Radhika Joshi1, Daniel Valdez2, Hosu Kim3, Douglas C Eikenburg4, Brian J Knoll5, Richard A Bond6. 1. Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 3455 Cullen Blvd., Houston, TX 77204-5027, USA. Electronic address: rjoshi@uh.edu. 2. Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 3455 Cullen Blvd., Houston, TX 77204-5027, USA. Electronic address: danvaldez2008@yahoo.com. 3. Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 3455 Cullen Blvd., Houston, TX 77204-5027, USA. Electronic address: hkim36@uh.edu. 4. Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 3455 Cullen Blvd., Houston, TX 77204-5027, USA. Electronic address: deikenbu@central.uh.edu. 5. Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 3455 Cullen Blvd., Houston, TX 77204-5027, USA. Electronic address: bknoll@central.uh.edu. 6. Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 3455 Cullen Blvd., Houston, TX 77204-5027, USA. Electronic address: rabond@uh.edu.
Abstract
BACKGROUND: Our previous studies suggested certain β-adrenoceptor blockers (β-blockers) attenuate the asthma phenotype in ovalbumin driven murine models of asthma. However, the ovalbumin model has been criticized for lack of clinical relevance. METHODS: We tested the non-selective β-blockers, carvedilol and nadolol, in house dust mite (HDM) driven murine asthma models where drugs were administered both pre- and post-development of the asthma phenotype. We measured inflammation, mucous metaplasia, and airway hyper-responsiveness (AHR). We also measured the effects of the β-blockers on extracellular-signal regulated kinase (ERK 1/2) phosphorylation in lung homogenates. RESULTS: We show that nadolol, but not carvedilol, attenuated inflammation and mucous metaplasia, and had a moderate effect attenuating AHR. Following HDM exposure, ERK1/2 phosphorylation was elevated, but the level of phosphorylation was unaffected by β-blockers, suggesting ERK1/2 phosphorylation becomes dissociated from the asthma phenotype. CONCLUSION: Our findings in HDM models administering drugs both pre- and post-development of the asthma phenotype are consistent with previous results using ovalbumin models and show differential effects for nadolol and carvedilol on the asthma phenotype. Lastly, our data suggest that ERK1/2 phosphorylation may be involved in development of the asthma phenotype, but may have a limited role in maintaining the phenotype.
BACKGROUND: Our previous studies suggested certain β-adrenoceptor blockers (β-blockers) attenuate the asthma phenotype in ovalbumin driven murine models of asthma. However, the ovalbumin model has been criticized for lack of clinical relevance. METHODS: We tested the non-selective β-blockers, carvedilol and nadolol, in house dust mite (HDM) driven murineasthma models where drugs were administered both pre- and post-development of the asthma phenotype. We measured inflammation, mucous metaplasia, and airway hyper-responsiveness (AHR). We also measured the effects of the β-blockers on extracellular-signal regulated kinase (ERK 1/2) phosphorylation in lung homogenates. RESULTS: We show that nadolol, but not carvedilol, attenuated inflammation and mucous metaplasia, and had a moderate effect attenuating AHR. Following HDM exposure, ERK1/2 phosphorylation was elevated, but the level of phosphorylation was unaffected by β-blockers, suggesting ERK1/2 phosphorylation becomes dissociated from the asthma phenotype. CONCLUSION: Our findings in HDM models administering drugs both pre- and post-development of the asthma phenotype are consistent with previous results using ovalbumin models and show differential effects for nadolol and carvedilol on the asthma phenotype. Lastly, our data suggest that ERK1/2 phosphorylation may be involved in development of the asthma phenotype, but may have a limited role in maintaining the phenotype.
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