupffer cells and circulating monocytes were selectively ablated using liposomal clodronate (LC) in the CD11b DTR mouse before induction of hepatic ischemia. Kupffer cell depletion resulted in loss of HO-1 expression and increased susceptibility to hepatic IRI, whereas ablation of circulating monocytes did not affect IRI phenotype. Targeted deletion of HO-1 rendered mice highly susceptible to hepatic IRI. In vivo, HO-1 deletion resulted in pro-inflammatory Kupffer cell differentiation characterized by enhanced Ly6c and MARCO (macrophage receptor with collagenous structure) expression as well as decreased F4/80 expression, mirrored by an expansion in immature circulating monocytes. In vitro, HO-1 inhibition throughout macrophage differentiation led to increased cell numbers, and pro-inflammatory Ly6c+ CD11c- F4/80- phenotype. These data support a critical role for tissue-resident macrophages in homeostasis following ischemic injury, and a co-dependence of HO-1 expression and tissue-resident macrophage differentiation.

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In males with pancreatic cancer, systemic inflammation and opioid use are associated with hypogonadism. Male hypogonadism and female hyperoestrogenism are associated with shortened survival in advanced pancreatic cancer.

BACKGROUND: Macrophage inhibitory cytokine-1(MIC-1) is a potential modulator of systemic inflammation and nutritional depletion, both of which are adverse prognostic factors in oesophago-gastric cancer (OGC). METHODS: Plasma MIC-1, systemic inflammation (defined as plasma C-reactive protein (CRP) of X10 mg l -1 or modified Glasgow prognostic score (mGPS) of X1), and nutritional status were assessed in newly diagnosed OGC patients (n ¼ 293). Healthy volunteers (n ¼ 35) served as controls. RESULTS: MIC-1 was elevated in patients (median ¼ 1371 pg ml -1 ; range 141 -39 053) when compared with controls (median ¼ 377 pg ml -1 ; range 141 -3786; Po0.001). Patients with gastric tumours (median ¼ 1592 pg ml -1 ; range 141 -12 643) showed higher MIC-1 concentrations than patients with junctional (median ¼ 1337 pg ml -1 ; range 383 -39 053) and oesophageal tumours (median ¼ 1180 pg ml -1 ; range 258 -31 184; P ¼ 0.015). Patients showed a median weight loss of 6.4% (range 0.0 -33.4%), and 42% of patients had an mGPS of X1 or plasma CRP of X10 mg l -1 (median ¼ 9 mg l -1 ; range 1 -200). MIC-1 correlated positively with disease stage (r 2 ¼ 0.217; Po0.001), age (r 2 ¼ 0.332; Po0.001), CRP (r 2 ¼ 0.314; Po0.001), and mGPS (r 2 ¼ 0.336; Po0.001), and negatively with Karnofsky Performance Score (r 2 ¼ À0.269; Po0.001). However, although MIC-1 correlated weakly with dietary intake (r 2 ¼ 0.157; P ¼ 0.031), it did not correlate with weight loss, BMI, or anthropometry. Patients with MIC-1 levels in the upper quartile showed reduced survival (median ¼ 204 days; 95% CI 157 -251) when compared with patients with MIC-1 levels in the lower three quartiles (median ¼ 316 days; 95% CI 259 -373; P ¼ 0.036), but MIC-1 was not an independent prognostic indicator. CONCLUSIONS: There is no independent link between plasma MIC-1 levels and depleted nutritional status or survival in OGC.