Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the effect of inhaled nitric oxide (NO) at increasing fractional inspired O2 concentrations (FIO2) on hemodynamic and pulmonary function during Escherichia coli pneumonia. Thirty-eight conscious, spontaneously breathing, tracheotomized 2-yr-old beagles had intrabronchial inoculation with either 0.75 or 1.5 x 10(10) colony-forming units/kg of E. coli 0111:B4 (infected) or 0.9% saline (noninfected) in one or four pulmonary lobes. We found that neither the severity nor distribution (lobar vs. diffuse) of bacterial pneumonia altered the effects of NO. However, in infected animals, with increasing FIO2 (0.08, 0.21, 0.50, and 0.85), NO (80 parts/million) progressively increased arterial PO2 [-0.3 +/- 0.6, 3 +/- 1, 13 +/- 4, 10 +/- 9 (mean +/- SE) Torr, respectively] and decreased the mean arterial-alveolar O2 gradient (0.5 +/- 0.3, 4 +/- 2, -8 +/- 7, -10 +/- 9 Torr, respectively). In contrast, in noninfected animals, the effect of NO was significantly different and opposite; NO progressively decreased mean PO2 with increasing FIO2 (2 +/- 1, -5 +/- 3, -2 +/- 3, and -12 +/- 5 Torr, respectively; P < 0.05 compared with infected animals) and increased mean arterial-alveolar O2 gradient (0.3 +/- 0.04, 2 +/- 2, 1 +/- 3, 11 +/- 5 Torr; P < 0.05 compared with infected animals). In normal and infected animals alike, only at FIO2 < or = 0.21 did NO significantly lower mean pulmonary artery pressure, pulmonary artery occlusion pressure, and pulmonary vascular resistance index (all P < 0.01). However, inhaled NO had no significant effect on increases in mean pulmonary artery pressure associated with bacterial pneumonia. Thus, during bacterial pneumonia, inhaled NO had only modest effects on oxygenation dependent on high FIO2 and did not affect sepsis-induced pulmonary hypertension. These data do not support a role for inhaled NO in bacterial pneumonia. Further studies are necessary to determine whether, in combination with ventilatory support, NO may have more pronounced effects.
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PMID:Cardiopulmonary effects of inhaled nitric oxide in normal dogs and during E. coli pneumonia and sepsis. 945 24

CD14, a pattern recognition receptor found on myeloid cells, is a critical component of the innate immune system that mediates local and systemic host responses to Gram-negative and Gram-positive bacterial products. Previous studies in normal animals have tested the effect of CD14 blockade on the systemic response to i.v. LPS. The goals of the study were to determine whether CD14 blockade protected against the deleterious systemic response associated with Escherichia coli pneumonia and to determine whether this strategy affected the pulmonary response to tissue infection. Rabbits were pretreated with either anti-CD14 mAb or isotype control mAb at 2.5 mg/kg. E. coli (1 x 109 CFU) was inoculated into the lungs, and the animals were observed for either 4 or 24 h. The blockade of CD14 improved the mean arterial blood pressure (p = 0.001) and decreased the i.v. fluid requirements (p = 0.01). Although this therapy protected the vascular compartment, rabbits treated with anti-CD14 mAb had increased bacterial burdens in the bronchoalveolar lavage fluid recovered from the instilled lung (p = 0.005) and widened alveolar-arterial oxygen difference. Blockade of CD14 prevents the deleterious systemic responses that occur in sepsis; however, other measures are necessary to control bacterial proliferation at the primary site of infection.
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PMID:Effect of CD14 blockade in rabbits with Escherichia coli pneumonia and sepsis. 1079 10

