Allergic Asthma

 

Clinical Background

Asthma is an inflammatory disorder of the lung that has a high and increasing prevalence in developed society. It is characterized by chronic airway inflammation, reversible airway obstruction, airway hyper-responsiveness, and ultimately airway tissue remodeling. Current treatments generally include targeting the underlying inflammation while concurrently dilating airways with long acting bronchodilators in an effort to minimize irreversible airway remodeling and control the frequency of exacerbations. Despite this, no treatment exists that addresses the underlying disease or reverses lung remodeling during chronic asthma.
Due to its complex nature, there is no single animal model that can completely recapitulate all the etiologies of adult and childhood asthma. Consequently, customization of the model, challenge, and treatment are critical to optimize effective and clinically translatable outcomes.
 
 

Preclinical Models

Model Description Length Attributes Endpoints
Ovalbumin (OVA) Sensitized I.P. with OVA and adjuvant on days 0 and 7 followed by intranasal challenge on days 13-15 (acute) 16 Days (Acute) up to 12 Weeks (Chronic) Most Widely Used Allergic Asthma Model Total and differential cell count in the BAL
 
Airway hyper-reactivity and detailed lung mechanics; flexiVent™
 
BAL inflammatory mediator content
 
Histopathology and immunohistochemistry
 
House Dust Mite (HDM) Sensitized with HDM by intranasal administration on days 0 and 7 followed by intranasal challenge on day 14 (acute) 14 Days (Acute) up to 7 Weeks (Chronic) Clinically Relevant Allergen and Route of Exposure (Adjuvant Free)
Cockroach Allergen (CRA) Sensitized via intratracheal (IT) instillation of CRA on day 0 and 14 followed by IT challenge on day 21 (acute) 21 days (Acute) up to 6 weeks (Chronic) Clinically Relevant Allergen and Route of Exposure (Adjuvant Free)
Treatment Routes:
Intranasal, intratracheal; Microsprayer®, nebulized, intravenous, subcutaneous, intraperitoneal, oral gavage

 
 

Ovalbumin (OVA)-Induced Allergic Asthma


Biomodels offers a mouse model of Ovalbumin (OVA) induced allergic asthma. In the acute model, mice are sensitized with an I.P. injection of OVA and adjuvant on days 0 and 7. Mice are then challenged with intranasal delivery of OVA (10-200 µg) in saline on days 13-15 with endpoints being conducted on or about day 16. Chronic versions of this model run from 28 days up to 12 weeks depending on the specific application need. The OVA model has been the most widely used pre-clinical allergic asthma model and recapitulates many of the hallmarks of allergic asthma in humans. These include elevated IgE and TH2 related cytokines, mucus hypersecretion, airway inflammation, goblet cell hyperplasia, epithelial hypertrophy, and airway hyperreactivity to stimuli. Endpoints in this model generally include total and differential cell counts as well as inflammatory mediator content in the broncho-alveolar lavage fluid, airway hyperreactivity and detailed lung mechanics measured with the flexiVent™ rodent mechanical ventilator as well as histopathology and immunohistochemistry on lung sections.
 
 

Acute Ovalbumin (OVA) Regimen

Acute-Ovalbumin-

Balb/c mice were sensitized with I.P. injection of OVA with adjuvant on days 0 and 7. Mice were challenged with 20 or 200 µg OVA intranasally. A subset of the animals received low dose dexamethasone (0.3 mg/kg) I.P. 1 hour prior to challenge.

 
 

Acute-Ovalbumin-

Total inflammatory cells and eosinophils recovered in broncho-alveolar lavage fluid on day 16 of an acute OVA model. Mice demonstrated a dose responsive increase in total cells and eosinophils. Dexamethasone significantly lowered total inflammatory cell counts and eosinophils in the BAL.

 
 

Acute-Ovalbumin-

Lung Resistance and Elastance measured day 16 of an acute OVA model. OVA challenge significantly increased lung resistance and elastance parameters as a result of methacholine challenge. Low dose dexamethasone treatment significantly reduced airway hyperreactivity in this model.

 
 

Acute-Ovalbumin-

H&E stained lung sections from naïve mice and mice on day 16 of an acute OVA model with and without 3 mg/kg dexamethasone.

 
 

House Dust Mite (HDM) and Cockroach Allergen (CRA) -Induced Allergic Asthma

As an alternative to the OVA model, Biomodels offers house dust mite (HDM) and cockroach allergen (CRA) models of allergic asthma. An example of the acute HDM regimen would include sensitization on days 0 and 7 via the respiratory tract, challenge on day 14 with endpoints on day 15. A CRA regimen would include intratracheal administration of CRA allergen on days 0 and 14 followed by challenge on day 21. Similar to the OVA model, the HDM and CRA models recapitulate many of the chronic asthma hallmarks seen in humans, however the HDM and CRA models utilize more clinically relevant allergens, (in general, OVA is not implicated in human asthma), as well as a more relevant route of sensitization, the respiratory tract.

 
 

Acute-Ovalbumin-

In an acute HDM model Balb/c mice were sensitized via IN administration of HDM on days 0 and 7. Mice were challenged with 20 or 50 µg HDM intranasally. A subset of animals received dexamethasone (3 mg/kg) I.P. 1 hour prior to challenge.

 
 

Acute-Ovalbumin-

Total eosinophils and neutrophils recovered in BAL fluid on day 15 of an acute HDM model. Mice demonstrated an increase in eosinophils and neutrophils. Note the HDM model results in some neutrophil influx, while OVA demonstrates a primarily eosinophilic response. Dexamethasone significantly lowered total eosinophils and neutrophils in the BAL.