Combined zinc supplementation with proinsulin C-peptide treatment decreases the inflammatory response and mortality in murine polymicrobial sepsis.

Zinc is a trace element vital for immune function during host response to infection. The proinsulin C-peptide has been shown to exert beneficial effects through activation of the anti-inflammatory peroxisome proliferator-activated receptor γ (PPARγ) in experimental endotoxemia. Some in vitro activities of C-peptide appear dependent on the presence of zinc. We investigated the effect of zinc supplementation before onset of sepsis on the anti-inflammatory properties of C-peptide. Male C57BL/6 mice were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). Mice received zinc gluconate (1.3 mg/kg) intraperitoneally (i.p.) for 3 days before CLP. One hour after CLP, animals received C-peptide (280 nmol/kg i.p.) or the antimicrobial agent imipenem (25 mg/kg i.p.). Cecal ligation and puncture was associated with an 11% survival rate, pulmonary leukosequestration, and liver injury. Molecular analysis in lungs of septic mice showed increased nuclear activation of the proinflammatory extracellular signal-regulated kinases 1 and 2 and nuclear factor κB, but decreased PPARγ expression, when compared with sham animals. Combination of zinc supplementation with C-peptide posttreatment significantly improved survival rate (61%) similarly to antibiotic treatment (60%), ameliorated lung architecture and liver function, reduced tissue neutrophil infiltration, and increased bacterial clearance when compared with vehicle, C-peptide, or zinc treatment alone. These beneficial effects were associated with restored lung nuclear expression of PPARγ and reduction of phosphorylated extracellular signal-regulated kinases 1 and 2 and nuclear factor κB activities in comparison to vehicle or single treatment protocols. Our data demonstrate that short-term zinc prophylaxis before the infectious insult is a requisite for the anti-inflammatory properties of C-peptide by facilitating modulation of inflammatory pathways.

Early treatment of blunt cerebrovascular injury with concomitant hemorrhagic neurologic injury is safe and effective.

BACKGROUND: Early pharmacologic treatment for blunt cerebrovascular injury (BCVI) is often withheld when concomitant traumatic brain injury or cervical spinal cord injury occurs. This study examines the safety and efficacy of early treatment for patients with both BCVI and traumatic neurologic injury (TNI). METHODS: Ten-year retrospective review of patients with BCVI and a TNI was performed. Stroke outcomes for those treated with pharmacologic therapy for their BCVI were compared with those not treated. In addition, the likelihood of worsening of TNI was determined for those exposed to pharmacologic therapy compared with those not exposed. Multivariate logistic regression techniques were used to analyze adjusted odds ratio for stroke risk. RESULTS: Seventy-seven patients were identified with BCVI + TNI. Strokes occurred in 27% patients with 3 of 21 (14%) strokes present at arrival. There were no differences in baseline characteristics between groups. Stroke rate was higher in the untreated group compared with treated (57% vs. 4%, p < 0.0001). On multivariate regression, treatment status was the most significant stroke predictor (adjusted odds ratio 4.4, 3.0-6.5, p < 0.0001, c-stat 0.93). There was no difference in risk of hemorrhagic deterioration of traumatic brain injury based on pharmacologic exposure versus no exposure (5% vs. 6%, p = 0.6). Likewise, no patient with spinal cord injury worsened as a result of pharmacologic exposure. Of the potentially preventable strokes, 24% (4 of 17) resulted in a stroke-related death and all four deaths occurred in the untreated group. CONCLUSION: The benefit of early treatment for BCVI markedly outweighs the risk of treatment for patients suffering concomitant BCVI and hemorrhagic neurologic injury. LEVEL OF EVIDENCE: : III.

A novel role for matrix metalloproteinase-8 in sepsis.

OBJECTIVES: Matrix metalloproteinase-8 messenger RNA expression was previously found to be increased in whole blood of children with septic shock. The impact of this finding on the severity and inflammatory response to sepsis is unknown. Here, we investigate the relationship between matrix metalloproteinase-8 and disease severity in children with septic shock. We further corroborate the role of matrix metalloproteinase-8 in sepsis in a murine model. DESIGN: Retrospective observational clinical study and randomized controlled laboratory experiments. SETTING: Pediatric intensive care units and an animal research facility at an academic children's hospital. PATIENTS AND SUBJECTS: Patients age ≤10 yrs admitted to the intensive care unit with a diagnosis of septic shock. For laboratory studies, we utilized male mice deficient for matrix metalloproteinase-8 and male wild-type C57BL/6J mice. INTERVENTIONS: Blood from children with septic shock was analyzed for matrix metalloproteinase-8 messenger RNA expression and matrix metalloproteinase-8 activity, and correlated with disease severity based on mortality and degree of organ failure. A murine model of sepsis was used to explore the effect of genetic and pharmacologic inhibition of matrix metalloproteinase-8 on the inflammatory response to sepsis. Finally, activation of nuclear factor-κB was assessed both in vitro and in vivo. MEASUREMENTS AND MAIN RESULTS: Increased matrix metalloproteinase-8 mRNA expression and activity in septic shock correlates with decreased survival and increased organ failure in pediatric patients. Genetic and pharmacologic inhibition of matrix metalloproteinase-8 leads to improved survival and a blunted inflammatory profile in a murine model of sepsis. We also identify matrix metalloproteinase-8 as a direct in vitro activator of the proinflammatory transcription factor, nuclear factor-κB. CONCLUSIONS: Matrix metalloproteinase-8 is a novel modulator of inflammation during sepsis and a potential therapeutic target.

Liver X receptor α activation with the synthetic ligand T0901317 reduces lung injury and inflammation after hemorrhage and resuscitation via inhibition of the nuclear factor κB pathway.

Liver X receptor α (LXRα) is a nuclear transcription factor that regulates lipid metabolism. Recently, it has been shown that activation of LXRα with synthetic ligands has anti-inflammatory effects in atherosclerosis and chemical-induced dermatitis. We investigated the effect of the LXRα agonist, T0901317, on lung inflammation in a rodent model of hemorrhagic shock. Hemorrhagic shock was induced in male rats by withdrawing blood to a goal mean arterial blood pressure of 50 mmHg. Blood pressure was maintained at this level for 3 h, at which point rats were rapidly resuscitated with shed blood. Animals were then treated with T0901317 (50 mg · kg) or vehicle i.p. and sacrificed at 1, 2, and 3 h after resuscitation. Treatment with T0901317 significantly improved the cardiac and stroke volume indices as well as the heart rate of rats during the resuscitation period as compared with vehicle-treated rats. The T0901317-treated animals showed significant improvement in the plasma level of lactate, whereas base deficit and bicarbonate levels both trended toward improvement. The T0901317-treated animals also showed lower levels of plasma cytokines and chemokines monocyte chemoattractant protein 1, macrophage inflammatory protein 1α, TNF-α, KC, and IL-6. Lung injury and neutrophil infiltration were reduced by treatment with T0901317, as evaluated by histology and myeloperoxidase assay. At molecular analysis, treatment with T0901317 increased nuclear LXRα expression and DNA binding while also inhibiting activation of nuclear factor κB, a proinflammatory transcription factor, in the lung. Thus, our data suggest that LXRα is an important modulator of the inflammatory response and lung injury after severe hemorrhagic shock, likely through the inhibition of the nuclear factor κB pathway.