CXCR2 inhibition suppresses hemorrhage-induced priming for acute lung injury in mice

Lomas-Neira, Joanne; Chung, Chun‐Shiang; Grutkoski, Patricia S.; Miller, Edmund J.; Ayala, Alfred

doi:10.1189/jlb.1103541

Cited by 71 publications

(84 citation statements)

References 37 publications

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“…In this regard, it is not clear whether programmed cell death plays an important role in the pathogenesis of ALI indirect (as has been suggested for ALI direct [19,22]), nor whether the pathways and cell types involved are sufficiently elucidated. In our previous studies, we have demonstrated that hemorrhage-primed neutrophils are capable of inducing ALI indirect in a septic environment, identifying them as a major contributor to the pathology of indirect ALI and supporting the neutrophil hypothesis (12,23,24). However, the upstream mechanisms that lead to the release of the major chemokines attracting these primed neutrophils, and potentially other leukocytes, as well as the cellular source of these chemotactic mediators, are unclear.…”

Section: At a Glance Commentary Scientific Knowledge On The Subjectmentioning

confidence: 55%

“…Indirect ALI (ALI indirect ) was induced as described previously (12,24,33,34) by hemorrhagic shock (HEM) followed by cecal ligation and puncture (CLP) 24 hours thereafter. Importantly, while we show only the sham group as our control (which we have not found to differ from HEM or CLP alone) for the studies here, we have previously documented that neither HEM nor CLP alone is capable of inducing substantial/consistent increases in indices of lung inflammation, apoptosis, or injury (12,24,33,34).…”

Section: Indirect Alimentioning

confidence: 99%

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Fas-induced Pulmonary Apoptosis and Inflammation during Indirect Acute Lung Injury

Perl

Chung²,

Perl³

et al. 2007

Am J Respir Crit Care Med

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Rationale: Indirect acute lung injury (ALI) is associated with high morbidity and mortality. No specific therapies have been developed, because the underlying pathophysiological processes remain elusive. Objectives: To investigate the contribution of Fas-induced apoptotic and nonapoptotic/inflammatory signaling to the pathology of indirect ALI. Methods: A mouse model of indirect ALI, induced by successive exposure to hemorrhagic shock and cecal ligation and puncture, was used. Quantification of active caspase-3 and the short splice variant of FLICE-inhibitory protein, (FLIP) short , was performed by Western blotting and immunohistochemistry, and cytokines/chemokines were assessed by cytometric bead array or ELISA. M30 immunostaining was done to evaluate epithelial cell apoptosis. Lung injury was assessed on the basis of myeloperoxidase activity, bronchoalveolar lavage protein, and lung histology. Measurements and Main Results: Twelve hours after insult, lung monocyte chemoattractant protein-1, keratinocyte-derived chemokine, macrophage inflammatory protein-2, IL-6, tumor necrosis factor-a, and caspase-3 were increased and FLIP short was decreased. Fas-and Fas ligand-deficient mice showed marked protection from lung inflammation and apoptosis and decreased ALI. This was associated with a 10-day survival benefit. Similarly, 4 hours after pulmonary instillation of Fas-activating antibody in vivo, lung chemokines were markedly elevated in background mice and, interestingly, to a similar degree in macrophage-deficient animals. Fas activation on lung epithelial cells in vitro led to chemokine production that was dependent on extracellular signal-regulated kinase. Conclusions: Activation of apoptotic and nonapoptotic/inflammatory Fas signaling is an early important pathophysiological event in the development of indirect ALI after hemorrhagic shock and sepsis, in which lung epithelial cells appear to play a central role.

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Section: At a Glance Commentary Scientific Knowledge On The Subjectmentioning

confidence: 55%

Section: Indirect Alimentioning

confidence: 99%

Fas-induced Pulmonary Apoptosis and Inflammation during Indirect Acute Lung Injury

Perl

Chung²,

Perl³

et al. 2007

Am J Respir Crit Care Med

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140

145

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“…The systemic inflammatory response causes tissue damage in the lung, which is the most insidious component in sepsis due to compromised gas exchange [4,21]. Convincing evidence has demonstrated that neutrophil recruitment is a critical component in the pathophysiology of septic lung injury [22][23]. However, the details of the recruitment process of leukocytes in the lung has been much less studied and seems to be more complex than that in peripheral organs.…”

