research

Teal Hallstrand

Associate Professor
Division of Pulmonary and Critical Care Medicine

MD, MPH

Faculty Web Page

Authored articles (PubMed)

Last Updated:  October 5, 2016

Research Focus

My laboratory studies the pathogenesis of asthma through translational human studies as well as in vitro models using primary human cells and selected in vivo models. We focus on two major areas 1) the regulation and function of a group of inflammatory lipid mediators called eicosanoids (e.g. leukotrienes and prostaglandins), and 2) the origin and function of mast cells in asthma. The release of mediators from mast cells and the increased production of lipid mediators play central roles in the pathogenesis of exercise-induced bronchoconstriction (EIB), and are also strongly implicated in other aspects of asthma, especially acute asthma exacerbations triggered by allergen and viral infection. We are particularly interested in understanding how the airway epithelium regulates the production of these inflammatory mediators by interacting with inflammatory cells such as mast cells and eosinophils that reside in close contact with the airway epithelium. Recent genome wide studies have identified several epithelial genes that may serve as primary regulators of the immune response leading to asthma. We recently worked with researchers from Benaroya Research Institute (BRI), the UW department of Immunology, and Seattle Children’s Research Institute (SCRI) to become part of the NIAID Asthma and Allergic Disease Cooperative Research Centers program. We have also had annual meetings with other researchers interested in Epithelial Biology for the past 8 years, including additional researchers from the Center for Lung Biology (CLB), Oregon Health and Science University (OHSU) and University of British Columbia (UBC). My lab also has strong ongoing collaborations with the section of Allergy and Clinical Immunology, and the medical enzymology program in Biochemistry of Dr. Michael Gelb (Gelb Lab) with a focus on the biology of lipid mediator formation. It is my hope that this research will lead to a better understanding of the biology of asthma and the development of new therapies for asthma.

For more information about our annual Epithelial Biology meeting, please send me an (email).

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Hallstrand Lab 2016 – Left to Right: Sydney Long (Allergy/Immunology Fellow), Teal Hallstrand (PI), Luke Ogden (Research Scientist), Ying Lai (Research Scientist, Lab Manager), Matthew Altman (Allergy/Immunology Faculty), Jimmy Nolin (Pulmonary Post-doctoral Fellow) and Andrew Parker (Allergy/Immunology Fellow)


Regulation of airway inflammation and hyperresponsiveness by secreted PLA2 group X
Exercise-induced bronchoconstriction (EIB) is a prototypical manifestation of indirect airway hyperresponsiveness (AHR), a specific feature of asthma. Our work in this area revealed that patients with this specific phenotype of asthma have epithelial injury and high levels of cysteinyl leukotrienes (CysLT)s and other pro-inflammatory eicosanoids (Click Here) and that the release of these eicosanoids plays an essential role in the pathogenesis of EIB (Click Here). Work on the regulation of eicosanoid formation led us to identify secreted phospholipase A2 group X (sPLA2-X) that regulates the first rate-limiting step in eicosanoid formation (Click Here). We have now shown that sPLA2-X is the predominant sPLA2 in the airways of patients with asthma (Click Here) and have demonstrated that sPLA2-X is increased in asthma, is expressed primarily in the epithelium and serves as a key regulator of eicosanoid formation in epithelial cells (Click Here). We have also developed several model systems to understand the function of sPLA2-X in the epithelium including an in vitro model using well-differentiated primary airway epithelial cells from patients with and without asthma, and murine model systems with selective deficiency of epithelial-derived sPLA2-X. Evidence from murine models indicates that sPLA2-X serves as a key regulator of both the innate and adaptive immune system, and that a receptor that binds sPLA2-X serves as a key regulator of airway hyperresponsiveness (Click Here). We have also demonstrated that sPLA2-X acts on human eosinophils to initiate CysLT synthesis (Click Here) and that endogenous sPLA2-X in human eosinophils regulates CysLT formation (Click Here).

