Inhibition of mucin secretion with MARCKS-related peptide improves airway obstruction in a mouse model of asthma

Agrawal, Anurag; Rengarajan, Subramaniam; Adler, Kenneth B.; Ram, Arjun; Ghosh, Balram; Fahim, Mohammad; Dickey, Burton F.

doi:10.1152/japplphysiol.00630.2006

Cited by 72 publications

(57 citation statements)

References 23 publications

(27 reference statements)

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“…Mucous metaplasia is a cardinal feature of the asthma phenotype that is thought to play a central role in death from asthma (24,25,31). Recent studies also suggest that mucin hypersecretion can contribute significantly to AHR (27,32,33). Thus, the finding that chronic administration of beta-blockers reduces mucin content in airway epithelial cells suggests a possible identification of a cell type involved in the decreased AHR that we previously observed (15).…”

Section: Discussionmentioning

confidence: 58%

Chronic Exposure to Beta-Blockers Attenuates Inflammation and Mucin Content in a Murine Asthma Model

Nguyen¹,

Omoluabi²,

Parra³

et al. 2008

Am J Respir Cell Mol Biol

127

132

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Single-dose administration of beta-adrenoceptor agonists produces bronchodilation and inhibits airway hyperresponsiveness (AHR), and is the standard treatment for the acute relief of asthma. However, chronic repetitive administration of beta-adrenoceptor agonists may increase AHR, airway inflammation, and risk of death. Based upon the paradigm shift that occurred with the use of betablockers in congestive heart failure, we previously determined that chronic administration of beta-blockers decreased AHR in a murine model of asthma. To elucidate the mechanisms for the beneficial effects of beta-blockers, we examined the effects of chronic administration of several beta-adrenoceptor ligands in a murine model of allergic asthma. Administration of beta-blockers resulted in a reduction in total cell counts, eosinophils, and the cytokines IL-13, IL-10, IL-5, and TGF-b1 in bronchoalveolar lavage, and attenuated epithelial mucin content and morphologic changes. The differences in mucin content also occurred if the beta-blockers were administered only during the ovalbumin challenge phase, but administration of beta-blockers for 7 days was not as effective as administration for 28 days. These results indicate that in a murine model of asthma, chronic administration of beta-blockers reduces inflammation and mucous metaplasia, cardinal features of asthma that may contribute to airflow obstruction and AHR. Similar to heart failure, our results provide a second disease model in which beta-blockers producing an acutely detrimental effect may provide a therapeutically beneficial effect with chronic administration.

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Section: Discussionmentioning

confidence: 58%

Chronic Exposure to Beta-Blockers Attenuates Inflammation and Mucin Content in a Murine Asthma Model

Nguyen¹,

Omoluabi²,

Parra³

et al. 2008

Am J Respir Cell Mol Biol

127

132

View full text Add to dashboard Cite

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“…This dissociation between IgE and AHR has been demonstrated in mast cell and B cell-deficient mice [52,53]. It is possible that the lack of mucus production seen in LPS-tolerant lungs contributes to the reduced airway resistance [54,55]. Further, airway sensitization has been shown to induce a strong Th17 response leading to robust AHR [56].…”

Section: Discussionmentioning

confidence: 98%

Pulmonary Endotoxin Tolerance Protects against Cockroach Allergen-Induced Asthma-Like Inflammation in a Mouse Model

Natarajan

Kim²,

Bouchard³

et al. 2012

Int Arch Allergy Immunol

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Background: Compounds which activate the innate immune system, such as lipopolysaccharide, are significant components of ambient air, and extremely difficult to remove from the environment. It is currently unclear how prior inhalation of endotoxin affects allergen sensitization. We examined whether lung-specific endotoxin tolerance induction prior to sensitization can modulate the response to allergen. Methods: Endotoxin tolerance was induced by repeated intratracheal exposure to endotoxin. All mice were then sensitized and challenged by direct intratracheal instillation of cockroach allergen. Results: After allergen sensitization and challenge, endotoxin tolerant mice had significantly decreased airways hyperresponsiveness to methacholine challenge, which was confirmed by invasive lung function tests. Decreased goblet cell hyperplasia and mucus production were also found by histological assessment. Tolerant mice were protected from airway eosinophilia through the mechanism of reduced CCL11 and CCL24. Interestingly, endotoxin tolerant mice had only a modest reduction in cockroach-specific IgE; however, total IgE was significantly reduced. Conclusions: These data show that induction of endotoxin tolerance prior to sensitization protects against the hallmark features of asthma-like inflammation, and that transient modulation of innate immunity can have long-lasting effects on adaptive responses.

