Mechanisms of acute inflammatory lung injury induced by abdominal sepsis

Neumann, Brigitte; Zantl, Niko; Veihelmann, A.; Emmanuilidis, Klaus; Pfeffer, Klaus; Heidecke, Claus–Dieter; Holzmann, Bernhard

doi:10.1093/intimm/11.2.217

Cited by 91 publications

(64 citation statements)

References 66 publications

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“…It has long been known that in systemic inflammatory states, peripheral PMN lose their responsiveness to CXC chemokines (54,55). Our work poses the question of whether these cells might gain responsiveness to CC chemokines, providing a possible mechanism for the PMN-mediated tissue damage associated with a variety of inflammatory conditions (55,56). Such scenarios of local and systemic PMN activation and responsiveness to CC chemokines lead to new and interesting questions on PMN participation in cytokine networks and in the pathogenesis of inflammatory lesions.…”

Section: Discussionmentioning

confidence: 83%

Granulocyte-Macrophage Colony Stimulating Factor Up-Regulates CCR1 in Human Neutrophils

Cheng

Lai

Lukacs³

et al. 2001

The Journal of Immunology

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Neutrophils (polymorphonuclear leukocytes; PMN) are phagocytic cells instrumental in the clearance of infectious pathogens. Human PMN are commonly thought to respond primarily to chemokines from the CXC family. However, recent findings suggest that under specific cytokine activation conditions, PMN can also respond to some CC chemokines. In this study, the effect of GM-CSF, a well-characterized PMN priming and maturation factor, on CC-chemokine receptor (CCR) expression in PMN was investigated. Constitutive expression of CCR1 and CCR3 mRNA in PMN was detected by ribonuclease protection assay. Following incubation of PMN with GM-CSF (0.01–10 ng/ml; 6 h) CCR1 mRNA expression was rapidly (∼1 h) up-regulated. In contrast, no significant induction of CCR2, CCR3, CCR4, or CCR5 mRNA was observed. CCR1 protein was also up-regulated by GM-CSF stimulation. GM-CSF-induced up-regulation of CCR1 showed functional consequences because GM-CSF-treated PMN, but not control cells, responded to the CC chemokines macrophage inflammatory protein-1α, monocyte chemoattractant protein-3, and RANTES in assays of chemotactic migration and intracellular calcium mobilization. These results suggest that PMN activated by the proinflammatory cytokine GM-CSF can change their receptor expression pattern and become responsive to CC chemokines.

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Section: Discussionmentioning

confidence: 83%

Granulocyte-Macrophage Colony Stimulating Factor Up-Regulates CCR1 in Human Neutrophils

Cheng

Lai

Lukacs³

et al. 2001

The Journal of Immunology

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“…Although locally restricted alterations of IFN-␥ production cannot be excluded, these results suggest that the protective effects of CpG-ODN are not mediated by an enhanced Th1 response. Moreover, the rapid progression of infection and early mortality in the CASP model (34,35) also indicate that host defense is mainly dependent on effector mechanisms of the innate rather than the adaptive immune system. Collectively, our observations provide strong evidence that the immune modulating activities of CpG-ODN are not restricted to the instruction and reprogramming of adaptive immunity but, in addition, may involve the amplification of the innate effector cell response during acute polymicrobial infection.…”

Section: Discussionmentioning

confidence: 99%

“…Production of oxygen metabolites was assessed by a flow cytometric method as described (35). Briefly, heparinized blood from CpG and control ODN-treated mice was collected, and erythrocytes were lysed as described above.…”

Section: Oxidative Burst and Phagocytosismentioning

confidence: 99%

Increased Resistance Against Acute Polymicrobial Sepsis in Mice Challenged with Immunostimulatory CpG Oligodeoxynucleotides Is Related to an Enhanced Innate Effector Cell Response