Central function of the epithelium as a regulator of innate cell function in asthma
My lab initially developed an interest in mast cells as we demonstrated that degranulation of these cells in the airways is a key feature of the pathogenesis of EIB (Click Here). Because the susceptibility to EIB varies widely among subjects with asthma, we conducted a genome-wide expression study of airway cells and found that mast cell genes are among the most strongly overexpressed in patients with EIB (Click Here). We subsequently demonstrated using epithelial brushings that mast cells with a unique phenotype of high Tryptase and CPA3 expression but low Chymase expression are increased in subjects with EIB. We used a technique called design-based stereology to demonstrate in humans that the density of intra-epithelial mast cells is uniquely elevated in the group of subjects with EIB relative to non-asthmatics as well as asthmatics who do not have EIB (Click Here). The relationship between mast cell infiltration of the airway epithelium and type-2 inflammation has led us to propose studies to determine the etiology of mast cell infiltration of the airway epithelium in asthma through altered trafficking of mast cell progenitors. We are also examining the cellular and molecular basis for the interactions between mast cells and epithelial cells. As recent genome wide association studies have strongly implicated IL-33 and the ST2 receptor in the pathogenesis of asthma, we have begun to focus on IL-33 and other epithelial-derived cytokines including thymic stromal lymphopoietin (TSLP) and IL-25 as key regulators of type-2 inflammation with a focus on the interactions between the epithelium and immune cells (Click Here). Mast cells and CD34+ progenitor cells represent a major target for IL-33 signaling. We are corroborating the hypothesis that sensitization and challenge in the absence of adjuvant induces airway inflammation and AHR in a mast cell dependent manner and that mast cells play a key role in the primary immune response (See Figure).

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Figure – Disease model of epithelial-derived IL-33 as a key initiator of the immune response to allergen such as house dust mite (HDM) and concurrent response to respiratory viruses acting through Pathogen Recognition Receptors (PRR).

 

Relevant Publications

Hallstrand, TS, Moody, MW, Aitken, ML, Henderson, WR, Jr. Airway immunopathology of asthma with exercise-induced bronchoconstriction. J Allergy Clin Immunol 2005; 116: 586-593.

Hallstrand, TS, Moody, MW, Wurfel, MM, Schwartz, LB, Henderson, WR, Jr., Aitken, ML. Inflammatory basis of exercise-induced bronchoconstriction. Am J Resp Crit Care Med 2005;172 : 679-686.

Hallstrand TS, Debley JS, Farin FM, Henderson WR, Jr. Role of MUC5AC in exercise-induced bronchoconstriction pathogenesis. J Allergy Clin Immunol 2007;119:1092-8. Epub 2007 Feb 26.

Hallstrand TS, Chi EY, Singer AG, Gelb MH, Henderson Jr WR. Secreted phospholipase A2 group X overexpression in asthma and bronchial hyperresponsiveness. Am J Respir Crit Care Med. 2007 176:1072-8. Epub 2007 Sep 27.

Jian-Qing H, Hallstrand TS, Knight D, Chan-Yeung M, Sandford A, Tripp B, Zamar D, Bossé Y, Kozyrskyj AL, James A, Laprise C, Daley D. A Thymic Stromal Lymphopoietin Gene Variant Is Associated with Asthma and Airway Hyperresponsiveness. J Allergy Clin Immunol. 2009 124: 222-9. Epub 2009 Jun 21.

Hallstrand TS, Wurfel MM, Lai Y, Ni Z, Gelb MH, Altemeier WA, Beyer RP, Aitken ML, Henderson WR Jr. Transglutaminase 2, a novel regulator of eicosanoid production in asthma revealed by genome-wide expression profiling of distinct asthma phenotypes. PLoS One. 2010 5: e8583.

Kicic A, Hallstrand TS, Sutanto EN, Stevens PT, Kobor MS, Taplin C, Pare PD, Beyer RP, Stick SM, Knight DM. Decreased fibronectin production significantly contributes to dysregulated repair of the asthmatic epithelium. Am J Respir Crit Care Med. 2010 181: 889-98. Epub 2010 Jan 28.

Lai Y, Oslund RC, Bollinger RC, Henderson WR, Jr., Santana L, Gelb MH, Hallstrand TS. Eosinophil cysteinyl leukotriene synthesis mediated by exogenous secreted phospholipase A2 group X. J Biol Chem. 2010 285:41491-500. Epub 2010 Oct 25.

