title: Proton pump inhibitors protect mice from acute systemic inflammation and induce long-term cross-tolerance.
abstract: Incidence of sepsis is increasing, representing a tremendous burden for health-care systems. Death in acute sepsis is attributed to hyperinflammatory responses, but the underlying mechanisms are still unclear. We report here that proton pump inhibitors (PPIs), which block gastric acid secretion, selectively inhibited tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) secretion by Toll-like receptor (TLR)-activated human monocytes in vitro, in the absence of toxic effects. Remarkably, the oversecretion of IL-1β that represents a hallmark of monocytes from patients affected by cryopyrin-associated periodic syndrome is also blocked. Based on these propaedeutic experiments, we tested the effects of high doses of PPIs in vivo in the mouse model of endotoxic shock. Our data show that a single administration of PPI protected mice from death (60% survival versus 5% of untreated mice) and decreased TNF-α and IL-1β systemic production. PPIs were efficacious even when administered after lipopolysaccharide (LPS) injection. PPI-treated mice that survived developed a long-term cross-tolerance, becoming resistant to LPS- and zymosan-induced sepsis. In vitro, their macrophages displayed impaired TNF-α and IL-1β to different TLR ligands. PPIs also prevented sodium thioglycollate-induced peritoneal inflammation, indicating their efficacy also in a non-infectious setting independent of TLR stimulation. Lack of toxicity and therapeutic effectiveness make PPIs promising new drugs against sepsis and other severe inflammatory conditions.
authors.affiliation: Cell Biology Unit, IRCCS AOU San Martino-IST, 16132 Genoa, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Balza
authors.affiliation: Cell Biology Unit, IRCCS AOU San Martino-IST, 16132 Genoa, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Piccioli
authors.affiliation: Cell Biology Unit, IRCCS AOU San Martino-IST, 16132 Genoa, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Carta
authors.affiliation: Cell Biology Unit, IRCCS AOU San Martino-IST, 16132 Genoa, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Lavieri
authors.affiliation: Pediatrics II Unit, G Gaslini Institute, 16147 Genoa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Gattorno
authors.affiliation: Protein Transport Unit, Division of Cell and Molecular Biology, San Raffaele Institute, 20132 Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Semino
authors.affiliation: Cell Biology Unit, IRCCS AOU San Martino-IST, 16132 Genoa, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Castellani
authors.affiliation: Cell Biology Unit, IRCCS AOU San Martino-IST, 16132 Genoa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Rubartelli
mesh_terms: D000818:Animals; D056587:Cryopyrin-Associated Periodic Syndromes / Q000235:genetics / Q000276:immunology / Q000473:pathology; D064098:Esomeprazole / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D009853:Omeprazole / Q000494:pharmacology*; D010538:Peritonitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D061251:Primary Cell Culture; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D015398:Signal Transduction; D016019:Survival Analysis; D013864:Thioglycolates / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D015054:Zymosan / Q000008:administration & dosage / Q000037:antagonists & inhibitors
chemical_list: C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D054328:Proton Pump Inhibitors; D013864:Thioglycolates; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C017487:2-mercaptoacetate; D015054:Zymosan; D009853:Omeprazole; D064098:Esomeprazole