Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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Trauma results in a persistent depression in adaptive immunity, which contributes to patient morbidity and mortality. This state of immune paralysis following trauma is characterized by a change in cell-mediated immunity, specifically a depression in T-cell function and a shift toward TH2 T-cell phenotype. Upregulation of inducible nitric oxide synthase (iNOS) is well recognized after injury and contributes to the inflammatory response and organ damage early after trauma. ⋯ This study utilized a murine model of severe peripheral tissue injury to show that iNOS is rapidly upregulated in macrophages and a (Gr-1-CD11b) myeloid-derived suppressor cell subpopulation in the spleen. Through the use of iNOS knockout mice, a specific iNOS inhibitor, and a nitric oxide (NO) scavenger, this study demonstrates that iNOS-derived NO is required for the depression in T-lymphocyte proliferation, interferon γ, and interleukin 2 production within the spleen at 48 h after trauma. These findings support the hypothesis that iNOS regulates immune suppression following trauma and suggest that targeting the sustained production of NO by iNOS may attenuate posttraumatic immune depression.
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Although prostaglandins (PGs) were reported to exert proinflammatory and anti-inflammatory effects in macrophages, their action mechanisms remain unclear. The effects of PGs including PGJ2 (J2), Δ-PGJ2 (Δ), 15-deoxy-Δ PGJ2 (15d), PGE2 (E2), and PGF2α (F2α) on lipopolysaccharide (LPS)-, lipoteichoic acid (LTA)-, and peptidoglycan (PGN)-induced inducible nitric oxide (NO) synthase (iNOS)/NO production by RAW264.7 macrophages were investigated. First, we found that induction of cyclooxygenase 2 (COX-2) protein occurred at a time earlier than that of heme oxygenase 1 (HO-1) protein, and the addition of the COX-2 inhibitor NS398 reduced HO-1 protein expression in LPS-, LTA-, and PGN-treated RAW264.7 macrophages. ⋯ Knockdown of HO-1 protein expression by HO-1 small interfering RNA blocked Δ and 15d inhibition of LPS- and LTA-induced events. Moreover, the compound, cyclopentenone (CP), which mimics the CP moiety of 15d, and its analog cyclohexenone were used, and cyclohexenone showed more potent induction of the HO-1 protein with effective inhibition of LPS-, LTA-, and PGN-induced iNOS/NO production than CP in macrophages. Reactive oxygen species-dependent HO-1 protein expression by PGs, which inhibited LPS-, LTA-, and PGN-induced iNOS/NO production, was identified in macrophages.
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The endogenous bacteria have been hypothesized to play a significant role in the pathophysiology of critical illness, although their role in sepsis is poorly understood. The purpose of this study was to determine how commensal bacteria alter the host response to sepsis. Conventional and germ-free (GF) C57Bl/6 mice were subjected to Pseudomonas aeruginosa pneumonia. ⋯ However, in a separate set of experiments, gut apoptosis was similar between septic GF Rag-1 mice and septic GF wild-type mice. These data demonstrate that the endogenous bacteria play a protective role in mediating mortality from pneumonia-induced sepsis, potentially mediated through altered intestinal apoptosis and the local proinflammatory response. In addition, sepsis-induced lymphocyte-dependent increases in gut epithelial apoptosis appear to be mediated by the endogenous bacteria.
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Comparative Study Clinical Trial
Global end-diastolic volume is associated with the occurrence of delayed cerebral ischemia and pulmonary edema after subarachnoid hemorrhage.
Predictive variables of delayed cerebral ischemia (DCI) and pulmonary edema following subarachnoid hemorrhage (SAH) remain unknown. We aimed to determine associations between transpulmonary thermodilution-derived variables and DCI and pulmonary edema occurrence after SAH. We reviewed 34 consecutive SAH patients monitored by the PiCCO system. ⋯ Global end-diastolic volume index was significantly higher in patients with pulmonary edema than in those without this condition (947 ± 126 vs. 766 ± 81 mL/m, P = 0.02); CVP was not significantly different (8.7 ± 2.8 vs. 9.2 ± 2.1 cm H2O, P = 0.78). Although significant correlation was found between extravascular lung water (EVLW) measures and GEDI (r = 0.58, P = 0.001), EVLW and CVP were not correlated (r = 0.03, P = 0.88). Thus, GEDI might be associated with DCI occurrence and EVLW accumulation after SAH.
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Clinical Trial
Factors influencing compliance with early resuscitation bundle in the management of severe sepsis and septic shock.
The Surviving Sepsis Campaign guidelines recommend implementing a 6-h resuscitation bundle, which has been associated with reduced mortality of patients presenting with severe sepsis or septic shock. However, this resuscitation bundle has not yet become a widely implemented treatment protocol. It is still unclear what factors are associated with the rate of compliance with the resuscitation bundle. ⋯ Factors related with lower compliance were cryptic shock (adjusted OR, 0.26; 95% CI, 0.13-0.52) and higher serum lactate levels (adjusted OR, 0.90; 95% CI, 0.82-0.98). Furthermore, we found several potential factors that influence compliance with the sepsis resuscitation bundle. To improve the compliance with the resuscitation bundle, interventions focusing on those factors will be needed.