Hallstrand TS, Lai Y, Ni Z, Oslund RC, Henderson WR, Jr., Gelb MH, Wenzel SE. Relationship between airway levels of secreted phospholipase A2 groups IIA and X and asthma severity. Clin Exp Allergy. 2011 Jun;41(6):801-10. Epub 2011 Jan 24. PMID: 21255140

Gharib SA, Nguyen EV, Lai Y, Plampin JD, Goodlett DR, Hallstrand TS. Induced sputum proteome in healthy subjects and asthmatic patients. J Allergy Clin Immunol. 2011 128:1176-1184.e6. Epub 2011 Sep 8.

Warner SM, Hackett TL, Shaheen F, Hallstrand TS, Kicic A, Stick SM, Knight DA. Transcription Factor p63 Regulates Key Genes and Wound Repair in Human Airway Epithelial Basal Cells. Am J Respir Cell Mol Biol 2013;49:978-988.

Hallstrand TS, Lai Y, Altemeier WA, Appel CL, Johnson B, Frevert CW, Hudkins KL, Bollinger JG, Woodruff PG, Hyde DM, et al. Regulation and function of epithelial secreted phospholipase A2 group X in asthma. Am J Respir Crit Care Med 2013;188:42-50.

Lai Y, Altemeier WA, Vandree J, Piliponsky AM, Johnson B, Appel CL, Frevert CW, Hyde DM, Ziegler SF, Smith DE, Henderson WR, Jr., Gelb MH, Hallstrand TS. Increased density of intraepithelial mast cells in patients with exercise-induced bronchoconstriction regulated through epithelially derived thymic stromal lymphopoietin and IL-33. J Allergy Clin Immunol. 2014 133:1448-55.

Hallstrand TS, Lai Y, Hooper KA, Oslund RC, Altemeier WA, Matute-Bello G, Gelb MH. Endogenous secreted phospholipase A group X regulates cysteinyl leukotrienes synthesis by human eosinophils. J Allergy Clin Immunol 2015; 137:268-277.

Nolin JD, Ogden HL, Lai Y, Altemeier WA, Frevert CW, Bollinger JG, Naika GS, Kicic A, Stick SM, Lambeau G, Henderson WR Jr, Gelb MH, Hallstrand TS. Identification of epithelial phospholipase A2 receptor 1 (PLA2R1) as a potential target in asthma. Am J Respir Cell Mol Biol. 2016 Jul 22. [Epub ahead of print]

 

Active Funding

Funding Source

Project Title

Invesigator
Role

Funding Dates

NIH/NHLBI
R01 HL089215

Secretory Phospholipase A2s in Airway Pathophysiology

PI

04/2008 - 07/2018

NIH/NIAID U19
AI3863366

Epithelial control of responses to allergen challenge and viral exacerbation

Project-PI

07/2016 - 06/2021

NIH/NIAID U19 AI3863366

Core B:  Human Airway and Epithelial Cell Culture Core

Core-Co-PI

07/2016 - 06/2021

Current Mentees

Name

Degree

Project & Funding

James Nolin

PhD

Function of secreted PLA2 in allergic inflammation

Andrew Parker

MD

Stereological assessment of mast cell infiltration and type-2 inflammation

Matthew Altman

MD

Systems biology of asthma exacerbations

Ryan Murphy

MD

Interactions between mast cells and epithelial cells

 

Past Mentees

Name

Degree

Current title

Location

Sydney Long

MD

Allergist

Turlock, CA

Rachel Blazevic

 

Undergraduate

Western Washington University

Pelle Arthur

 

Undergraduate

University of Washington

Ying Lai

PhD

Research Scientist

University of Washington

Kathryn Hooper

PhD

Scientist

Bluebird Bio

John Vandree

MD

Pulmonologist

Everett

Rob Oslund

PhD

Scientist

Neon Ventures

Chris Carlsten

MD, MPH

Associate Professor of Medicine

University of British Columbia

Jason S. Debley

MD, MPH

Associate Professor of Pediatrics

Seattle Children's Hospital

Kevin Sonn

MD

Orthopedic Surgery Resident

Loyola University

Mahtab Fakhari

MD

Post-doctoral Fellow

Harvard

Michael Compher

MS

Air and Radiation Division Member

US EPA


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