Section: Discussionmentioning

confidence: 99%

Direct in vivo observations of P-selectin glycoprotein ligand-1-mediated leukocyte–endothelial cell interactions in the pulmonary microvasculature in abdominal sepsis in mice

et al. 2012

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Thorlacius, H. (2013). Direct in vivo observations of P-selectin glycoprotein ligand-1-mediated leukocyte-endothelial cell interactions in the pulmonary microvasculature in abdominal sepsis in mice. Inflammation Research, 62(3), 275-282. DOI: 10.1007/s00011-012-0575-y General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal AbstractObjective P-selectin glycoprotein ligand-1 (PSGL-1) has been shown to play a significant role in septic lung injury. However, the detailed role of PSGL-1 in the pulmonary leukocyte recruitment remains elusive. We have developed a method based on intravital fluorescence microscopy of the lung microcirculation to examine the role of PSGL-1 in the extravasation process of leukocytes in septic lung damage.Methods Male C57BL/6 mice were treated with a control antibody or an anti-PSGL-1 antibody prior to cecal ligation and puncture (CLP). Leukocyte-endothelium interactions and microvascular hemodynamics were studied in pulmonary arterioles, capillaries and venules 4 hours after CLP.Results Immunoneutralization of PSGL-1 decreased CLP-induced leukocyte rolling in pulmonary arterioles and venules significantly. Inhibition of PSGL-1 had no effect on leukocyte adhesion in venules, whereas the number of adherent leukocytes in lung arterioles and the number of trapped leukocytes in capillaries were markedly decreased. Moreover, immunoneutralization of PSGL-1 improved microvascular perfusion in the lung of septic animals.Conclusions Taken together, these results document that PSGL-1 mediates leukocyte rolling in arterioles and venules. However, inhibition of PSGL-1 only decreases leukocyte adhesion in arterioles, suggesting that leukocyte rolling is not a prerequisite for pulmonary venular adhesion of leukocytes in sepsis. In addition, our data show that capillary trapping of leukocytes is dependent on PSGL-1 function.

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“…To our knowledge, this is the first case-control association study using CXCL2 as a candidate gene for sepsis susceptibility, although its key role in promoting inflammatory stress has been extensively studied in different models of the disease, [7][8][9][10][11][12] and has been listed as a candidate gene for susceptibility to lung injury occurring within the setting of critical illnesses. 3 The common disease-common variant hypothesis 27 proposes that most of the genetic risk for complex diseases is owing to common variants of the loci involved.…”

Section: Discussionmentioning

confidence: 99%

“…In a septic model, Walley et al 7 found that increased expression of CXCL2 was associated with the severity of sepsis, and that antibody blocking of CXCL2 activity decreased mortality. 8,9 Congruent with these results, different studies have shown that the attenuation of CXCL2 activity, by attenuating its expression by means of glucocorticoids 6 or by siRNA gene silencing, 10 by using inhibitors of its receptor 11 or using a model of CD8 þ T/NK cell-deficient mice in which the expression of CXCL2 is decreased, 12 leads to a reduction in inflammatory response and injury.…”

Section: Introductionmentioning

confidence: 92%

A CXCL2 tandem repeat promoter polymorphism is associated with susceptibility to severe sepsis in the Spanish population

et al. 2006

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Sepsis describes a complex clinical syndrome resulting from a systemic inflammatory response to bacteria. Functional studies in animal models of sepsis have catalogued CXCL2 as a candidate gene for the development of the disease. We hypothesized that CXCL2 polymorphisms may confer susceptibility to sepsis and performed an association study using 178 severe sepsis patients and 357 population-based controls. We selected two polymorphisms from the promoter of the gene (À437A/G and À665(AC) n ), and analyzed whether haplotypes or single loci were associated with disease susceptibility. An overall test of differentiation showed that haplotype distribution was not different between cases and controls (P ¼ 0.407). Likewise, À437A/G was not associated with disease susceptibility (heterozygote odds ratio (OR) 0.68 (0.47-1.03), and homozygote OR 0.86 (0.56-1.32); P ¼ 0.706). However, for the À665(AC) n , we found that the 2471 repeat alleles were associated with susceptibility (heterozygote OR 2.82 (1.10-7.24), and homozygote OR 3.65 (1.41-9.43); P ¼ 0.0006). This association remained significant when using a multiple logistic regression analysis (OR 2.23; 95% confidence intervals (95% CI) 1.22-4.03; P ¼ 0.008) and after a genomic control adjustment (P ¼ 0.017). Although replicate studies and functional assays are needed, these results suggest that CXCL2 gene variants may contribute to the development of severe sepsis.

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CXCR2 inhibition suppresses hemorrhage-induced priming for acute lung injury in mice

Cited by 71 publications

References 37 publications

Fas-induced Pulmonary Apoptosis and Inflammation during Indirect Acute Lung Injury

Fas-induced Pulmonary Apoptosis and Inflammation during Indirect Acute Lung Injury

Direct in vivo observations of P-selectin glycoprotein ligand-1-mediated leukocyte–endothelial cell interactions in the pulmonary microvasculature in abdominal sepsis in mice

A CXCL2 tandem repeat promoter polymorphism is associated with susceptibility to severe sepsis in the Spanish population

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