Heat Shock Protein 72 Expressing Stress in Sepsis: Unbridgeable Gap between Animal and Human Studies—A Hypothetical “Comparative” Study

Table 2

(a) Human in vivo studies relating intra- or extracellular Hsp72 (Hsp70) expression to outcome in sepsis. (b) Human in vitro studies relating intracellular Hsp72 (Hsp70) expression to outcome in sepsis.

(a)

In vivo	Study population/material	Expression in cells/Hsp72 challenge	Extracellular Hsp72 levels	Hsp72 is associated with	Conclusion on the Hsp72 role in sepsis
Patients with septic shock [15, 52]	Children with septic shock (1), adults with severe sepsis (1)	—	Elevated in septic shock (1) nonsurvivors (1) pronounced oxidative damage (1)	Septic shock-mortality (2) modulated according to oxidant status (1)	Related to mortality (2) patient oxidant status (1)
Healthy young men Gln-LPS [53]	Crossover study: Hsp70 in PBMCs (1)	Gln did not affect Hsp70 in PBMCs (1)	—	Gln did not affect LPS-WBC, TBF-𝛼, IL-6, temperature heart rate alterations	Not protective in experimental sepsis (1)

(b)

In vitro	Study population/material	Expression in cells/Hsp72 challenge	Hsp70 is associated with	Conclusion on the Hsp72 role in sepsis
PBMCs-Hsp inhibitor-inducers [54, 55]	PBMCs 24 hours after sepsis (1) sodium arsenite (inducer of Hsp) and quercetin (suppressor of Hsp) to regulate expression of Hsp70 in PMNLs (1)	Hsp70 increased (1) prevented by quercetin (1)	Enhanced TNF-𝛼 (1) increased oxidative activity, inhibited apoptosis (1)	Inconclusive (1) may inhibit apoptosis (1)
LPS-PBMC [56]	LPS inducibility of Hsp70 expression in the PBMC	Inhibits Hsp70 expression in PBMC (in septic patients more than in controls)	Decreased resistance to infectious insults during severe sepsis	May be related to infections
Heat shock, PBMC [57–60]	Heat stress Hsp70 in PBMC (2) or with LPS and training (1) or exercised in heat acclimation (1)	Hsp70 increase (3) inhibited by monensin, methyl-beta-cyclodextrin, and methylamine, reduced in patients with ARDS (2)	Hsp70 decreased in ARDS, recover 𝜀𝛿 over time (1) released from lysosomal lipid rafts (1) Reduced apoptosis, TNF-𝛼, IL-1b, increase 𝛿 CD14/CD16 (1)	Protective (3) not sufficient (1)
Recombinant Hsp70-neutrophils, monocytes [39]	Preconditioning of myeloid cells after LTA addition with rHsp70 (1)	Effect of human recombinant Hsp70 isolated from Spodoptera cells on neutrophil apoptosis and expression of CD11b/CD18 receptors and TNF on ROS production in neutrophils and monocytes	Ameliorated reactive oxygen species, TNF-𝛼, CD11b/CD18, did not normalize apoptosis (1)	Protective (1)
Glutamine-[61]-lymphocytes [62]	Glutamine-PBMCs (1) or lymphocytes (1)	After LPS-HS increased 3-fold Hsp70. A reduction of Gln led to a 40% lower Hsp70 level (2)	Gln decreased TNF-𝛼 (1) Reduced Gln = reduced Hsp70 = impaired stress response (1)	Protective (2)