Vascular Remodeling Is Airway Generation-Specific in a Primate Model of Chronic Asthma

Avdalovic, Mark V; Putney, Lei; Schelegle, Edward S.; Miller, Lisa; Usachenko, Jodie; Tyler, Nancy K.; Plopper, Charles G.; Gershwin, Laurel J.; Hyde, Dallas M.

doi:10.1164/rccm.200506-848oc

Cited by 39 publications

(37 citation statements)

References 29 publications

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“…These studies [6,66,72] demonstrate that allergic asthma can be produced experimentally in a nonhuman primate, the rhesus macaque monkey, using a recognised human allergen, house dust mite, and provides a valuable model for human asthma. Design-based stereological approaches to the tracheobronchial airways A common problem observed in lung stereology is profile counting of cells as a representation of cell number.…”

Section: Bronchial Vasculaturementioning

confidence: 94%

“…Asthma manifests itself by altering not only the epithelial compartment or the airway smooth muscle but also other compartments (e.g. interstitial, vascular, immunological and nervous [6,7]). …”

Section: The Epithelial-mesenchymal Trophic Unitmentioning

confidence: 99%

“…Airway generation-specific remodelling Intrapulmonary proximal and distal bronchi of sensitised and challenged monkeys have focal mucous goblet cell hyperplasia, thickening of the BMZ, hypercellularity in the epithelium and subepithelial connective tissue, and increases in smooth muscle and bronchial microvessels [6,66]. These changes are site-specific and vary greatly within various portions of the airway wall in the same airway generation, between airway generations in an individual sensitised and challenged animal, and from animal to animal in the sensitised and challenged group.…”

Section: Airway Physiologymentioning

confidence: 99%

“…Even patients with impaired left ventricular function have been shown to have increased airway hyperreactivity [105]. Rhesus monkeys with HDMA-induced allergic airways also show an increase in airway generation-specific bronchovascular density [6].…”

Section: Bronchial Vasculaturementioning

confidence: 99%

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Asthma: a comparison of animal models using stereological methods

et al. 2006

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Asthma is a worldwide health problem that affects 300 million people, as estimated by the World Health Organization. A key question in light of this statistic is: ''what is the most appropriate laboratory animal model for human asthma?''The present authors used stereological methods to assess airways in adults and during postnatal development, and their response to inhaled allergens to compare rodents and nonhuman primates to responses in humans.An epithelial-mesenchymal trophic unit was defined in which all of the compartments interact with each other. Asthma manifests itself by altering not only the epithelial compartment but also other compartments (e.g. interstitial, vascular, immunological and nervous). All of these compartments show significant alteration in an airway generation-specific manner in rhesus monkeys but are limited to the proximal airways in mice. The rhesus monkey model shares many of the key features of human allergic asthma including the following: 1) allergen-specific immunoglobulin (Ig)E and skin-test positivity; 2) eosinophils and IgE+ cells in airways; 3) a Thelper type 2 cytokine profile in airways; 4) mucus cell hyperplasia; 5) subepithelial fibrosis; 6) basement membrane thickening; and 7) persistent baseline hyperreactivity to histamine or methacholine.In conclusion, the unique responses to inhaled allergens shown in rhesus monkeys make it the most appropriate animal model of human asthma.

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Section: Bronchial Vasculaturementioning

confidence: 94%

Section: The Epithelial-mesenchymal Trophic Unitmentioning

confidence: 99%

Section: Airway Physiologymentioning

confidence: 99%

Section: Bronchial Vasculaturementioning

confidence: 99%

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Asthma: a comparison of animal models using stereological methods

et al. 2006

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“…Previous research shows that vascular remodeling in HDMA-exposed airways is generation specific (60). It is possible that O 3 1 HDMA exposure may have differential effects along segments of the tracheobronchial tree.…”

Section: Direct Effect Of 5-ht On Asm Tensionmentioning

confidence: 99%

Persistence of Serotonergic Enhancement of Airway Response in a Model of Childhood Asthma

Moore

Hyde

Miller

et al. 2014

Am J Respir Cell Mol Biol

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The persistence of airway hyperresponsiveness (AHR) and serotonergic enhancement of airway smooth muscle (ASM) contraction induced by ozone (O 3 ) plus allergen has not been evaluated. If this mechanism persists after a prolonged recovery, it would indicate that early-life exposure to O 3 plus allergen induces functional changes predisposing allergic individuals to asthmarelated symptoms throughout life, even in the absence of environmental insult. A persistent serotonergic mechanism in asthma exacerbations may offer a novel therapeutic target, widening treatment options for patients with asthma. The objective of this study was to determine if previously documented AHR and serotonin-enhanced ASM contraction in allergic monkeys exposed to O 3 plus house dust mite allergen (HDMA) persist after prolonged recovery. Infant rhesus monkeys sensitized to HDMA were exposed to filtered air (FA) (n = 6) or HDMA plus O 3 (n = 6) for 5 months. Monkeys were then housed in a FA environment for 30 months. At 3 years, airway responsiveness was assessed. Airway rings were then harvested, and ASM contraction was evaluated using electrical field stimulation with and without exogenous serotonin and serotoninsubtype receptor antagonists. Animals exposed to O 3 plus HDMA exhibited persistent AHR. Serotonin exacerbated the ASM contraction in the exposure group but not in the FA group.Serotonin subtype receptors 2, 3, and 4 appear to drive the response. Our study shows that AHR and serotonin-dependent exacerbation of cholinergic-mediated ASM contraction induced by early-life exposure to O 3 plus allergen persist for at least 2.5 years and may contribute to a persistent asthma phenotype.

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The bronchial circulation—worth a closer look: A review of the relationship between the bronchial vasculature and airway inflammation

McCullagh

Rosenthal

Wanner

et al. 2009

Pediatric Pulmonology

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Until recently, the bronchial circulation has been relatively ignored in the research and clinical arenas, perhaps because of its small volume and seeming dispensability relative to the pulmonary circulation. Although the bronchial circulation only receives around 1% of the cardiac output in health, it serves functions that are critical to maintaining airway and lung function. The bronchial circulation also plays an important role in many lung and airway diseases; through its ability to increase in size, the bronchial circulation is able to provide lung parenchymal perfusion when the pulmonary circulation is compromised, and more recently the role of the bronchial circulation in the pathogenesis of inflammatory airway disease has been explored. Due to the anatomic variability and small volume of the bronchial circulation, much of the research to date has necessitated the use of animal models and invasive procedures. More recently, non-invasive techniques for measuring bronchial blood flow in the mucosal microvascular network have been developed and offer a new avenue for the study of this circulation in humans. In conjunction with molecular research, measurement of airway blood flow (Q(aw)) may help elucidate the role of the bronchial circulation in inflammatory airway disease and become a useful tool for monitoring therapy.

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Vascular Remodeling Is Airway Generation-Specific in a Primate Model of Chronic Asthma

Cited by 39 publications

References 29 publications

Asthma: a comparison of animal models using stereological methods

Asthma: a comparison of animal models using stereological methods

Persistence of Serotonergic Enhancement of Airway Response in a Model of Childhood Asthma

The bronchial circulation—worth a closer look: A review of the relationship between the bronchial vasculature and airway inflammation

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