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

Department of Medicine and the Cardiovascular Research Institute (CVRI)

513 Parnassus Avenue
UCSF Box 0130, HSE-1307
San Francisco, CA 94143

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

Fahy Lab Website
Biomedical Sciences Graduate Program
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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. We use the data from analysis of pathologic mucus to inform strategies for development of novel mucolytics. Dr Stefan Oscarson at University College Dublin and Dr Anne Marie Healy at Trinity College Dublin are important collaborators for our mucolytic drug development program.

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 the Woodruff lab at UCSF and with investigators in the NIH Severe Asthma Research Program (SARP).

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. Fahy JV, Fleming HE, Wong HH, Liu JT, Su JQ, Reimann J, Fick RB, Boushey HA.  The effect of an anti-IgE monoclonal antibody-E25 on the early and late phase responses to allergen inhalation in asthmatic subjects.  Am J Respir Crit Care Med 1997; 155:1828-1834.
  2. Fahy JV, Cockcroft DW, Boulet LP, Wong HH, Deschesnes F, Davis EE, Ruppel J, Su JQ, Adelman DC.  Effect of aerosolized anti-IgE (E25) on airway responses to inhaled allergen in asthmatic subjects. Am J Resp Crit Care Med 1999; 160:1023-27
  3. Longpre M, Li D, Matovinovic E, Ordoñez C, Redman T, Fahy JV, Basbaum C. Allergen-induced IL-9 directly stimulates mucin transcription in respiratory epithelial cells. J Clin Invest 1999; 104: 1375-1382.
  4. Ordoñez CL, Khashayar, R, Wong HH, Ferrando R, Wu R, Hyde DM, Hotchkiss JA, Zhang Y, Novikov A, Dolganov G, Fahy JV. Mild and moderate asthma is associated with goblet cell hyperplasia and abnormalities in mucin gene expression. Am J Resp Crit Care Med 2001; 163:517-523.
  5. Dolganov GM, Woodruff PW, Novikov AA, Zhang Y, Ferrando RE, Fahy JV.  A novel method of gene transcript profiling in airway biopsy homogenates reveals increased expression of a Na+K+ Cl- co-transporter in asthmatic subjects.  Genome Research. 2001:11; 1473-1483.
  6. Woodruff PG, Khashayar R, Lazarus, SC, Janson S, Avila P, Boushey HA, Segal M, Fahy JV.  Relationship between airway inflammation, airway hyperresponsiveness, and airway obstruction in asthma.  J Allergy Clin Immunol 2001; 108:753-758.
  7. Hays SR, Woodruff PG, Khashayar R, Ferrando RE, Liu J, Fung P, Zhao CQ, Wong HH, Fahy JV. Allergen challenge causes inflammation but not goblet cell degranulation in asthmatic subjects. J Allergy Clin Immunol 2001; 108:784-790.
  8. Avila PC, Boushey HA, Wong HH, Grundland H, Liu J, Fahy JV.  Effect of a single dose of the selectin inhibitor TBC1269 on early and late asthmatic responses. Clin Exp Allergy 2004; 34: 77-84.
  9. Woodruff PG, Dolganov GM, Ferrando RE, Donnelly S, Hays SR, Segal MR, Solberg OD, Carter R, Wong HH, Cadbury PS, Fahy JV.  Airway smooth muscle in mild moderate asthma demonstrates hyperplasia but not hypertrophy or increased expression of genes coding for contractile proteins. Am J Respir Crit Care Med. 2004; 169:1001-1006.
  10. Djukanovic R, Wilson SJ, Kraft M, Jarjour NN, Steel M, Chung KF, Bao W, Fowler-Taylor A, Matthews J, Busse WW, Holgate ST, Fahy JV. The Effects of Anti-IgE (Omalizumab) on Airways Inflammation in Allergic Asthma.  Am J Respir Crit Care Med 2004; 170:583-93.
  11. Woodruff PG, Boushey HA, Dolganov GM, Barker CS, Yang YH, Donnelly S, Ellwanger A, Sidhu S, Dao-Pick TP, Pantoja C, Erle DJ, Yamamoto KR, Fahy JV. Genome-Wide Profiling Identifies Epithelial Cell Genes Associated with Asthma and with Treatment Response to Corticosteroids. Proc Natl Acad Sci USA 2007; 104:15858-63.
  12. Seibold MA, Donnelly S, Solon M, Innes A, Woodruff PG, Boot R, Burchard EG, Fahy JV.  Chitotriosidase is the primary active chitinase in the human lung and is modulated by genotype and disease. J Allergy Clin Immunol.  2008; 122:944-950.
