Aggravation of Different Types of Experimental Colitis by Depletion or Adhesion Blockade of Neutrophils

Kühl, Anja A.; Kakirman, Hacer; Janotta, M.; Dreher, Stefan; Cremer, Philipp; Pawlowski, Nina N.; Loddenkemper, Christoph; Heimesaat, Markus M.; Grollich, Katja; Zeitz, Martin; Farkas, S.; Hoffmann, Jörg

doi:10.1053/j.gastro.2007.08.073

Cited by 159 publications

(126 citation statements)

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“…Previous studies of chemically induced colitis in rats revealed that depletion or adhesion blockade of neutrophils aggravated the intestinal histopathology, and promotion of bone marrow-derived granulocyte differentiation facilitated the mucosal repair processes. 28,55,56 One report indicates that neutrophil-derived IL-1b is involved in promoting epithelial restitution and mucosal wound healing after ischemic challenge via a cyclooxygenase-2-dependent mechanism. 57 Previous studies showed that adaptive hypoxia protects the intestinal epithelial barrier integrity via transcriptional regulation of hypoxiainducible factor 1.…”

Section: Discussionmentioning

confidence: 99%

“…Although previous literature implicates neutrophil activation as a cause of gut reperfusion injury, 25,26 others have shown contradictory data in which depletion of neutrophils fails to attenuate mucosal histopathology in intestinal I/R and experimental colitis models. 27,28 Other reports also argue against the initiating role of neutrophils in gut tissue damage since the onset of mucosal destruction occurs before neutrophil infiltration. 29,30 These findings suggest that neutrophil activation is secondary to intestinal barrier defects and BT, supposedly to engage in antimicrobial activities.…”

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confidence: 99%

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Neutrophil priming by hypoxic preconditioning protects against epithelial barrier damage and enteric bacterial translocation in intestinal ischemia/reperfusion

Huang

et al. 2012

Laboratory Investigation

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Intestinal ischemia/reperfusion (I/R) induces mucosal barrier dysfunction and bacterial translocation (BT). Neutrophilderived oxidative free radicals have been incriminated in the pathogenesis of ischemic injury in various organs, but their role in the bacteria-containing intestinal tract is debatable. Primed neutrophils are characterized by a faster and higher respiratory burst activity associated with more robust bactericidal effects on exposure to a second stimulus. Hypoxic preconditioning (HPC) attenuates ischemic injury in brain, heart, lung and kidney; no reports were found in the gut. Our aim is to investigate whether neutrophil priming by HPC protects against intestinal I/R-induced barrier damage and bacterial influx. Rats were raised in normoxia (NM) or kept in a hypobaric hypoxic chamber (380 Torr) 17 h/day for 3 weeks for HPC, followed by sham operation or intestinal I/R. Gut permeability was determined by using an ex vivo macromolecular flux assay and an in vivo magnetic resonance imaging-based method. Liver and spleen homogenates were plated for bacterial culturing. Rats raised in HPC showed diminished levels of BT, and partially improved mucosal histopathology and epithelial barrier function compared with the NM groups after intestinal I/R. Augmented cytokineinduced neutrophil chemoattractant (CINC)-1 and -3 levels and myeloperoxidase activity correlated with enhanced infiltration of neutrophils in intestines of HPC-I/R compared with NM-I/R rats. HPC alone caused blood neutrophil priming, as shown by elevated production of superoxide and hydrogen peroxide on stimulation, increased membrane translocation of cytosolic p47 phox and p67 phox , as well as augmented bacterial-killing and phagocytotic activities. Neutrophil depletion reversed the mucosal protection by HPC, and aggravated intestinal leakiness and BT following I/R. In conclusion, neutrophil priming by HPC protects against I/R-induced BT via direct antimicrobial activity by oxidative respiratory bursts and through promotion of epithelial barrier integrity for luminal confinement of enteric bacteria.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Neutrophil priming by hypoxic preconditioning protects against epithelial barrier damage and enteric bacterial translocation in intestinal ischemia/reperfusion

Huang

et al. 2012

Laboratory Investigation

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“…Furthermore, neutrophil depletion or blockade of their adhesion by monoclonal antibodies has been examined in experimental colitis [138]. Chemically-induced and transfer colitis models were exacerbated by both of these interventions, again suggesting that neutrophils are required to prevent the transition to a chronic phase of inflammation.…”

