John V. Fahy, M.D, M.Sc.

Professor of Medicine in Residence
Department of Medicine and the Cardiovascular Research Institute (CVRI)
Director, Airway Clinical Research Center (ACRC)

University of California, San Francisco
513 Parnassus Avenue
Room HSE-1307, Box 0130
San Francisco, CA 94143

Tel: 415-476-9940
Fax: 415-476-5712

Fahy Lab Website
Biomedical Sciences Graduate Program
UCSF Profile

John Fahy, M.D. is a longstanding supporter of SABRE research and a formal faculty member in the SABRE Center for the past 6 years. He is a physician scientist with a primary appointment in the Division of Pulmonary and Critical Care Medicine (Department of Medicine and CVRI). He directs a mechanism-oriented clinical research program in airways disease that emphasizes studies in humans and in human-derived tissues and cells. For asthmatics with prominent airway type 2 inflammation (“type 2-high asthma”), his current research focuses on mechanisms underlying regional variation in type 2 inflammation in the lung and airway epithelial cell dysfunction in patients with “ultra-high” type 2 inflammation who are steroid-resistant and have mucus plugs and severe airflow obstruction. Dr Fahy’s lab is a leader in advancing understanding for how pathologic mucus gels form in asthma and other mucus-associated airway diseases. He leads a PO1 program in type 2 airway inflammation in asthma (includes Drs. Locksley, Ansel and Woodruff), a translational PO1 program in academic drug discovery that aims to advance mucolytic to the clinic, and an RO1 program investigating mechanisms of airway inflammation and mucus pathology in acute severe asthma. In addition, he leads the UCSF center in the NHLBI funded PrecISE program (biomarker driven clinical trials in severe asthma). Recent honors include election to AAP in 2016 and a Recognition Award for Scientific Accomplishments from the ATS in 2017.

Dr. Fahy directs a research program in asthma and other airway diseases that is human centered and focused on uncovering abnormalities in airway epithelial cell function that contribute to abnormal type 2 immune responses in asthma, exploring mechanisms of formation of pathologic mucus gels in the airway, and investigating the heterogeneity of molecular mechanisms in asthma to improve prospects for personalized treatments.

ABNORMAL TYPE 2 IMMUNE RESPONSES IN HUMAN ASTHMA: The airway epithelium has emerged as an important regulator of innate and adaptive immune responses that result in type 2 allergic airway inflammation. My lab is specifically investigating epithelial mechanisms that contribute to upregulation of Th2 cytokines in the asthmatic airway. Our experimental approaches include gene and protein expression analysis of airway epithelial brushings, biopsies, and secretions, and cell culture studies in airway epithelial cells from human donors. We collaborate with multiple other UCSF labs, including the Locksley, Ansel, and Woodruff labs, and the Seibold lab at National Jewish Healthy is a key non-UCSF collaborator.

PATHOLOGIC MUCUS GELS: The formation of pathologic mucus is a feature of multiple lung diseases and has multiple consequences for lung health, including airflow obstruction and infections. My lab is investigating how pathologic mucus gels form. Our experimental approaches include detailed analyses of sputum samples using rheology-, imaging- and biochemistry-based approaches. Most recently we have publi9shed several pares on mucus plugs in asthma and COPD that can be identified using CT images of the lungs of patients. We are planning additional publications to further described the mucus plug phenotypes that occur in asthma and how their shear features may influence airflow and treatment responses to muco-active drugs.

HETEROGENEITY OF MOLECULAR MECHANISMS IN ASTHMA: Many asthmatics do not respond well to currently available treatments and one reason is that current medications assume a one size fits all approach. My lab is applying a variety of targeted and unbiased approaches to investigate disease mechanism in large numbers of asthmatics with a view to improving understanding of the range and frequency of disease mechanisms that underlie asthma. Our experimental approaches include detailed analysis of the differential expression of genes and proteins in airway biospecimens collected from highly characterized patients with asthma and healthy controls. We also simultaneously explore how simpler tests in blood might reveal specific disease mechanisms and serve as biomarkers for personalizing treatment. Our work in this area is done in collaboration with NIH/NHLBI networks in North America including the Severe Asthma Research Program (SARP) and the Precision Interventions for Severe Asthma (Precise) network.

