Airway hyperresponsiveness in asthma: lessons from in vitro model systems and animal models

Abstract

Airway hyperresponsiveness (AHR) is a hallmark clinical symptom of asthma. At least two components of AHR have been identified: 1) baseline AHR, which is persistent and presumably caused by airway remodelling due to chronic recurrent airway inflammation; and 2) acute and variable AHR, which is associated with an episodic increase in airway inflammation due to environmental factors such as allergen exposure.Despite intensive research, the mechanisms underlying acute and chronic AHR are poorly understood. Owing to the complex variety of interactive processes that may be involved, in vitro model systems and animal models are indispensable to the unravelling of these mechanisms at the cellular and molecular level.The present paper focuses on a number of translational studies addressing the emerging central role of the airway smooth muscle cell, as a multicompetent cell involved in acute airway constriction as well as structural changes in the airways, in the pathophysiology of airway hyperresponsiveness.

Increased arginase activity contributes to airway remodelling in chronic allergic asthma

“…In addition, structural changes in the airway wall, including thickening of the basement membrane, increased airway smooth muscle (ASM) mass, subepithelial fibrosis, goblet cell hyperplasia, submucosal gland hypertrophy and increased vascularisation, are observed, which may contribute to the progressive decline in lung function and persistent AHR in chronic asthma [2,3].…”

β-Agonist-associated Reduction in RGS5 Expression Promotes Airway Smooth Muscle Hyper-responsiveness

“…In allergic asthma, mediators secreted by activated inflammatory leukocytes or resident lung cells including histamine, leukotrienes, bradykinin, and thrombin promote ASM contraction by activating GPCRs linked to activation (GTP binding) of G␣ q (5). This initiates a signaling route culminating in generation of inositol (3,4,5)-trisphosphate and release of Ca 2ϩ from endoplasmic reticulum by activation of IP3 receptors. Hydrolysis of GTP by G␣ q promotes pathway deactivation through formation of inactive G␣ q -GDP-G␤␥ heterotrimers.…”

“…A cardinal feature of asthma is "airway hyper-responsiveness" (AHR), 2 which refers to the increased bronchial contraction to inhaled procontractile agonists such as methacholine that is observed in asthmatics relative to healthy controls. AHR manifests as reduced airflow (1)(2)(3)(4). In allergic asthma, mediators secreted by activated inflammatory leukocytes or resident lung cells including histamine, leukotrienes, bradykinin, and thrombin promote ASM contraction by activating GPCRs linked to activation (GTP binding) of G␣ q (5).…”

Animal models of airway hyperresponsiveness

“…We read with interest the recent paper by VAN DEN NIEUWENHOF et al [1] who reported no statistically significant association of airway hyperresponsiveness (AHR) with asthma incidence over 14 yrs in 123 asymptomatic adolescents aged 10-22 yrs at baseline. They concluded that AHR is not a risk factor for the development of asthma in adulthood and that screening for AHR in adolescents to detect subjects at risk for asthma cannot be recommended.…”

“…I read with much interest the review by MEURS et al [1], in which they examined the relative merits of several animal models of airway hyperresponsiveness (AHR), and the insights these models provide into the mechanisms of airway physiology and pathophysiology. The study appropriately focused on the role of nitric oxide (NO) as a transmitter of the inhibitory (i.e.…”