Section: Animal Models and Genome-wide Association Studies: Evidence Fomentioning

confidence: 99%

Crohn’s disease as an immunodeficiency

Hayee

Rahman

Sewell

et al. 2010

Expert Review of Clinical Immunology

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The pathogenesis of Crohn's disease (CD) has widely been regarded as the consequence of a dysregulated T-cell-mediated response to intestinal microbes, and the majority of the worldwide research effort has focused on characterizing and treating the chronic inflammatory phase of the disease. However, recent molecular biological and clinical investigations indicate that CD is actually a primary immunodeficiency. At first counter-intuitive, the apparent paradox of a pathogenic innate immune defect can be linked mechanistically to the granulomatous chronic inflammation characteristic of the disease. Genome-wide association studies have corroborated the involvement of innate immune dysfunction in the pathogenesis of CD, but less than 20% of the heritable risk is accounted for. By contrast, in vitro and in vivo stimulation of the immune system has highlighted novel areas of interest that may lead to the development of targeted therapeutic and diagnostic tools. Keywordsbacteria; Crohn's disease; immunodeficiency; innate immunity; macrophage; neutrophil Established intestinal lesions in Crohn's disease (CD) contain a massive, mixed inflammatory cell infiltrate associated with a complex storm of cytokines in a selfperpetuating, chronic inflammatory response [1][2][3]. Most research to date has focused on the the immunological characteristics of established lesions and drawn inferences about their initiation. The predominance of a classically Th1-associated cytokine profile in these lesions led to the assumption that T lymphocytes were central to the initial pathogenesis. More recently, the role of regulatory (Treg) FoxP3 + and IL-23-induced responsive Th17-type T lymphocytes has gained popularity [2,4,5]. Treg cell populations are diminished in patients with CD [6] and, although the hypothesis of CD as an immunodeficiency does not necessarily exclude defects in T-cell function, to date, no convincing intrinsic (primary) defect has been identified to implicate these cells in the pathogenesis of human CD.The hypothesis that immunodeficiency underpins the development of CD seems, at first, to be in direct contrast with histological observations of established intestinal lesions and the † Author for correspondence: Tel.: +44 207 679 6170 Fax: +44 207 679 0967 b.hayee@nhs.net. Financial & competing interests disclosure The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Europe PMC Funders Group Association between immunodeficiency diseases & CDThere is a well-known and strong association between primary immunodeficiency disorders and non-infectious granulomatous intestinal inflammation. Chronic granulomatous disease (CGD), glycogen storage disease type 1b, leukocyte adhesion deficiency, Chediak-Higashi and Hermansky-Pudlak syndromes are all strongly associated with intestinal inflammation that is indistinguishable from CD [...

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“…Genetic deficiency in neutrophil oxidative defense has been discovered as the cause of chronic granulomatous diseases, rendering the affected individuals susceptible to bacterial and fungal infections (11,12). Conversely, increased and deregulated PMN recruitment and overactivation have been accused to pivotally contribute to tissue damage in chronic inflammatory disorders and are key pathological features of both human IBD and experimental colitis models (13)(14)(15).…”

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confidence: 99%

G Protein-Coupled Receptor 43 Is Essential for Neutrophil Recruitment during Intestinal Inflammation

Sina

Gavrilova²,

Förster³

et al. 2009

The Journal of Immunology

321

291

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Molecular danger signals attract neutrophilic granulocytes (polymorphonuclear leukocytes (PMNs)) to sites of infection. The G protein-coupled receptor (GPR) 43 recognizes propionate and butyrate and is abundantly expressed on PMNs. The functional role of GPR43 activation for in vivo orchestration of immune response is unclear. We examined dextrane sodium sulfate (DSS)-induced acute and chronic intestinal inflammatory response in wild-type and Gpr43-deficient mice. The severity of colonic inflammation was assessed by clinical signs, histological scoring, and cytokine production. Chemotaxis of wild-type and Gpr43-deficient PMNs was assessed through transwell cell chemotactic assay. A reduced invasion of PMNs and increased mortality due to septic complications were observed in acute DSS colitis. In chronic DSS colitis, Gpr43−/− animals showed diminished PMN intestinal migration, but protection against inflammatory tissue destruction. No significant difference in PMN migration and cytokine secretion was detected in a sterile inflammatory model. Ex vivo experiments show that GPR43-induced migration is dependent on activation of the protein kinase p38α, and that this signal acts in cooperation with the chemotactic cytokine keratinocyte chemoattractant. Interestingly, shedding of L-selectin in response to propionate and butyrate was compromised in Gpr43−/− mice. These results indicate a critical role for GPR43-mediated recruitment of PMNs in containing intestinal bacterial translocation, yet also emphasize the bipotential role of PMNs in mediating tissue destruction in chronic intestinal inflammation.

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Aggravation of Different Types of Experimental Colitis by Depletion or Adhesion Blockade of Neutrophils

Cited by 159 publications

References 57 publications

Neutrophil priming by hypoxic preconditioning protects against epithelial barrier damage and enteric bacterial translocation in intestinal ischemia/reperfusion

Neutrophil priming by hypoxic preconditioning protects against epithelial barrier damage and enteric bacterial translocation in intestinal ischemia/reperfusion

Crohn’s disease as an immunodeficiency

G Protein-Coupled Receptor 43 Is Essential for Neutrophil Recruitment during Intestinal Inflammation

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