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Sex Dependent Role of Activating Transcription Factor 3 (ATF3) Expression In Modulating The Asthmatic Phenotype In An Acute Mouse Model Of Airway Neutrophilia
Author(s) -
Spinelli Amy,
Ortiz Nathalie Fuentes,
Nicoleau Marvin,
Sinha Utkarshna,
Caruso Carla R,
DiAngelo Susan,
Chroneos Zissis,
Silveyra Patricia
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.656.9
Subject(s) - neutrophilia , bronchoalveolar lavage , medicine , immunology , asthma , airway , lung , anesthesia
Background Asthma is a chronic lung disease that affects more than 300 million people worldwide, causing more than 250,000 annual deaths. A sub‐population of severe asthma patients have been identified that are distinguished by their high incidence of airway neutrophilia. Patients presenting with this inflammatory profile tend to be less responsive to corticoid steroid treatment and have a higher mortality rate. Therefore, identifying molecules that promote this excessive neutrophil recruitment is essential for better treatment options for these patients. In this study, we aimed to generate and characterize an acute mouse model of airway neutrophilia that could be used to study this particular asthma phenotype. Methods Both male and female C57BL/6J mice were challenged with either filtered air (FA) or ozone (1 or 2ppm for 3h). The asthmatic phenotype was assessed by testing airway hyperresponsiveness (AHR) to methacholine challenge using the Buxco system (Penh) and airway remodeling was characterized using the multi‐photon imaging technique‐second harmonic generation to determine collagen content in challenged airways. The extent of airway inflammation was quantified by cell differential assessment of bronchoalveolar lavage fluid (BALF) and lung tissue was harvested for mRNA expression measurements. Results We found that ozone exposure leads to airway neutrophilia and AHR. We also saw that expression levels of the stress response activating transcription factor 3 (ATF3) were enhanced in ozone challenged animals with females showing a higher level of up‐regulation compared to males. Interestingly, global knockout of ATF3 was not protective against airway neutrophilia as ATF3−/− male and female mice were observed to have higher levels of neutrophil BALF counts, and female ATF3−/− mice had higher Penh values as compared to wild‐type ozone challenged mice. Conclusion This study presents an acute model of refractory asthma whereby ozone challenge initiates AHR and airway neutrophilia. This study also demonstrates the complex role ATF3 plays in regulating airway neutrophilia whereby up‐regulation of this transcription factor is observed to promote the inflammatory phenotype but loss of this protein enhances this inflammatory response in a sex dependent manner. Support or Funding Information The authors also thank Todd Umstead for assistance, training and experiments. Dr. Joanna Floros for use of her ozone equipment. NIH Grant KO1HL133520