We evaluated the effects of a combined therapy of pre-blockade endogenous nitric oxide synthase (NOS) with N-nitro-L-arginine methyl ester (L-NAME) and continuous inhaled NO (iNO) on the gas exchange and hemodynamics of Escherichia coli pneumonia and sepsis in newborn piglets. Seven to ten day old ventilated newborn piglets were randomized into 5 groups: control, E. coli pneumonia control, pneumonia with iNO 10 ppm, pneumonia pre-treated with L-NAME 10 mg/kg, and pneumonia with the combined therapy of L-NAME pretreatment and iNO. E. coli pneumonia was induced via intratracheal instillation of Escherichia coli, which resulted in progressively decreased cardiac index and oxygen tension; increased pulmonary vascular resistance index (PVRI), intrapulmonary shunting, and developed septicemia at the end of 6 hr experiment. iNO ameliorated the progressive hypoxemia and intrapulmonary shunting without affecting the PVRI. Only two of 8 animals with L-NAME pretreated pneumonia survived. Whereas when iNO was added to infected animals with L-NAME pretreatment, the progressive hypoxemia was abolished as a result of a decrease in intrapulmonary shunting without reverse of the high PVRI and systemic vascular resistance index induced by the L-NAME injection. This result suggests that a NOS blockade may be a possible supportive option for oxygenation by iNO treatment in neonatal Gram-negative bacterial pneumonia and sepsis.
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PMID:Pretreatment with N-nitro-L-arginine methyl ester improved oxygenation after inhalation of nitric oxide in newborn piglets with Escherichia coli pneumonia and sepsis. 1717 70

Bacteraemic pneumonia is a common cause of sepsis in critically ill patients today and is characterized by dysregulation of inflammation. The genetic factors predisposing to bacteraemic pneumonia are not yet fully understood. Innate immunity is pivotal for host defence against invading bacteria, and nuclear factor-kappa B (NF-kappaB) is central to bacteria-induced inflammation and immune responses. The deubiquitinating enzyme CYLD has been identified as a key negative regulator for NF-kappaB. In the present study, we investigated the role of CYLD in innate immune response in Escherichia coli pneumonia. Upon E. coli inoculation, Cyld(-/-) mice were hypersusceptible to E. coli pneumonia with higher mortality. Innate immune response to E. coli was enhanced in Cyld(-/-) cells and mice. Cyld(-/-) cells exhibited enhanced NF-kappaB activation upon E. coli inoculation, and the enhanced NF-kappaB activation by E. coli was abolished by perturbing IkappaB kinase (IKK) signalling. Furthermore, IKK inhibitor rescued Cyld(-/-) mice from lethal infection during E. coli pneumonia along with reduced inflammation. Taken together, these data showed that CYLD acts as a crucial negative regulator for E. coli pneumonia by negatively regulating NF-kappaB. These findings provide novel insight into the regulation of bacteraemic pneumonia and related diseases and may help develop novel therapeutic strategies for these diseases.
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PMID:CYLD is a crucial negative regulator of innate immune response in Escherichia coli pneumonia. 1864 24

Mesenchymal stromal cells (MSC) have been reported to improve bacterial clearance in preclinical models of Acute Respiratory Distress Syndrome (ARDS) and sepsis. The mechanism of this effect is not fully elucidated yet. The primary objective of this study was to investigate the hypothesis that the antimicrobial effect of MSC in vivo depends on their modulation of macrophage phagocytic activity which occurs through mitochondrial transfer. We established that selective depletion of alveolar macrophages (AM) with intranasal (IN) administration of liposomal clodronate resulted in complete abrogation of MSC antimicrobial effect in the in vivo model of Escherichia coli pneumonia. Furthermore, we showed that MSC administration was associated with enhanced AM phagocytosis in vivo. We showed that direct coculture of MSC with monocyte-derived macrophages enhanced their phagocytic capacity. By fluorescent imaging and flow cytometry we demonstrated extensive mitochondrial transfer from MSC to macrophages which occurred at least partially through tunneling nanotubes (TNT)-like structures. We also detected that lung macrophages readily acquire MSC mitochondria in vivo, and macrophages which are positive for MSC mitochondria display more pronounced phagocytic activity. Finally, partial inhibition of mitochondrial transfer through blockage of TNT formation by MSC resulted in failure to improve macrophage bioenergetics and complete abrogation of the MSC effect on macrophage phagocytosis in vitro and the antimicrobial effect of MSC in vivo. Collectively, this work for the first time demonstrates that mitochondrial transfer from MSC to innate immune cells leads to enhancement in phagocytic activity and reveals an important novel mechanism for the antimicrobial effect of MSC in ARDS. Stem Cells 2016;34:2210-2223.
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PMID:Mitochondrial Transfer via Tunneling Nanotubes is an Important Mechanism by Which Mesenchymal Stem Cells Enhance Macrophage Phagocytosis in the In Vitro and In Vivo Models of ARDS. 2705 13