Acute pancreatitis (AP), with severe complications and high mortality under severe condition which called SAP, is an inflammatory condition of the pancreas. A manifestation of the inflammatory response is a hallmark of AP. In early SAP, the acinar cell injury causes the pancreatic cells secret inflammatory mediators like TNF-α and IL-10, which extend the inflammatory response and cause the organ injury. Our study showed that in the early stage of SAP, the HO-1 gene expression increased in the pancreas and liver. Also, induction of HO-1 by hemin treatment significantly increased plasma IL-10 and also decreased TNF-α, which modulated the inflammatory reaction, oxidative damage, and organs injury. These results demonstrated the beneficial effects of HO-1 in early SAP through mediating the systemic inflammatory response, indicating that HO-1 plays an important role in protecting pancreas and nearby organs from injury under SAP [
3,
11,
15‐
17].
SAP is associated with the induction of several cytokines, including pro-inflammatory and anti-inflammatory mediators [
18‐
20]. Some studies have demonstrated that TNF-α, which is secreted by activated macrophage and lymphocyte, plays an important role in the occurrence and development of SAP [
21]. Induction of TNF-α subsequently induces the expression and secretion of IL-6, IL-8 as well as itself, causing the inflammatory cascade and the uncontrolled releasing of inflammatory mediators [
18], which eventually cause the organs failure or even death. In contrast, IL-10, which is produced by macrophages, Th2 cells, hepatocytes and stellate cells, has the anti-inflammation effect in inflammatory diseases [
22]. IL-10 inhibits the synthesis of pro-inflammatory cytokines, such as IL-2, IL-3 and TNF-α, and also prevents MODS caused by SAP [
20,
23]. In our study, induction of HO-1 by Hemin in early SAP significantly decreased TNF-α in plasma and tissues, while the plasma and tissues IL-10 level was increased. In contrast, inhibition of HO-1 expression by Zn-PP treatment increased TNF-α and decreased IL-10 in plasma and tissues. So, it suggested that HO-1 plays a protective role in SAP through anti-inflammatory pathways. The heme metabolites catalyzed by HO-1 have anti-inflammatory effects through induction of IL-10 [
10,
24]. It is still need to illuminate whether the protective effects of HO-1 in SAP is attributed to its metabolites, CO or the antioxidant bilirubin [
25‐
28]. Dependent on the modulation of p38 mitogen-activated protein kinase (MAPK), CO showed anti-inflammation effect through inhibition of pro-inflammatory cytokines production [
29,
30]. Our data demonstrated that the induction of HO-1 in early SAP can inhibit the inflammatory response through mediating the cytokines production and mitigate the damage to pancreas and nearby organs such as liver, indicating that HO-1 may function as therapeutic target for the treatment of SAP.
HO-1 is a stress-inducible enzyme which catalyzes the degradation of heme into CO, iron and biliverdin [
7]. Under oxidative stress, such as inflammation and ischemia-reperfusion, HO-1 is induced and protects organs from damage, which in part by the anti-inflammatory effect of heme metabolites [
31‐
35]. The expression of genes responsible for oxidative stress, especially HO-1 [
16,
36,
37], are remarkably upregulated in the course of SAP, which suggests the existence of a compensatory mechanism against stress. Like most of the antioxidants, which protect organs from oxidative stress caused apoptosis and failure [
38‐
40], hemin treatment induced HO-1 expression in early SAP and mitigated pancreas injury caused by oxidative stress and inflammation. In contrast, inhibition of HO-1 expression by Zn-PP aggravated the organs injury in SAP. These results indicated that induction of HO-1 in SAP may provide a new and effective therapeutic strategy for SAP.