Weighardt

Feterowski

Veit

et al. 2000

The Journal of Immunology

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121

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Recent reports support the concept that the major defect in polymicrobial sepsis is an impaired immunologic response to infection. Oligodeoxynucleotides containing CpG sequence motifs (CpG-ODN) were previously shown to induce immune protection in models of chronic infection with intracellular bacteria, parasites, and viruses due to their ability to augment IFN-γ-dependent Th1 responses. Here, we demonstrate that challenging mice with CpG-ODN substantially increases the resistance against acute polymicrobial sepsis. Systemic levels of IL-12, IL-18, and IL-10 were not altered in CpG-ODN-treated mice as compared with controls. In contrast, administration of CpG-ODN resulted in a strongly enhanced accumulation of neutrophils at the primary site of infection. Neutrophils of CpG-ODN-treated mice exhibited an up-regulation of phagocytic receptors, an increased phagocytic activity, and an elevated production of reactive oxygen metabolites. These results suggest that the protective effects of CpG-ODNs in acute polymicrobial sepsis are related to an enhanced effector cell response of innate immunity. CpG-ODN may therefore represent potent agents for the treatment of sepsis-associated immunoparalysis.

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“…Despite significant advances and extensive therapeutic approaches, sepsis remains a major health concern and leading cause of high mortality worldwide (2)(3)(4). Human and animal studies have demonstrated that progressive multiple organ failure is the most common cause of death following sepsis, with the lungs usually representing the first organ to fail (5). Predisposition of the immune response has been shown to be critical in the development of an exaggerated inflammatory reaction and ensuing acute lung injury (ALI) (6).…”

Section: Introductionmentioning

confidence: 99%

Stimulation of Brain AMP-Activated Protein Kinase Attenuates Inflammation and Acute Lung Injury in Sepsis

Mulchandani

Yang

Khan

et al. 2015

Mol Med

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Sepsis and septic shock are enormous public health problems with astronomical financial repercussions on health systems worldwide. The central nervous system (CNS) is closely intertwined in the septic process but the underlying mechanism is still obscure. AMP-activated protein kinase (AMPK) is a ubiquitous energy sensor enzyme and plays a key role in regulation of energy homeostasis and cell survival. In this study, we hypothesized that activation of AMPK in the brain would attenuate inflammatory responses in sepsis, particularly in the lungs. Adult C57BL/6 male mice were treated with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR, 20 ng), an AMPK activator, or vehicle (normal saline) by intracerebroventricular (ICV) injection, followed by cecal ligation and puncture (CLP) at 30 min post-ICV. The septic mice treated with AICAR exhibited elevated phosphorylation of AMPKα in the brain along with reduced serum levels of aspartate aminotransferase, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), compared with the vehicle. Similarly, the expressions of TNF-α, IL-1β, keratinocyte-derived chemokine and macrophage inflammatory protein-2 as well as myeloperoxidase activity in the lungs of AICAR-treated mice were significantly reduced. Moreover, histological findings in the lungs showed improvement of morphologic features and reduction of apoptosis with AICAR treatment. We further found that the beneficial effects of AICAR on septic mice were diminished in AMPKα2 deficient mice, showing that AMPK mediates these effects. In conclusion, our findings reveal a new functional role of activating AMPK in the CNS to attenuate inflammatory responses and acute lung injury in sepsis.

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Mechanisms of acute inflammatory lung injury induced by abdominal sepsis

Cited by 91 publications

References 66 publications

Granulocyte-Macrophage Colony Stimulating Factor Up-Regulates CCR1 in Human Neutrophils

Granulocyte-Macrophage Colony Stimulating Factor Up-Regulates CCR1 in Human Neutrophils

Increased Resistance Against Acute Polymicrobial Sepsis in Mice Challenged with Immunostimulatory CpG Oligodeoxynucleotides Is Related to an Enhanced Innate Effector Cell Response

Stimulation of Brain AMP-Activated Protein Kinase Attenuates Inflammation and Acute Lung Injury in Sepsis

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