Alpha 4-integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep.

Abraham, William M.; Sielczak, M. W.; Ahmed, Awad A.; Cortes, Alejandro; Lauredo, Isabel T.; Kim, J; Pepinsky, Blake; Benjamin, Christopher D.; Leone, Diane R.; Lobb, Roy R.

doi:10.1172/jci117032

Cited by 206 publications

(136 citation statements)

References 55 publications

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“…Thus, while described above, BIO-1211, HMR 1031, IVL745, TR14035, or GW559090X α4β1 antagonists have negligible benefit in human asthma clinical trials, these compounds have had significant effects in sheep [118,121,126], mouse [121,127], rat [118,123,128], or guinea pig [123] models of asthma. The HP1/2, PS2/3, PS/2, TA-2, or Max-68P anti-α4 blocking antibodies, CS-1 peptide ligand anti-α4β1 mimic, or α4β1 small molecule inhibitors reduce either numbers of eosinophils in the airway or ameliorate inflammatory histopathology or airway allergic responses in the guinea pig [129][130][131][132][133], sheep [134][135][136][137], mouse [138][139][140], rat [141,142], or rabbit [143]. A complication of such studies is the failure to differentiate between effects resulting from eosinophils, roles of integrins of eosinophils, or roles of other cell types [144][145][146][147].…”

Section: Targeting Eosinophil Integrins In Vivomentioning

confidence: 99%

Roles of integrin activation in eosinophil function and the eosinophilic inflammation of asthma

Barthel

Johansson

McNamee

et al. 2007

Journal of Leukocyte Biology

143

128

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Eosinophilic inflammation is a characteristic feature of asthma. Integrins are highly versatile cellular receptors that regulate extravasation of eosinophils from the postcapillary segment of the bronchial circulation to the airway wall and airspace. Such movement into the asthmatic lung is described as a sequential, multistep paradigm, whereby integrins on circulating eosinophils become activated, eosinophils tether in flow and roll on bronchial endothelial cells, integrins on rolling eosinophils become further activated as a result of exposure to cytokines, eosinophils arrest firmly to adhesive ligands on activated endothelium, and eosinophils transmigrate to the airway in response to chemoattractants. Eosinophils express seven integrin heterodimeric adhesion molecules: alpha4beta1 (CD49d/29), alpha6beta1 (CD49f/29), alphaMbeta2 (CD11b/18), alphaLbeta2 (CD11a/18), alphaXbeta2 (CD11c/18), alphaDbeta2 (CD11d/18), and alpha4beta7 (CD49d/beta7). The role of these integrins in eosinophil recruitment has been elucidated by major advances in the understanding of integrin structure, integrin function, and modulators of integrins. Such findings have been facilitated by cellular experiments of eosinophils in vitro, studies of allergic asthma in humans and animal models in vivo, and crystal structures of integrins. Here, we elaborate on how integrins cooperate to mediate eosinophil movement to the asthmatic airway. Antagonists that target integrins or the effectors that regulate integrins of eosinophils represent potentially promising therapies in the treatment of asthma.

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Section: Targeting Eosinophil Integrins In Vivomentioning

confidence: 99%

Roles of integrin activation in eosinophil function and the eosinophilic inflammation of asthma

Barthel

Johansson

McNamee

et al. 2007

Journal of Leukocyte Biology

143

128

View full text Add to dashboard Cite

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“…However, results of antibody studies vary with the animal model used or the route of antibody administration, and off-target effects can not be excluded [10][11][12][13][14]. To avoid the ambiguity of antibody-based studies and to carry out long-term observations, mouse models with genetically modified integrin genes have been generated [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Unique and redundant roles of α4 and β2 integrins in kinetics of recruitment of lymphoid vs myeloid cell subsets to the inflamed peritoneum revealed by studies of genetically deficient mice

Ulyanova

Priestley

Banerjee

et al. 2007

Experimental Hematology

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OBJECTIVE-Leukocyte recruitment to inflammatory sites is a prominent feature of acute and chronic inflammation. Instrumental in this process is the coordinated upregulation of leukocyte integrins (among which α4β1 and β2 integrins are major players) and their cognate receptors in inflamed tissues. To avoid the ambiguity of previous short-term antibody-based studies and to allow for long-term observation, we used genetically deficient mice to compare roles of α4 and β2 integrins in leukocyte trafficking.METHODS-Aseptic peritonitis was induced in α4 or β2 integrin-deficient (conditional and conventional knockouts, respectively) and control mice, and recruitment of major leukocyte subsets to the inflamed peritoneum was followed for up to 4 days. RESULTS-Despite normal chemokine levels in the peritoneum and adequate numbers, optimal recruitment of myeloid cells was impaired in both α4-and β2-deficient mice. Furthermore, clearance of recruited neutrophils and macrophages was delayed in these mice. Lymphocyte migration to the peritoneum in the absence of α4 integrins was drastically decreased, both at steady state and during inflammation, a finding consistent with impaired lymphocyte in vitro adhesion and signaling. By contrast, in the absence of β2 integrins, defects in lymphocyte recruitment were only evident when peritonitis was established.CONCLUSIONS-Our data with concurrent use of genetic models of integrin deficiency reveal non-redundant functions of α4 integrins in lymphocyte migration to the peritoneum and further refine specific roles of α4 and β2 integrins concerning trafficking and clearance of other leukocyte subsets at homeostasis and during inflammation.

