Volume 10 Supplement 1

2nd Cross Company Respiratory Symposium

Open Access

Alternaria alternata induced inflammatory lung responses: a novel in vivo PK/PD model

  • Malgorzata Gil1,
  • Michael Caniga1,
  • Joseph Eckman1,
  • Robbie McLeod1,
  • Lily Moy1,
  • Alan Wilhelm1,
  • Janice Woodhouse1,
  • Jie Zhang-Hoover1 and
  • Milenko Cicmil1Email author
Journal of Inflammation201310(Suppl 1):P10

https://doi.org/10.1186/1476-9255-10-S1-P10

Published: 14 August 2013

Rationale

Asthma is a heterogeneous disorder characterized by several physiologic and immunologic phenotypes. Common environmental allergens such as pollen, house dust mite and mold induce airway inflammation and exacerbate asthmatic symptoms. Traditional rodent models of asthma use multiple sensitizations and challenges with allergens such as OVA and HDM to induce asthma like responses. Alternaria alternata is a fungal allergen linked to the development of severe asthma [1]. This allergen is capable of eliciting robust immune responses in the lungs [2]. In the current study we evaluated a single intratracheal (i.t.) instillation of Alternaria to model immune responses in Brown Norway rats.

Methods

Brown Norway rats are commonly used to study allergic asthma. In this study, animals were subjected to a single i.t. challenge with gradient doses of Alternaria alternata. A temporal profile was performed following Alternaria challenge. Inflammatory cell infiltration and cytokines (IL-5, and IL-13) were assessed in bronchoalveolar lavage fluid (BALF). Pharmacological profiling was conducted using oral dosing of cotricosteriods.

Results

Alternaria induced dose and time- dependent recruitment of inflammatory cells in the lungs along with increased cytokine levels in BALF. Here we report, a time related infiltration of neutrophils in BALF. Oral dosing of corticosteroids administered prior to Alternaria instillation led to a dose-dependent attenuation of Alternaria induced airway inflammation.

Conclusions

A single i.t. instillation of Alternaria induced significant inflammation in the lung. Preliminary profiling suggests that Alternaria challenge has the potential to be a robust and reliable PK/PD model to assess in vivo compound potency.

Authors’ Affiliations

(1)
Merck Research Laboratories

References

  1. Denning DW, O'Driscoll BR, Hogaboam CM, Bowyer P, Niven RM: The link between fungi and severe asthma: a summary of the evidence. ERJ. 2006, 27 (3): 615-626. 10.1183/09031936.06.00074705.View ArticleGoogle Scholar
  2. Doherty TA, Khorram N, Kotaro Sugimoto K, Sheppard D, Rosenthal P, Cho JY, Pham A, Miller M, Croft M, Broide DH: Alternaria Induces STAT6-Dependent Acute Airway Eosinophilia and Epithelial FIZZ1 Expression That Promotes Airway Fibrosis and Epithelial Thickness. J Immunol. 2012, 188 (6): 2622-9. 10.4049/jimmunol.1101632.PubMed CentralView ArticlePubMedGoogle Scholar

Copyright

© Gil et al; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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