Increased extracellular heat shock protein 90α in severe sepsis and SIRS associated with multiple organ failure and related to acute inflammatory-metabolic stress response in children

Abstract

Mammalian heat-shock-protein (HSP) 90α rapidly responses to environmental insults. We examined the hypothesis that not only serum HSP72 but also HSP90α is increased in the systemic inflammatory response syndrome (SIRS), severe-sepsis (SS), and/or sepsis (S) compared to healthy children (H); we assessed HSP90α relation to (a) multiple organ system failure (MOSF) and (b) inflammatory-metabolic response and severity of illness.A total of 65 children with S, SS, or SIRS and 25 H were included. ELISA was used to evaluate extracellular HSP90α and HSP72, chemiluminescence interleukins (ILs), flow-cytometry neutrophil-CD64 (nCD64)-expression.HSP90α, along with HSP72, were dramatically increased among MOSF patients. Patients in septic groups and SIRS had elevated HSP90α compared to H (P < 0.01). HSP90α was independently related to predicted death rate and severity of illness; positively to HSP72, nCD64, ILs, length of stay, days on ventilator, and fever; negatively to HDL and LDL (P < 0.05). The HSP72 was increased in SS/S and related negatively to HDL and LDL (P < 0.05).Serum HSP90α is markedly elevated in children with severe sepsis and is associated with MOSF. Better than the HSP72, also increased in SS, SIRS, and MOSF, HSP90α is related to the inflammatory stress, fever, outcome endpoints, and predicted mortality and inversely related to the low-LDL/low-HDL stress metabolic pattern.

Figure 1

(A) Patients with severe sepsis, sepsis, or SIRS had increased extracellular HSP90α in comparison to healthy controls; (B) patients with severe sepsis or sepsis had increased extracellular HSP72 in comparison to healthy controls and/or SIRS (Mann–Whitney tests). HSP = heat shock protein, SIRS = systemic inflammatory response syndrome.

Figure 2

Patients with MOSF had increased. (A) Extracellular HSP90α and (B) extracellular HSP72 compared to non-MOSF patients (Mann–Whitney test). HSP = heat shock protein, MOSF = multiple organ system failure.

Figure 3

Positive correlations of HSP90α serum concentrations with serum levels of: (A–D) Interleukins and CRP; (E–H) days on ventilator, length of stay (LOS), organ dysfunction (PELOD), and PRISM-predicted death rate as indicated. Spearman rank correlation test, correlation coefficient r, and P values are given. CRP = C-reacting protein, HSP = heat shock protein, IL = interleukin, LOS = length of stay, PELOD = Pediatric Logistic Organ Dysfunction Score, PRISM = Pediatric Risk of Mortality Score.

Figure 4

Positive correlations of HSP90α serum concentrations with: (A–D) Serum levels of HSP72, nCD64 expression, glucose and triglycerides; (E–H) negative correlations of HSP90α and HSP72 serum concentrations with LDL and HDL as indicated. Spearman rank correlation test, correlation coefficient r, and P values are given. HDL = high-density lipoproteins, HSP = heat shock protein, LDL = low-density lipoproteins, nCD64 = neutrophil CD64.