Glutamine's protection against sepsis and lung injury is dependent on heat shock protein 70 expression

Abstract

Glutamine (GLN) has been shown to protect against inflammatory injury and illness in experimental and clinical settings. The mechanism of this protection is unknown; however, laboratory and clinical trial data have indicated a relationship between GLN-mediated protection and enhanced heat shock protein 70 (HSP70) expression. The aim of this study was to examine the hypothesis that GLN's beneficial effect on survival, tissue injury, and inflammatory response after inflammatory injury is dependent on HSP70 expression. Mice with a specific deletion of the HSP70 gene underwent cecal ligation and puncture (CLP)-induced sepsis and were treated with GLN (0.75 g/kg) or a saline placebo 1 h post-CLP. Lung tissue NF-kappaB activation, inflammatory cytokine response, and lung injury were assessed post-CLP. Survival was assessed for 5 days post-CLP. Our results indicate that GLN administration improved survival in Hsp70(+/+) mice vs. Hsp70(+/+) mice not receiving GLN; however, GLN exerted no survival benefit in Hsp70(-/-) mice. This was accompanied by a significant decrease in lung injury, attenuation of NF-kappaB activation, and proinflammatory cytokine expression in GLN-treated Hsp70(+/+) mice vs. Hsp70(+/+) mice not receiving GLN. In the Hsp70(-/-) mice, GLN's attenuation of lung injury, NF-kappaB activation, and proinflammatory cytokine expression was lost. These results confirm our hypothesis that HSP70 expression is required for GLN's effects on survival, tissue injury, and the inflammatory response after global inflammatory injury.

Glutamine attenuates inflammation and NF-κB activation via Cullin-1 deneddylation

“…This effect has been associated with attenuated NF-kB activation. Further, GLN administration can decrease lung injury and improve survival in models of experimental sepsis [2]. The mechanism responsible for GLN's ability to regulate the inflammatory response and attenuate NF-kB expression is currently unclear.…”

Loss of stress response as a consequence of viral infection: implications for disease and therapy

“…The child rapidly becomes ill and develops multi-organ failure. Low Hsps are observed in sepsis and acute respiratory distress syndrome (Singleton and Wischmeyer 2007;Weiss et al 2000). Does the fact that aspirin activates eIF2α, the same molecule activated by interferon and viral illness, lead to a doubled impact of impaired Hsp protein translation and loss of tissue defenses?…”

Glutamina: aspectos bioquímicos, metabólicos, moleculares e suplementação

“…A modulação da expressão de genes relacionados com a síntese e degradação de proteínas, a proliferação celular e a ativação de vias envolvidas com a apoptose celular estão entre os papéis exercidos pela glutamina mais estudados (4,5,26,27) .…”

“…, em especial da HSP de 70kDa (HSP-70) e HSP-72 (27,33) . Outrossim, o efeito da glutamina no aumento da expressão das HSPs ocorre de maneira dose-dependente, pois maiores concentrações são necessárias de acordo com a intensidade do processo, fato que provavelmente está relacionado com a necessidade da cé-lula de aumentar sua proteção e, consequentemente, sobreviver em condições de estresse (27) .…”

“…Em animais submetidos a estado de sepse, a maior disponibilidade de glutamina atenuou a ativação do complexo NF-κB, por meio da inibição da degradação de sua proteína inibidora, IκB-α, e inibiu a fosforilação e a ativação da MAPK (26) . Em outro estudo, Singleton e Wischmeyer (27) verificaram que a administração de glutamina promoveu aumento de maneira dose-dependente da expressão da HSP-70, inibindo a ativação do NF-κB e das proteínas quinases que compõem a via da MAPK, sobretudo a c-JUN NH 2 -terminal quinase (JNK).…”