Anti–interferon-α receptor 1 antibodies attenuate inflammation and organ injury following hemorrhagic shock


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Abstract

BACKGROUNDHemorrhagic shock (HS) is a life-threatening condition resulting from rapid and significant loss of intravascular volume, leading to hemodynamic instability and death. Inflammation contributes to the multiple organ injury in HS. Type I interferons (IFNs), such as IFN-α and IFN-β, are a family of cytokines that regulate the inflammatory response through binding to IFN-α receptor (IFNAR) which consists of IFNAR1 and IFNAR2 chains. We hypothesized that type I IFNs provoke inflammation and worsen organ injury in HS.METHODSMale C57BL/6 mice (20–25 g) underwent hemorrhage by controlled bleeding via the femoral artery to maintain a mean arterial pressure of 27 ± 2.5 mm Hg for 90 minutes, followed by resuscitation for 30 minutes with two times shed blood volume of Ringer's lactate solution containing 1 mg/kg body weight of anti-IFNAR1 antibody (Ab) or control isotype-matched IgG (IgG). Blood and tissue samples were collected at 20 hours after the resuscitation for various analyses.RESULTSThe expression of IFN-α and IFN-β mRNAs was significantly elevated in lungs and liver of the mice after HS. The IFNAR1-Ab treatment significantly decreased serum levels of organ injury markers lactate dehydrogenase and aspartate aminotransferase, as well as improved the integrity of lung and liver morphology, compared to the IgG control. The protein levels of proinflammatory cytokines TNF-α and IL-6, and mRNA expression of proinflammatory chemokines monocyte chemoattractant protein (MCP)-1, MCP-2, macrophage inflammatory protein 2 (MIP-2), and keratinocyte cytokine (KC) in the lungs of the HS mice were significantly decreased after treated with IFNAR1-Ab. Moreover, the myeloperoxidase activity and number of apoptotic cells in the lungs of HS mice treated with IFNAR1-Ab were decreased in comparison to the IgG control.CONCLUSIONAdministration of IFNAR1-Ab reduces inflammation and tissue injury. Thus, type I IFN signaling may be a potential therapeutic target for mitigating organ dysfunction in patients suffering from HS.STUDY TYPETranslational animal model.

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