CXCR2 is essential for maximal neutrophil recruitment and methacholine responsiveness after ozone exposure

Johnston, Richard A.; Mizgerd, Joseph P.; Shore, Stephanie A.

doi:10.1152/ajplung.00101.2004

Cited by 88 publications

(112 citation statements)

References 67 publications

(83 reference statements)

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“…On the contrary, we observed that APAP-induced liver injury was markedly attenuated in CXCR2-KO mice with reduced neutrophil infiltration, compared with WT mice, in line with previous reports that CXCR2-KO mice exhibited attenuated neutrophil infiltration in various disease models [16][17][18][19][20][21][22][23][24][25][26][27]. Indeed, Hogaboam and colleagues [38] observed that only a low level of CXCR2 was expressed on untreated hepatocytes and that APAP could enhance CXCR2 protein expression only transiently with a time lag.…”

Section: The Roles Of Ho-1 In Apap-induced Liver Injurysupporting

confidence: 91%

“…Several lines of evidence demonstrated that the recruitment of neutrophils was significantly reduced in some disease models using mice lacking CXC chemokine receptor 2 (CXCR2), a receptor for CXCL1 and CXCL2 [19][20][21][22][23][24][25][26]. Our previous study demonstrated that the magnitude of liver injury induced by APAP well correlated with intrahepatic neutrophil number and intrahepatic myeloperoxidase activity, suggesting that neutrophil recruitment was involved in the pathogenesis of APAP-induced liver injury [13,14].…”

Section: Introductionmentioning

confidence: 99%

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Opposite roles of neutrophils and macrophages in the pathogenesis of acetaminophen‐induced acute liver injury

et al. 2006

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Neutrophils and macrophages infiltrate after acetaminophen (APAP)-induced liver injury starts to develop. However, their precise roles still remain elusive. In untreated and control IgG-treated wild-type (WT) mice, intraperitoneal APAP administration (750 mg/kg) caused liver injury including centrilobular hepatic necrosis and infiltration of neutrophils and macrophages, with about 50% mortality within 48 h after the injection. APAP injection markedly augmented intrahepatic gene expression of inducible nitric oxide synthase (iNOS) and heme oxygenase (HO)-1. Moreover, neutrophils expressed iNOS, which is presumed to be an aggravating molecule for APAP-induced liver injury, while HO-1 was mainly expressed by macrophages. All antigranulocyte antibody-treated neutropenic WT and most CXC chemokine receptor 2 (CXCR2)-deficient mice survived the same dose of APAP, with reduced neutrophil infiltration and iNOS expression, indicating the pathogenic roles of neutrophils in APAPinduced liver injury. However, APAP caused more exaggerated liver injury in CXCR2-deficient mice with reduced macrophage infiltration and HO-1 gene expression, compared with neutropenic WT mice. An HO-1 inhibitor, tin-protoporphyrin-IX, significantly increased APAP-induced mortality, implicating HO-1 as a protective molecule for APAP-induced liver injury. Thus, CXCR2 may regulate the infiltration of both iNOS-expressing neutrophils and HO-1-expressing macrophages, and the balance between these two molecules may determine the outcome of APAP-induced liver injury. IntroductionAcetaminophen (APAP) is widely prescribed as an analgesic and antipyretic drug in clinics and is also sold as numerous over-counter preparations as a single compound or in combination with other medications [1, 2]. Although it is generally safe, an overdose of APAP can cause severe liver failure with a significant morbidity and mortality. Thus, its wide availability and severe toxicities has placed APAP overdose as the leading cause for calls to Poison Control Centers in the United States (>100 000/year). Moreover, APAP overdose accounts for more than 56 000 emergency room visits, 2600 hospitalizations, and an estimated 458 deaths due to acute liver failure each year in the United States alone [3]. The toxic response is initiated by the metabolism of APAP to a toxic metabolite, N-acetyl-p-benzoquinone imine. Because N-acetyl-p-benzoquinone imine can react rapidly with sulfhydryl groups, it first depletes glutathione in hepatocytes and then reacts with a number of intracellular proteins, thereby causing their dysfuntions [4, 5]. APAP-induced liver injury is histopathologically characterized by centrilobular hepatic necrosis with a massive infiltration of leukocytes, particularly neutrophils. The recruitment of leukocytes in the damaged tissue is a hallmark of the inflammatory process, which may contribute to the development of APAP-induced liver injury [6,7]. In line with this assumption, accumulating evidence has implicated neutrophils as the leukocyte type essentially involved i...

