A single dose of eHSP72 attenuates sepsis severity in mice

Abstract

High levels of extracellular 72 kDa heat shock protein (eHSP72) can be detected in the serum of septic patients and are associated with increased oxidative profiles and elevated rates of mortality among these patients. However, a possible immunomodulatory role for this protein, resulting in tissue protection during sepsis, has never been assessed. In this study, we investigated whether eHSP72 administration could attenuate the severity of sepsis in a mouse peritonitis model. Animals (90-day-old male C57BL/6J mice) were divided into Sepsis (n = 8) and Sepsis + eHSP72 (n = 9) groups, which both received injections of 20% fecal solution [1 mg/g body weight (wt), intraperitoneal (i.p.)], to trigger peritonitis induced-sepsis, whereas a Control group (n = 7) received a saline injection. eHSP72 was administered (1.33 ng/g body wt) to the Sepsis+eHSP72 group, 12 h after sepsis induction. All animals were evaluated for murine sepsis score (MSS), hemogram, core temperature, and glycemia (before and 4, 12, and 24 h after sepsis induction). Treatment with eHSP72 promoted reduced sepsis severity 24 h after sepsis induction, based on MSS scores (Control = 1.14 ± 1.02; Sepsis = 11.07 ± 7.24, and Sepsis + eHSP72 = 5.62 ± 1.72, P < 0.001) and core temperatures (°C; Control = 37.48 ± 0.58; Sepsis = 35.17 ± 2.88, and Sepsis + eHSP72 = 36.94 ± 2.02; P = 0.006). eHSP72 treatment also limited the oxidative profile and respiratory dysfunction in mice with sepsis. Although sepsis modified glycemic levels and white and red blood cell counts, these variables were not influenced by eHSP72 treatment (P > 0.05). Finally, eHSP72 improved the survival rate after sepsis (P = 0.0371). Together, our results indicated that eHSP72 may ameliorate sepsis severity and possibly improve some sepsis indices in mice.

Protective Effect of Arbidol Against Pulmonary Fibrosis and Sepsis in Mice

“…As the most common source of infection in patients with sepsis comes from the abdominal cavity, in recent years, the abdominal infection model has been gradually used as a commonly used animal model of sepsis. Animal models of fecal peritonitis have been widely used in sepsis research ( Dyson et al, 2011 ; Rudiger et al, 2013 ; Jeger et al, 2017 ; Sulzbacher et al, 2020 ). Since our laboratory cannot perform virus tests, in this study, we used fecal diluent-induced sepsis mice to simulate the cytokine storm symptoms of COVID-19 to a certain extent.…”

Suppressed anti-inflammatory heat shock response in high-risk COVID-19 patients: lessons from basic research (inclusive bats), light on conceivable therapies

“…High levels eHSP72 are found in the plasma of septic patients and are related with fatal outcome if associated with a concomitant high plasma oxidative profile [ 202 ], which probably involves loss of eHSP72 immune signaling property after oxidation [ 203 ]. However, a single dose of non-oxidized (native) recombinant mouse eHSP72 attenuates sepsis severity and enhances survival rate in mice, perhaps because eHSP72 may be taken up by immune cells leading to a new immunoinflammatory poise [ 204 ]. Otherwise, intracellular HSP72 (iHSP72) expression in monocytes and polymorphonuclear cells are repressed and related to decreased CD14/HLA-DR expression and mortality in critically ill patients with sepsis [ 205 ], while anti-inflammatory HSR would be increased by glutamine administration in septic patients [ 92 , 150 ].…”

Therapeutic role of Filarial HSP70 in murine models of polymicrobial sepsis and H1N1 Influenza

“…Our observation that FHSP70 being a pro-inflammatory molecule improves survival against polymicrobial Sepsis only when administered after onset of sepsis (which simulates real life scenario in human patients) and not when administered early (within 6 hours) after CLP procedure, fits into the existing conundrum of pathogenesis of Sepsis viz., immune paralysis observed in later stages of sepsis needing reversal and reprogramming by induction of host inflammatory responses using pro-inflammatory molecules. A recent report on therapeutic benefit of extracellular mammalian HSP72 in a mouse model of peritonitis offers further credence (30) since FHSP70 was found to be a TLR2 and TLR4 agonist as shown in this manuscript. Filarial HSP70 homologue was superior to human HSP70 in inducing protection against sepsis possibly attributable to 22% dissimilarity between Human and Filarial HSP70 in their C-terminal sequence.…”