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“…Significant differences compared with control isotype (challenged with OA) are indicated: *, P < 0.05; t, P < 0.005; *, P < 0.001. mark of asthma (10). Although BHR is reported to correlate with the number of eosinophils in lungs staining positively with a monoclonal antibody that recognizes secreted eosinophil cationic protein (10)(11)(12)(13), there is no formal evidence for a causal relationship between eosinophil recruitment per se and BHR in humans (14,15), sheep (16), and guinea pigs (4). Few studies have addressed the correlation between eosinophil recruitment to the airways and BHR in mice, possibly because the evaluation of their pulmonary functions was considered difficult or unreliable.…”

mentioning

confidence: 99%

Eosinophil recruitment into the respiratory epithelium following antigenic challenge in hyper-IgE mice is accompanied by interleukin 5-dependent bronchial hyperresponsiveness.

Eum

Hailé

Lefort

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

185

132

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A murine model for antigen-induced bronchial hyperreactivity (BHR) and airway eosinophilia, two hallmarks of asthma, was developed using ovalbuminimmunized mice, which produce large amounts of IgE (named BP2, "Bons Producteurs 2," for High Line of Selection 2). A single intranasal ovalbumin challenge failed to modify the bronchial responses, despite the intense eosinophil recruitment into the bronchoalveolar lavage fluid and airways. When mice were challenged twice a day for 2 days or once a day for 10 days, BHR in response to i.v. 5-hydroxytryptamine or to inhaled methacholine was induced in BP2 mice but not in BALB/c mice. Histological examination showed that eosinophils reached the respiratory epithelium after multiple ovalbumin challenges in BP2 mice but remained in the bronchial submucosa in BALB/c mice. Total IgE titers in serum were augmented significantly with immunization in both strains, but much more so in BP2 mice. Interleukin 5 (IL-5) titers in serum and bronchoalveolar lavage fluid of BP2 mice were augmented by the antigenic provocation, and a specific anti-IL-5 neutralizing antibody suppressed altogether airway eosinophilia and BHR, indicating a participation of IL-5 in its development. Our results indicate that the recruitment of eosinophils to the airways alone does not induce BHR in mice and that the selective effect on BP2 mice is related to their increased IgE titers associated with antigen-driven eosinophil migration to the epithelium, following formation and secretion of IL-5.Bronchial hyperreactivity (BHR) Evaluation of Bronchoconstriction. In a first procedure, mice were prepared as described (5), using the computerized pulmonary analyzer (Mumed PR800 system, UK) adapted to mice. To evaluate the effect of antigenic challenge on airway responsiveness, 5-hydroxytryptamine (5-HT; Sigma) was injected into the cannulated jugular vein at 10, 20, 40, 80, 160, and 320 jig/kg in a volume of 100 ,ul during 10 sec at 5-min intervals. The results were expressed as PD30, PD60, and PD90 (the amount of 5-HT needed to augment the bronchial resistance by 30%, 60%, and 90%). In a second procedure, unrestrained conscious mice were placed in a whole body plethysmographic chamber (Buxco Electronics, Sharon, CT) to analyze the respiratory waveforms. After a few minutes for stabilization, an aerosol of methacholine (3 x 10-2 M in the aerosolator; Aldrich) was delivered during 20 and 60 sec, at a 10-min interval. The airway resistance was expressed as Penh = [Te (expiratory time)/40% of Tr (relaxation time) -1] x Pef (peak expiratory flow)/Pif (peak inspiratory flow) x 0.67, according to the recommendations of the manufacturer. To calculate the APenh (difference between the basal and maximal value), the average of five maximal values was used.

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Alpha 4-integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep.

Abstract: Invest. 1994. 93:776-787.)

Cited by 206 publications

References 55 publications

Roles of integrin activation in eosinophil function and the eosinophilic inflammation of asthma

Roles of integrin activation in eosinophil function and the eosinophilic inflammation of asthma

Unique and redundant roles of α4 and β2 integrins in kinetics of recruitment of lymphoid vs myeloid cell subsets to the inflamed peritoneum revealed by studies of genetically deficient mice

Eosinophil recruitment into the respiratory epithelium following antigenic challenge in hyper-IgE mice is accompanied by interleukin 5-dependent bronchial hyperresponsiveness.

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