Lab Objectives:
  1. To define abnormalities in airway epithelial cell function that contribute to abnormal type 2 immune responses in asthma.
  2. To explore mechanisms of formation of pathologic mucus gels in the airway so that novel mucolytics can be developed.
  3. To explore the heterogeneity of molecular mechanisms in asthma to improve prospects for treatment approaches that are patient specific.
Selected Publications:
  1. Dunican EM,Elicker BM, Henry T, Gierada DS, Schiebler ML, Anderson W, Barjaktarevic I, Barr RG, Bleecker ER, Boucher RC, Bowler R, Christenson SA, Comellas A, Cooper CB, Couper D, Criner GJ, Dransfield M, Doerschuk CM, Drummond MB, Hansel NN, Han MK, Hastie AT, Hoffman EA, Krishnan JA, Lazarus SC, Martinez FJ, McCulloch CE, O'Neal WK, Ortega VE, Paine R, Peters S, Schroeder JD, Woodruff PG, Fahy JV. Mucus Plugs and Emphysema in the Pathophysiology of Airflow Obstruction and Hypoxemia in Smokers. Am J Respir Crit Care Med. 2021 04 15; 203(8):957-968.
  2. Kerr SC, Gonzalez JR, Schanin J, Peters MC, Lambrecht BN, Brock EC, Charbit A, Ansel KM, Youngblood BA, Fahy JV. An anti-siglec-8 antibody depletes sputum eosinophils from asthmatic subjects and inhibits lung mast cells. Clin Exp Allergy. 2020 08; 50(8):904-914.
  3. Peters MC, Sajuthi S, Deford P, Christenson S, Rios CL, Montgomery MT, Woodruff PG, Mauger DT, Erzurum SC, Johansson MW, Denlinger LC, Jarjour NN, Castro M, Hastie AT, Moore W, Ortega VE, Bleecker ER, Wenzel SE, Israel E, Levy BD, Seibold MA, Fahy JV. COVID-19-related Genes in Sputum Cells in Asthma. Relationship to Demographic Features and Corticosteroids. Am J Respir Crit Care Med. 2020 07 01; 202(1):83-90.
  4. Dunican ED, Elicker BM, Gierada DS, Nagle SK, Schiebler ML, Newell JD, Raymond WW, Lachowicz-Scroggins ME, Di Maio S, Hoffman EA, Castro M, Fain SB, Jarjour NN, Israel E, Levy BD, Erzurum SC, Wenzel SE, Meyers DA, Bleecker ER, Phillips BR, Mauger DT, Gordon ED, Woodruff PG, Peters MC, Fahy JV. Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction. J Clin Invest. 2018;128:997-1009.
  5. Fahy JV, Locksley RM. Making Asthma Crystal Clear. N Engl J Med. 2019 08 29; 381(9):882-884.
  6. Lambrecht BN, Hammad H, Fahy JV. The Cytokines of Asthma. Immunity. 2019 Apr 16; 50(4):975-991.
  7. Dunican EM, Watchorn DC, Fahy JV. Autopsy and Imaging Studies of Mucus in Asthma. Lessons Learned about Disease Mechanisms and the Role of Mucus in Airflow Obstruction. Ann Am Thorac Soc. 2018 Nov; 15(Supplement_3):S184-S191.
  8. Peters MC, Kerr S, Dunican EM, Woodruff PG, Fajt ML, Levy BD, Israel E, Phillips BR, Mauger DT, Comhair SA, Erzurum SC, Johansson MW, Jarjour NN, Coverstone AM, Castro M, Hastie AT, Bleecker ER, Wenzel SE, Fahy JV. Refractory airway type 2 inflammation in a large subgroup of asthmatic patients treated with inhaled corticosteroids. J Allergy Clin Immunol. 2019 Jan; 143(1):104-113.e14.
