Combined effect of anti‐high‐mobility group box‐1 monoclonal antibody and peramivir against influenza A virus‐induced pneumonia in mice

Abstract

Human pandemic H1N1 2009 influenza virus causes significant morbidity and mortality with severe acute lung injury due to the excessive inflammatory reaction, even with neuraminidase inhibitor use. The anti‐inflammatory effect of anti‐high‐mobility group box‐1 (HMGB1) monoclonal antibody (mAb) against influenza pneumonia has been reported. In this study, we evaluated the combined effect of anti‐HMGB1 mAb and peramivir against pneumonia induced by influenza A (H1N1) virus in mice. Nine‐week‐old male C57BL/6 mice were inoculated with H1N1 and treated with intramuscularly administered peramivir at 2 and 3 days post‐infection (dpi). The anti‐HMGB1 mAb or a control mAb was administered at 2, 3, and 4 dpi. Survival rates were assessed, and lung lavage and pathological analyses were conducted at 5 and 7 dpi. The combination of peramivir with the anti‐HMGB1 mAb significantly improved survival rate whereas the anti‐HMGB1 mAb alone did not affect virus proliferation in the lungs. This combination therapy also significantly ameliorated histopathological changes, neutrophil infiltration, and macrophage aggregation by inhibiting HMGB1, inflammatory cytokines, and oxidative stress. Fluorescence immunostaining showed that the anti‐HMGB1 mAb inhibited HMGB1 translocation from type I alveolar epithelial cells. In summary, combining anti‐HMGB1 with conventional anti‐influenza therapy might be useful against severe influenza virus infection.

Targeting Inflammation Driven by HMGB1

“…Successful therapeutic interventions are reported in a number of experimental neuro-inflammatory conditions, including stroke (70), traumatic brain injury (71), cognitive dysfunction after traumatic brain injury (72), spinal cord injury (73), epilepsy (74,75), blood brain barrier dysfunction after CNS ischemia (76), hemorrhageinduced brain injury (77), neuropathic pain (78)(79)(80)(81)(82)(83), and neuropathic pain-related depressive behavior (84). The antibody has also demonstrated beneficial effects in severe mouse influenza models (85,86). Taken together, these findings demonstrated impressive treatment results in severe preclinical disease models.…”

Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?

“…The biological implications of this mechanism may be of tremendous importance for the pathogenesis of severe pulmonary inflammation because the high constitutive cell surface RAGE expression. It has been demonstrated in preclinical and clinical studies that severe respiratory infections including influenza and human respiratory syncytial virus (HRSV) generate substantial extracellular HMGB1 release in pulmonary inflammation and that HMGB1-specific antagonists ameliorate these conditions (Ito et al 2011;Nosaka et al 2015;Nosaka et al 2018;Hatayama et al 2019;Manti et al 2018;Rayavara et al 2018;Rallabhandi et al 2012;Simpson et al 2020). Extracellular HMGB1 accumulates locally due to passive release from dying cells and active secretion from innate immunity cells and additional cell types.…”

“…Successful preclinical treatment results using specific HMGB1-, TLR4or RAGE-antagonists further support that the HMGB1/ RAGE/TLR4-axis is central in the pathogenesis of influenza infections. Treatment with anti-HMGB1 mAb provided partial protection against both pneumonia and encephalopathy in murine models of influenza infections despite that the treatments did not affect virus propagation in the lungs (Nosaka et al 2015;Nosaka et al 2018;Hatayama et al 2019). Combined anti-HMGB1 mAb and anti-viral treatment offered almost complete protection against lung injury (Hatayama et al 2019).…”

“…Treatment with anti-HMGB1 mAb provided partial protection against both pneumonia and encephalopathy in murine models of influenza infections despite that the treatments did not affect virus propagation in the lungs (Nosaka et al 2015;Nosaka et al 2018;Hatayama et al 2019). Combined anti-HMGB1 mAb and anti-viral treatment offered almost complete protection against lung injury (Hatayama et al 2019). Improved survival combined with significantly attenuated histological changes and neutrophil infiltration in the lungs of influenza-inoculated mice have been reported, despite that the treatment was based on xenogenic polyclonal antibodies against HMGB1 .…”

Pharmacological inhibition of poly (ADP-ribose) polymerase by olaparib ameliorates influenza-virus-induced pneumonia in mice

“…The murine model of viral pneumonia was constructed by intranasal infection with H1N1 according to previously described [13]. Briefly, ketamine (50 mg/kg weight) and pentobarbital (30 mg/kg weight) were intraperitoneally injected to induce the mild anesthesia in mice.…”