Anti-IFNAR1 Antibodies Attenuate Inflammation and Organ Injury Following Hemorrhagic Shock

Background Hemorrhagic 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. Methods Male C57BL/6 mice (20-25 g) underwent hemorrhage by controlled bleeding via the femoral artery to maintain a mean arterial pressure (MAP) of 27±2.5 mmHg for 90 min, followed by resuscitation for 30 min 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 h after the resuscitation for various analyses. Results The expression of IFN-α and IFN-β mRNAs was significantly elevated in lungs and liver of the mice after HS. IFNAR1-Ab treatment significantly decreased serum levels of organ injury markers LDH and AST, as well as improved the integrity of lung and liver morphology, compared to the IgG control. The protein levels of pro-inflammatory cytokines TNF-α and IL-6, and mRNA expression of pro-inflammatory chemokines MCP-1, MCP-2, MIP-2, and 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. Conclusion Administration of IFNAR1-Ab reduce 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 type Translational animal model Level of evidence Basic Science – Class 1 (http://www.ahrq.gov/) Ethics approval. All experiments involving live animals were carried out in accordance with the National Institutes of Health guidelines for the use of experimental animals and were reviewed and approved by the Institutional Animal Care and Use Committee at the Feinstein Institute for Medical Research. Availability of data and materials. The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Conflict of Interest Statement: The authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest. Funding: This work was supported by National Institutes of Health grant R01HL076179 and R35GM118337 (to P.W.). © 2019 Lippincott Williams & Wilkins, Inc.

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