Effect of Antiasthma Simplified Herbal Medicine Intervention on neutrophil predominant airway inflammation in a ragweed sensitized murine asthma model Kamal D. Srivastava, PhD * ; David Dunkin, MD y ; Changda Liu, PhD * ; Nan Yang, PhD * ; Rachel L. Miller, MD z ; Hugh A. Sampson, MD *; and Xiu-Min Li, MD, MS * * Division of Allergy and Immunology, Department of Pediatrics, The Icahn School of Medicine at Mount Sinai, New York, New York y Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, The Icahn School of Medicine at Mount Sinai, New York, New York z Department of Medicine, Department of Pediatrics, Department of Environmental Health Sciences, Columbia University, New York, New York A R T IC L E IN F O Article history: Received for publication December 10, 2013. Received in revised form January 9, 2014. Accepted for publication January 26, 2014. A B ST R AC T Background: Neutrophil-predominant asthma is less responsive to steroids and associated with poorer disease control. The effects of Antiasthma Simplified Herbal Medicine Intervention (ASHMI), a traditional Chinese medicine formula reported to be efficacious in asthmatic patients and murine asthma models, on neutrophil predominant asthma are unknown. Objective: To determine the effects of standard ASHMI and refined formula ASHMI (ASHMI II ) in a neutrophil-predominant murine model of ragweed (RW) asthma and explore underlying mechanisms. Methods: BALB/c mice were systemically sensitized, intranasallychallenged with RWextract, and orally treated with ASHMI, ASHMI II , or vehicle (water). In a separate experiment, some RW sensitized mice were treated with dexamethasone before challenge. After RW challenge, airway hyperreactivity (AHR), total and differential bronchoalveolar lavage fluid leukocyte counts, lung histologic features, and bronchoalveolar lavage fluid cytokine and chemokine levels were assessed. RW stimulation of the murine macrophage cell line RAW264.7 was used to determine effects of ASHMI active compound ganoderic acid C1 (GAC1) on tumor necrosis factor a (TNF-a) production and regulation of phosphorylated IkB and histone deacetylase 2 (HDAC2) levels. Results: ASHMI and ASHMI II markedly reduced AHR, mucous production, neutrophilic inflammation, and TNF-a, interleukin 8, and interleukin 17 levels and decreased eosinophilic inflammation and T H 2 responses in vivo (P < .01-.001 for all). GAC1 inhibited TNF-a production in RW-stimulated RAW264.7 cells in asso- ciation with suppression of phosphorylated IkB and increased HDAC2 expression. Dexamethasone failed to reduce AHR and neutrophilic inflammation. Conclusion: ASHMI treatment was efficacious in a murine model of neutrophil-predominant asthma via modulation of innate chemokines, T H 2 responses, nuclear factorekB, and HDAC2. ASHMI, and/or its con- stituent GAC1, may be a valuable option for treating neutrophil-predominant asthma. Ó 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved. Introduction Asthma is a heterogeneous airway disease that includes eosinophil-predominant, neutrophil-predominant, and mixed eosinophil and neutrophil airway inflammation. 1 Increasing evi- dence indicates that severe and steroid refractory asthma are often characterized by mixed granulocytic airway inflammation. 2e5 The presence of neutrophils or neutrophil predominance in sputum of asthmatic patients has been reported to be associated with poor lung function and disease outcomes, 4 as well as sudden asthma fatalities. 6e8 Currently, there is no effective therapy for neutrophil- predominant airway inflammation. We previously found that the Antiasthma Simplified Herbal Medicine Intervention (ASHMI) derived from traditional Chinese medicine was efficacious as a stand-alone therapy in adults with moderate-to-severe allergic asthma. Treatment benefits were asso- ciated with increased T H 1 responses and reduced T H 2 responses. 9 Further, ASHMI significantly reduced airway eosinophilic inflam- mation and airway hyperreactivity (AHR) in an ovalbumin sensitized murine asthma model in which eosinophilic inflammation was Reprints: Xiu-Min Li, MD, MS, Division of Allergy and Immunology, Department of Pediatrics, Jaffe Food Allergy Institute, Center for Chinese Herbal Therapy for Allergy and Asthma, Mount Sinai School of Medicine, The Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, New York, NY 10029; E-mail: xiu-min.li@ mssm.edu. Disclosures: Drs Sampson and Li hold US Patent PCT/US05/08600 for Antiasmtha Simplified Herbal Medicine Intervention (ASHMI) and are shareholders of Herb Springs LLC. The remaining author have nothing to disclose. Funding Sources: This work was supported by the National Institutes of Health grant PO1 AT002647 and the Sean Parker Foundation, Winston Wolkoff Integrative Medicine for Allergies and Wellness to Dr Li. Dr Srivastava was supported by KL2 Faculty Scholar Award KL2TR000069, a Mount Sinai Clinical and Translational Sciences Award. Contents lists available at ScienceDirect 1081-1206/14/$36.00 - see front matter Ó 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.anai.2014.01.021 Ann Allergy Asthma Immunol 112 (2014) 339e347