  13. Innes AL. Carrington SD, David J. Thornton DJ, Kirkham S, Dougherty RH, Raymond WW, Caughey GH, Muller SJ, Fahy JV. Ex vivo sputum analysis reveals impairment of protease-dependent mucus degradation by plasma proteins in acute asthma. Am J Respir Crit Care Med. 2009; 180:203-10. PMCID: PMC2724713.
  14. Woodruff PG, Modrek M, Choy DF, Guiquan J. Abbas AR, Ellwanger A, Koth LL, Arron JR, Fahy JV. Th2-driven inflammation defines major sub-phenotypes of asthma. Am J Respir Crit Care Med. 2009; 180:388-95.
  15. Dougherty RH, Sidhu SS, Raman K, Solon M, Solberg OD, Caughey GH, Woodruff PG, Fahy JV. Accumulation of Intra-Epithelial Mast Cells with a Unique Protease Phenotype in Th2-high Asthma. J Allergy Clin Immunol. 2010; 125:1046-1053.
  16. Sukhvinder SS, Yuan S, Innes AL, Kerr S, Woodruff PG, Solon M, Hou L, Muller SL, Fahy JV. Epithelial cell-derived periostin: roles in TGFb activation, collagen production and collagen elasticity in asthma. Proc Natl Acad Sci USA. 2010; 107:14170-5.
  17. Innes AL, Wong McGrath K, Dougherty RH, McCulloch CE, Woodruff PG, Seibold MA, Okamoto KS, Kelsey J. Ingmundson KJ, Solon MC, Carrington SD, Fahy JV. The H Antigen at Epithelial Surfaces is Associated with Susceptibility to Asthma Exacerbation. Am J Respir Crit Care Med. 2011; 183:189-94.
  18. Gordon ED, Sidhu SS, Wang ZE, Woodruff PG, Yuan S, Solon MC, Conway SJ, Huang X, Locksley RM, Fahy JV. A protective role for periostin and TGFb in IgE-mediated allergy and airway hyperresponsiveness. Clinical and Experimental Allergy 2012; 42:144-55.
  19. McGrath KW, Icitovic N, Boushey HA, Lazarus SC, Sutherland ER, Chinchilli VM, Fahy JV. A large subgroup of mild-to-moderate asthma is persistently noneosinophilic. Am J Respir Crit Care Med 2012; 185:612-619.
  20. Bhakta NR, Solberg OD, Nguyen CP, Nguyen CN, Arron JR, Fahy JV, Woodruff PG. A qpcr-based metric of th2 airway inflammation in asthma. Clin Transl Allergy 2013; 3:24.
  21. Fahy JV. Chair's summary: Mechanisms of relevance to clinical heterogeneity of asthma and chronic obstructive pulmonary disease. Ann Am Thorac Soc 2013;10 Suppl: S108.
  22. Peters MC, Fahy JV. Type 2 immune responses in obese individuals with asthma. Am J Respir Crit Care Med 2013; 188:633-634.
  23. Jackson DJ, Hartert TV, Martinez FD, Weiss ST, Fahy JV. Asthma: Nhlbi workshop on the primary prevention of chronic lung diseases. Ann Am Thorac Soc 2014; 11 Suppl 3: S139-145.
  24. Kerr SC, Carrington SD, Oscarson S, Gallagher ME, Solon M, Yuan S, Ahn JN, Dougherty RH, Finkbeiner WE, Peters MC, Fahy JV. Intelectin-1 is a prominent protein constituent of pathologic mucus associated with eosinophilic airway inflammation in asthma. Am J Respir Crit Care Med 2014; 189:1005-1007.    
  25. Locksley RM, Fahy JV. Asthma and the flu: A tricky two-step. Immunol Cell Biol 2014; 92:389-391.         
  26. Peters MC, Mekonnen ZK, Yuan S, Bhakta NR, Woodruff PG, Fahy JV. Measures of gene expression in sputum cells can identify th2-high and th2-low subtypes of asthma. J Allergy Clin Immunol 2014; 133:388-394.   
  27. Fahy JV.  Type 2 inflammation in asthma; Present in most, absent in many.  Nat Rev Immunol. 2014 Dec 23;15(1):57-65.
  28. Yuan S, Hollinger M, Lachowicz-Scroggins ME, Kerr SC,  Daniel BM, 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 Feb 25;7(276).
  29. Dunican EM, Fahy JV. The role of type 2 inflammation in the pathogenesis of asthma exacerbations. Ann Am Thorac Soc. 2015 Nov;12 Suppl 2:S144-9.
  30. 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.
  31. 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.
  32. 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 May 1;193(9):935-6
  33. 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.
  34. Lachowicz-Scroggins ME, Yuan S, Kerr SC, Dunican EM, Yu M, Carrington SD, Fahy JV. Abnormalities in MUC5AC and MUC5B Protein in Airway Mucus in Asthma.  Am J Respir Crit Care Med. 2016 Nov 15;194(10):1296-1299
  35. 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.
  36. 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.
  37. 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.
  38. 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. JCI. In Press.