Center for Allergy and Inflammation

Laboratory Research
 

William R. Henderson, Jr., M.D.  
Professor

Center for Allergy and Inflammation

Head, Allergy Section

Division of Allergy and Infectious Diseases, Department of Medicine

University of Washington

Background
William R. Henderson, Jr., M.D. is Professor of Medicine at the University of Washington Center for Allergy and Inflammation. He received his A.B. in Zoology (1969) at the University of California, Berkeley graduating first in his class (University Medalist).  He received his M.D. at the University of California, San Francisco in 1973 (Alpha Omega Alpha) and residency training in Internal Medicine at Stanford University, 1973-1975.  He was trained in Allergy and Immunology as a Clinical Associate in the Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland (1975-1978).  Since 1978, he has been on the faculty of the University of Washington where he is now Head of the Allergy Section, Division of Allergy and Infectious Diseases and Director of the Allergy and Immunology Fellowship Training Program.  He was the recipient of a NIH Allergic Diseases Academic Award and has served as Director of the NIAID Asthma and Allergic and Immunologic Diseases Cooperative Research Center at the University of Washington. He has served on the Board of Directors of the American Board of Allergy and Immunology (Chair, 2003) and the American Academy of Allergy, Asthma and Immunology. Dr. Henderson is a member of the Association of American Physicians and the American Society of Clinical Investigation.  

His research studies have focused on the interaction between eosinophils and mast cells, and the production by these and other inflammatory cells of the potent 5-lipoxygenase products of arachidonic acid, the cysteinyl leukotriene (CysLT)s. Dr. Henderson and colleagues have developed a protocol for administration of ovalbumin (OVA) as allergen to induce late-phase allergen-specific pulmonary disease in normal mice.  OVA-treated mice display a disease strikingly similar to allergen-induced human asthma.  The CysLTs play an important role in the airway remodeling seen in persistent asthma that includes increases of airway goblet cells, mucus, blood vessels, smooth muscle, myofibroblasts, and airway fibrosis.  In the mouse model of asthma with airway remodeling, Dr. Henderson and colleagues found that leukotrienes are key mediators of the mucus release and eosinophil infiltration of the airways and that CysLT₁ receptor antagonists inhibit the airway remodeling processes, including airway smooth muscle cell hyperplasia and fibrosis. His current research is summarized as follows:

 

5-Lipoxygenase Products in Asthmatic Immune Response

Although considerable progress has made in determining the role played by cytosolic phospholipase A₂ (cPLA₂) and secretory PLA₂ (sPLA₂)s in release of arachidonic acid for leukotriene synthesis, with the recent identification of several new mammalians PLA₂s, evaluation of the role of specific PLA₂s in the mediation of allergic airway inflammation and remodeling is indicated. The specific aims of this study are: To determine the role of a) specific sPLA₂s versus cPLA₂ and b) cysteinyl leukotrienes in the mediation of airway inflammation and remodeling in a mouse asthma model. Functional genomic studies (i.e., microarray and proteomic studies) are in progress to determine the molecular mechanisms that mediate allergen-induced airway inflammation and remodeling.

Chemogenomics to Identify New Molecular Targets in Pulmonary Fibrosis

Activation of redox-sensitive transcription factor, activator protein-1 (AP-1) is associated with profibrotic gene expression and is regulated by redox proteins, macrophage inhibitory factor (MIF) and redox effector factor-1 (Ref-1). Transforming growth factor b (TGFb) signaling activates AP-1 (profibrotic) transcription pathways and is important in cell proliferation/differentiation, apotosis, and deposition of extracellular matrix proteins. Prolonged release of TGFb in the airways of patients with pulmonary fibrosis (PF), via increased AP-1-mediated transcription, may lead to development of airway fibrosis. In this proposal, a novel chemogenomics approach is used to identify and validate small molecule inhibitors of AP-1 transcription and TGFb-driven profibrotic gene expression as potential therapies for PF patients.  The specific aims are: To develop small molecule inhibitor(s) of TGFb-mediated pulmonary fibrosis and determine their effect on airway inflammation and profibrotic gene expression in a mouse model of PF and lung tissue of PF patients.  These studies represent a focused effort using chemogenomics to identify, develop, and validate small molecule inhibitors of AP-1/TGFb-driven profibrotic gene expression as novel therapies in PF patients. 

These studies address previously unexplored areas of pulmonary immune responses and have the potential to suggest new approaches to therapy in asthma and other immunologic disorders.


Selected Recent Publications
 
Henderson, W.R., Jr., L.-O. Tang, S.-J. Chu, S.-M. Tsao, G.K.S. Chiang, F. Jones, M. Jonas, C. Pae, H. Wang, and E.Y. Chi. 2002. A role for cysteinyl leukotrienes in airway remodeling in a mouse asthma model. Am. J. Respir. Crit. Care Med. 165:108-116. 

The number of citations this article has received places it in the top 1% within its field according to Essential Science Indicators^SM.
 
Oh, S.W., I.P. Chong, L. Dong-Keun, F. Jones, G.K.S. Chiang, H.O. Kim, S.-H. Moon, B. Cao, C. Ogbu, K.-W. Jeong, G. Kozu, H. Nakanishi, M. Kahn, E.Y. Chi, and W.R. Henderson, Jr. 2002. Tryptase inhibition blocks airway inflammation in a mouse asthma model. J. Immunol. 168:1992-2000.
 
Henderson, W.R., Jr., E.Y. Chi, J.-L. Teo, C. Nguyen, and M. Kahn. 2002. A small molecule inhibitor of redox-regulated NF-kB and AP-1 transcription blocks allergic airway inflammation in a mouse asthma model. J. Immunol. 169:5294-5299.

 

Henderson, W.R., Jr. and M.J. Lodewick 2003. Animal models of asthma. In Middleton's Allergy. Principles and Practice. N.F.Adkinson, Jr., J.W.Yuninger, W.W.Busse, B.S.Bochner, S.T.Holgate, and F.E.R.Simons, editors. Mosby, St. Louis, MO. 6^th Edition, pp. 465-481.
 
Holgate, S.T., M. Peters-Golden, R.A. Panettieri, and W.R. Henderson, Jr. 2003. Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling. J. Allergy Clin. Immunol. 111:S18-S34.
 
Nguyen, C., J.-L. Teo, A. Matsuda, M. Eguchi, E. Chi, W.R. Henderson, Jr., and M. Kahn. 2003. Chemogenomic identification of Ref-1/AP-1 as a novel therapeutic target for asthma. Proc. Natl. Acad. Sci. U. S. A. 100:1169-1173.

Hallstrand, T.S., J.D. Sprenger, J.M. Agosti, G.M. Longton, R.P. Witherspoon, and W.R. Henderson, Jr.  2004. Long-term acquisition of allergen-specific IgE and asthma following allogeneic bone marrow transplantation from allergic donors.  Blood. 104:3086-3090. Epub 2004 Jul 27.

Henderson, W.R., Jr., E. Ray Banerjee, and E.Y. Chi. 2005. Differential effects of (S)- and (R)-enantiomers of albuterol in mouse asthma model.  J Allergy Clin Immunol. 116:332-340.

Hallstrand, T.S., M.W. Moody, M.L. Aitken, and W.R. Henderson, Jr. 2005. Airway immunopathology of asthma with exercise-induced bronchoconstriction.  J Allergy Clin Immunol, in press.