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“…An obvious possibility is mucus plugging. Agrawal and coworkers (25) showed that treatment with a MARCKS-related peptide that blocks the release of mucin can ameliorate AHR in allergically inflamed mice. Presumably other components of the inflammatory exudates that accumulate in the airspaces of the asthmatic lung could also contribute to blockage of airways.…”

Section: Mechanisms Of Airway Closurementioning

confidence: 99%

Physiologic Dysfunction of the Asthmatic Lung: What's Going On Down There, Anyway?

Irvin

Bates²

2009

Proceedings of the American Thoracic Society

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Asthma is a syndrome of lung dysfunction characterized by airflow obstruction, reversibility to bronchodilators, and airways hyperresponsiveness (AHR). There is a growing body of evidence that suggests that the principle defect in asthma is the occlusion of the airway lumen by liquid, fibrin, and mucus. The fall in FEV 1 observed in asthma is best explained by a loss of communicating airspaces and the rise in residual lung volume. Imaging studies in both human patients and experimental animals support this hypothesis. An increased propensity for the airways to close can be a cause of AHR. We conclude that loss of lung volume plays a central role in determining the dysfunction of the asthmatic lung as measured by FEV 1 . Together, these recent findings provide a better understanding of the causes of airflow obstruction and AHR, suggesting new avenues for the development of more effective asthma therapies.Keywords: lung volume; peripheral resistance; FEV 1 ; airways hyperresponsiveness; airway closure Asthma as a common syndrome that presents as a physiologic dysfunction of the lung characterized by airflow limitation and airways hyperresponsiveness (AHR). Importantly, patients with asthma respond to b-agonists. A typical example is the patient with asthma who presents to a pulmonary clinic with an FEV 1 of 2 L, or 65% of predicted. After treatment with two puffs of albuterol, the FEV 1 improves significantly to 75% of predicted, consistent with the pretest diagnosis of asthma. The first question one might ask is: ''What exactly is the nature of the mechanical defect in the lung that caused this reversible reduction in FEV 1 ?'' This has no simple answer, however, because FEV 1 is a polyvalent measure that is influenced by a myriad of factors, including the volume inspired before forced expiration (i.e., TLC), the level of muscular effort, airways resistance (caliber), airway wall stiffness, and lung elastic recoil (1). Thus, despite being extremely useful from a clinical standpoint (2), FEV 1 is highly nonspecific. This has led physiologists to search for more sensitive and specific measures of lung function. In this review, we will cover the recent investigations using classic physiologic methods and imaging modalities, and discuss how the findings have markedly changed our view of the pathophysiology of the asthmatic lung. MEASUREMENT OF PERIPHERAL LUNG FUNCTIONA number of studies have directly demonstrated the involvement of the lung periphery in asthma. In 1989, Wagner and coworkers (3) published an investigation that employed the wedged bronchoscope technique to assess peripheral airflow resistance (Rp) in normal subjects and in subjects with asthma, and reported two important findings. First, the magnitude of Rp in subjects with asthma was about an order of magnitude larger than in normal subjects, despite the fact that FEV 1 in the subjects with asthma was within normal limits; saliently illustrating the insensitivity of the FEV 1 to peripheral lung dysfunction. Second, Rp was significantly correlated to A...

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Inhibition of mucin secretion with MARCKS-related peptide improves airway obstruction in a mouse model of asthma

Cited by 72 publications

References 23 publications

Chronic Exposure to Beta-Blockers Attenuates Inflammation and Mucin Content in a Murine Asthma Model

Chronic Exposure to Beta-Blockers Attenuates Inflammation and Mucin Content in a Murine Asthma Model

Pulmonary Endotoxin Tolerance Protects against Cockroach Allergen-Induced Asthma-Like Inflammation in a Mouse Model

Physiologic Dysfunction of the Asthmatic Lung: What's Going On Down There, Anyway?

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