title: Anti-inflammatory actions of Chemoattractant Receptor-homologous molecule expressed on Th2 by the antagonist MK-7246 in a novel rat model of Alternaria alternata elicited pulmonary inflammation.
abstract: Alternaria alternata is a fungal allergen linked to the development of severe asthma in humans. In view of the clinical relationship between A. alternata and asthma, we sought to investigate the allergic activity of this antigen after direct application to the lungs of Brown Norway rats. Here we demonstrate that a single intratracheal instillation of A. alternata induces dose and time dependent eosinophil influx, edema and Type 2 helper cell cytokine production in the lungs of BN rats. We established the temporal profile of eosinophilic infiltration and cytokine production, such as Interleukin-5 and Interleukin-13, following A. alternata challenge. These responses were comparable to Ovalbumin induced models of asthma and resulted in peak inflammatory responses 48h following a single challenge, eliminating the need for multiple sensitizations and challenges. The initial perivascular and peribronchiolar inflammation preceded alveolar inflammation, progressing to a more sub-acute inflammatory response with notable epithelial cell hypertrophy. To limit the effects of an A. alternata inflammatory response, MK-7246 was utilized as it is an antagonist for Chemoattractant Receptor-homologous molecule expressed in Th2 cells. In a dose-dependent manner, MK-7246 decreased eosinophil influx and Th2 cytokine production following the A. alternata challenge. Furthermore, therapeutic administration of corticosteroids resulted in a dose-dependent decrease in eosinophil influx and Th2 cytokine production. Reproducible asthma-related outcomes and amenability to pharmacological intervention by mechanisms relevant to asthma demonstrate that an A. alternata induced pulmonary inflammation in BN rats is a valuable preclinical pharmacodynamic in vivo model for evaluating the pharmacological inhibitors of allergic pulmonary inflammation.
authors.affiliation: Pharmacology, Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Malgorzata A
authors.initials: MA
authors.lastname: Gil
authors.affiliation: Pharmacology, Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Caniga
authors.affiliation: Pharmacology, Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Janice D
authors.initials: JD
authors.lastname: Woodhouse
authors.affiliation: Pharmacology, Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Eckman
authors.affiliation: Biology Discovery, Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Hyun-Hee
authors.initials: HH
authors.lastname: Lee
authors.affiliation: Biology Discovery, Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Salmon
authors.affiliation: Discovery Pharmaceutical Sciences, Merck Research Laboratories, Boston, MA 02115 , USA.
authors.forename: John
authors.initials: J
authors.lastname: Naber
authors.affiliation: Safety Assessment and Laboratory Animal Sciences, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Valerie T
authors.initials: VT
authors.lastname: Hamilton
authors.affiliation: Imaging, Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Raquel S
authors.initials: RS
authors.lastname: Sevilla
authors.affiliation: Target & Pathway Biology, Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Bettano
authors.affiliation: Target & Pathway Biology, Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Klappenbach
authors.affiliation: Pharmacology, Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Lily
authors.initials: L
authors.lastname: Moy
authors.affiliation: Biology Discovery, Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Craig C
authors.initials: CC
authors.lastname: Correll
authors.affiliation: Target & Pathway Biology, Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Francois G
authors.initials: FG
authors.lastname: Gervais
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Phieng
authors.initials: P
authors.lastname: Siliphaivanh
authors.affiliation: Imaging, Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Weisheng
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Pharmacology, Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang-Hoover
authors.affiliation: Pharmacology, Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Robbie L
authors.initials: RL
authors.lastname: McLeod
authors.affiliation: Pharmacology, Merck Research Laboratories, Boston, MA 02115, USA. Electronic address: milenko.cicmil@merck.com.
authors.forename: Milenko
authors.initials: M
authors.lastname: Cicmil
mesh_terms: D000485:Allergens / Q000276:immunology; D000528:Alternaria / Q000187:drug effects* / Q000276:immunology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D002243:Carbolines / Q000494:pharmacology*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism; D015848:Interleukin-5 / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D011014:Pneumonia / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D044042:Receptors, Formyl Peptide / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology
chemical_list: C554899:((7R)-7-(((4-fluorophenyl)sulfonyl)(methyl)amino)-6,7,8,9-tetrahydropyrido(1,2-a)indol-10-yl)acetic acid; D000485:Allergens; D000893:Anti-Inflammatory Agents; D002243:Carbolines; D016207:Cytokines; D018793:Interleukin-13; D015848:Interleukin-5; D044042:Receptors, Formyl Peptide; D010047:Ovalbumin
keywords: Alternaria alternata; Brown Norway Rat; CRTH2; MK-7246