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Section: The Roles Of Ho-1 In Apap-induced Liver Injurysupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Opposite roles of neutrophils and macrophages in the pathogenesis of acetaminophen‐induced acute liver injury

et al. 2006

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“…KC and MIP-2 are sufficient to induce neutrophil recruitment, and they are necessary in many types of pulmonary inflammation (3,42,43). The present results demonstrate that TNFR and IL-1R are essential to the expression of KC and MIP-2 during pneumococcal pneumonia.…”

Section: Discussionmentioning

confidence: 52%

Lung NF-κB Activation and Neutrophil Recruitment Require IL-1 and TNF Receptor Signaling during Pneumococcal Pneumonia

Jones

Simms

Lupa

et al. 2005

The Journal of Immunology

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143

126

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Pulmonary inflammation is an essential component of the host defense against Streptococcus pneumoniae infection of the lungs. The early response cytokines, TNF-α and IL-1, are rapidly induced upon microbial exposure. Mice deficient in all TNF- and IL-1-dependent signaling receptors were used to determine the roles of these cytokines during pneumococcal pneumonia. The deficiency of signaling receptors for TNF and IL-1 decreased bacterial clearance. Neutrophil recruitment to alveolar air spaces was impaired by receptor deficiency, as was pulmonary expression of the neutrophil chemokines KC and MIP-2. Because NF-κB mediates the expression of both chemokines, we assessed NF-κB activation in the lungs. During pneumococcal pneumonia, NF-κB proteins translocate to the nucleus and activate gene expression; these functions were largely abrogated by the deficiency of receptors for TNF-α and IL-1. Thus, the combined deficiency of TNF and IL-1 signaling reduces innate immune responses to S. pneumoniae in the lungs, probably due to essential roles for these receptors in activating NF-κB.

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“…We hypothesized that higher doses of LPS must have caused productions of neutrophil chemoattractants to induce neutrophil recruitment. MIP-2 and KC are chemoattractants for neutrophil recruitment, MIP-2 has been reported previously to mediate neutrophil recruitment into lung in response to LPS (23). Level of MIP-2 ( Fig.…”

Section: Direct Endothelium Activation Was Sufficient For Neutrophil mentioning

confidence: 85%

Role of Endothelial TLR4 for Neutrophil Recruitment into Central Nervous System Microvessels in Systemic Inflammation

Zhou

Andonegui

Wong

et al. 2009

The Journal of Immunology

142

127

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Brain inflammation is a frequent consequence of sepsis and septic shock. We imaged leukocyte recruitment in brain postcapillary venules induced by i.p. administration of LPS as a simple model of systemic inflammation. The i.p. injection of LPS (0.5 mg/kg) induced significant leukocyte rolling and adhesion in brain postcapillary venules of wild-type (WT) mice and more than 90% were neutrophils. However, no emigrated neutrophils were detected in brain parenchyma. High levels of TNF-α and IL-1β were detected in the plasma after LPS injection but a different profile (IL-1β but not TNF-α) was detected in the brain. LPS caused no recruitment in TLR4 knockout mice. In chimeric mice with TLR4-expressing resident cells but TLR4-deficient bone marrow-derived circulating cells, neutrophil rolling and adhesion was similar to WT mice. This observation is consistent with a requirement for resident cells in the LPS-induced neutrophil recruitment into brain microvessels. Transgenic mice engineered to express TLR4 exclusively on endothelial cells had a similar level of leukocyte recruitment in brain as WT mice in response to LPS. High dose LPS (10 mg/kg) led to neutrophil infiltration in the brain parenchyma in WT mice. High KC and MIP-2 production was observed from brain parenchyma microglial cells, and CXCR2 knockout mice failed to recruit neutrophils. However, neither neutrophil infiltration nor KC or MIP-2 was observed in endothelial TLR4 transgenic mice in response to this LPS dose. Our results demonstrate that direct endothelial activation is sufficient to mediate leukocyte rolling and adhesion in cerebral microvessels but not sufficient for emigration to brain parenchyma.

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CXCR2 is essential for maximal neutrophil recruitment and methacholine responsiveness after ozone exposure

Abstract: Shore. CXCR2 is essential for maximal neutrophil recruitment and methacholine responsiveness after ozone exposure.

Cited by 88 publications

References 67 publications

Opposite roles of neutrophils and macrophages in the pathogenesis of acetaminophen‐induced acute liver injury

Opposite roles of neutrophils and macrophages in the pathogenesis of acetaminophen‐induced acute liver injury

Lung NF-κB Activation and Neutrophil Recruitment Require IL-1 and TNF Receptor Signaling during Pneumococcal Pneumonia

Role of Endothelial TLR4 for Neutrophil Recruitment into Central Nervous System Microvessels in Systemic Inflammation

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