  9. Lachowicz-Scroggins ME, Gordon ED, Wesolowska-Andersen A, Jackson ND, MacLeod HJ, Sharp LZ, Sun M, Seibold MA, Fahy JV. Cadherin-26 (CDH26) regulates airway epithelial cell cytoskeletal structure and polarity. Cell Discov. 2018; 4:7.
  10. Gordon ED, Wesolowska-Anderson A, Ringel B, Urbanek C, Lachowicz-Scroggins M, Sharp L, Everman J, MacLeod H, Woo Lee J, Mason RJ, Matthay MA, Sheldon R, Peters M, Nocka K, Fahy JV, Seibold, MA. IL1RL1 Asthma Risk Variants Regulate Airway Type 2 Inflammation. JCI Insight. 2016;1(14):e87871.
  11. Gordon ED, Simpson LJ, Rios CL, Ringel L, Lachowicz-Scroggins ME, Peters MC, Wesolowska-Andersen A, Gonzalez JR, MacLeod HJ, Christian LS, Yuan S, Barry L, Woodruff PG, Ansel KM, Nocka K, Seibold MA, Fahy JV. Alternative splicing of interleukin-33 and type 2 inflammation in asthma. PNAS. 2016;113(31):8765-70.
  12. Peters MC, McGrath KW, Hawkins GA, Hastie AT, Levy BD, Israel E, Phillips BR, Mauger DT, Comhair SA, Erzurum SC, Johansson MW, Jarjour NN, Coverstone AM, Castro M, Holguin F, Wenzel SE, Woodruff PG, Bleecker ER, Fahy JV. Plasma IL6 levels, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts. Lancet Respiratory Medicine. 2016 Jul;4(7):574-84.
  13. Lachowicz-Scroggins ME, Yuan S, Kerr SC, Dunican EM, Yu M, Carrington SD, Fahy JV. Abnormalities in MUC5AC and MUC5B Protein in AirwayMucus in Asthma. Am J Respir Crit Care Med. 2016 Nov 15;194(10):1296-1299.
  14. Gordon ED, Locksley RM, Fahy JV. Cross-Talk between Epithelial Cells and Type 2 Immune Signaling. The Role of IL-25. Am J Respir Crit Care Med. 2016 May 1;193(9):935-6.
  15. Reber LL, Fahy JV. Mast cells in asthma: biomarker and therapeutic target. Eur Respir J. 2016;47(4):1040-2. Am J Respir Crit Care Med. 2016 May1;193(9):935-6.
  16. Fahy JV. Asthma Was Talking, But We Weren't Listening. Missed or Ignored Signals That Have Slowed Treatment Progress. Ann Am Thorac Soc. 2016;13 Suppl 1:S78-82. Epub 2016/03/31. doi:10.1513/AnnalsATS.201508-515MG.
  17. Levy BD, Noel PJ, Freemer MM, Cloutier MM, Georas SN, Jarjour NN, Ober C, Woodruff PG, Barnes KC, Bender BG, Camargo CA Jr, Chupp GL, Denlinger LC, Fahy JV, Fitzpatrick AM, Fuhlbrigge A, Gaston BM, Hartert TV, Kolls JK, Lynch SV, Moore WC, Morgan WJ, Nadeau KC, Ownby DR, Solway J, Szefler SJ, Wenzel SE, Wright RJ, Smith RA, Erzurum SC. Future research directions in asthma. An NHLBI working group report. Ann Am Thorac Soc. 2015 Nov;12 Suppl 2:S144-9.
  18. Dunican EM, Fahy JV. The role of type 2 inflammation in the pathogenesis of asthma exacerbations. Ann Am Thorac Soc. 2015 Nov;12 Suppl2:S144-9.
  19. Yuan S, Hollinger M, Lachowicz-Scroggins ME, Kerr SC, DanielBM, Ghosh S, Erzurum SC, Willard B, S.L. Hazen SL, Huang X, Carrington SD, Oscarson S, Fahy JV. Oxidation Increases Mucin Polymer Cross-links to Stiffen Airway Mucus Gels. Science Translational Medicine. Sci Transl Med. 2015 Feb25;7(276).
  20. Fahy JV. Type 2 inflammation in asthma; Present in most, absent in many. Nat Rev Immunol. 2014 Dec23;15(1):57-65.