Research Summary

Defining Functions for Epithelial and Inflammatory Cell Proteases in Lung Diseases

The Caughey lab is interested in understanding how protein-cleaving enzymes of mast cells, white blood cells, and cells lining the airway contribute to inflammation, host defense, tissue remodeling and barrier function in the lung. These studies relate to clinical problems in asthma, cystic fibrosis, bronchitis, lung transplantation and bacterial pneumonia. These areas of research are especially related to veterans who have inhaled toxins, who smoke cigarettes, who have received allografts to treat end-stage lung disease, or have lung and bronchial infections. The Caughey lab is perhaps best known for his work with mast cells, which play major roles in allergic diseases, including asthma and fatal reactions to bee stings. He has focused on mast cell proteases, which are enzymes that break down proteins. Over the past decade, the Caughey lab has developed several compelling lines of evidence to suggest that these proteases play deleterious roles in allergic diseases. This work has assisted pharmaceutical development of new classes of anti-inflammatory drugs to treat asthma and other diseases involving mast cells. More recently, he has focused on the positive contributions of mast cells and their proteases to host defense against bacteria and other pathogens, on their role in modulating the inflammatory response to infection, and on defining genetic variation in mast cell protease genes that influence diseases like asthma.

Research Funding

  • July 1, 1979 - March 31, 2016 - Evolving Microenvironments in Airway Inflammation , Principal Investigator . Sponsor: NIH, Sponsor Award ID: P01HL024136
  • September 30, 1996 - August 31, 2006 - Interactions of Lymphocytes, Cytokines and Airway Cells , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P50HL056385
  • July 1, 1995 - June 30, 1999 - HUMAN TRYPTASE GENE EXPRESSION , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01HL054774
  • March 1, 1997 - February 28, 1999 - AMIDINE INHIBITORS OF LUNG MAST CELL TRYPTASE , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R41HL057634
  • May 1, 1986 - April 30, 1991 - REGULATION FUNCTION OF AIRWAY PROTEASES , Principal Investigator . Sponsor: NIH, Sponsor Award ID: K08HL001736

Education

Arizona State University, BS, 1975, Chemistry
Stanford University School of Medicine, MD, 1979, Medicine
Pennsylvania Hospital, 1982, Internal Medicine
University of California, San Francisco, 1986, Pulmonary Medicine

Honors & Awards

  • 1974
    American Chemical Society Outstanding Undergraduate Award, ASU
  • 1975
    Phi Beta Kappa and Merck Award in Chemistry, ASU
  • 1986
    NIH Clinical Investigator Award
  • 1992
    American Lung Association Career Investigator Award
  • 1992
    Elected to American Society for Clinical Investigation
  • 2000
    Elected to American Association of Physicians
  • 2004
    Recipient of Julius and Lillian Endowed Chair of Medicine

Selected Publications

  1. Chovanec J, Tunc I, Hughes J, Halstead J, Mateja A, Liu Y, O'Connell MP, Kim J, Park YH, Wang Q, Le Q, Pirooznia M, Trivedi NN, Bai Y, Yin Y, Hsu AP, McElwee J, Lassiter S, Nelson C, Bandoh J, DiMaggio T, Šelb J, Rijavec M, Carter MC, Komarow HD, Sabato V, Steinberg J, Hafer KM, Feuille E, Hourigan CS, Lack J, Khoury P, Maric I, Zanotti R, Bonadonna P, Schwartz LB, Milner JD, Glover SC, Ebo DG, Korošec P, Caughey GH, Brittain EH, Busby B, Metcalfe DD, Lyons JJ. Genetically defined individual reference ranges for tryptase limit unnecessary procedures and unmask myeloid neoplasms. Blood Adv. 2023 05 09; 7(9):1796-1810.  View on PubMed
  2. Glover SC, Carter MC, Korošec P, Bonadonna P, Schwartz LB, Milner JD, Caughey GH, Metcalfe DD, Lyons JJ. Clinical relevance of inherited genetic differences in human tryptases: Hereditary alpha-tryptasemia and beyond. Ann Allergy Asthma Immunol. 2021 12; 127(6):638-647.  View on PubMed
  3. Maun HR, Jackman JK, Choy DF, Loyet KM, Staton TL, Jia G, Dressen A, Hackney JA, Bremer M, Walters BT, Vij R, Chen X, Trivedi NN, Morando A, Lipari MT, Franke Y, Wu X, Zhang J, Liu J, Wu P, Chang D, Orozco LD, Christensen E, Wong M, Corpuz R, Hang JQ, Lutman J, Sukumaran S, Wu Y, Ubhayakar S, Liang X, Schwartz LB, Babina M, Woodruff PG, Fahy JV, Ahuja R, Caughey GH, Kusi A, Dennis MS, Eigenbrot C, Kirchhofer D, Austin CD, Wu LC, Koerber JT, Lee WP, Yaspan BL, Alatsis KR, Arron JR, Lazarus RA, Yi T. An Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma. Cell. 2020 Jan 23; 180(2):406.  View on PubMed
  4. Maun HR, Jackman JK, Choy DF, Loyet KM, Staton TL, Jia G, Dressen A, Hackney JA, Bremer M, Walters BT, Vij R, Chen X, Trivedi NN, Morando A, Lipari MT, Franke Y, Wu X, Zhang J, Liu J, Wu P, Chang D, Orozco LD, Christensen E, Wong M, Corpuz R, Hang JQ, Lutman J, Sukumaran S, Wu Y, Ubhayakar S, Liang X, Schwartz LB, Babina M, Woodruff PG, Fahy JV, Ahuja R, Caughey GH, Kusi A, Dennis MS, Eigenbrot C, Kirchhofer D, Austin CD, Wu LC, Koerber JT, Lee WP, Yaspan BL, Alatsis KR, Arron JR, Lazarus RA, Yi T. An Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma. Cell. 2019 Oct 03; 179(2):417-431.e19.  View on PubMed
  5. Korkmaz B, Caughey GH, Chapple I, Gauthier F, Hirschfeld J, Jenne DE, Kettritz R, Lalmanach G, Lamort AS, Lauritzen C, L?gowska M, Lesner A, Marchand-Adam S, McKaig SJ, Moss C, Pedersen J, Roberts H, Schreiber A, Seren S, Thakker NS. Therapeutic targeting of cathepsin C: from pathophysiology to treatment. Pharmacol Ther. 2018 10; 190:202-236.  View on PubMed
  6. Prabhakaran A, Dhaliwal G, Schilf CR, Caughey GH, Pile J. A shocking diagnosis. J Hosp Med. 2017 02; 12(2):104-108.  View on PubMed
  7. Lyons JJ, Yu X, Hughes JD, Le QT, Jamil A, Bai Y, Ho N, Zhao M, Liu Y, O'Connell MP, Trivedi NN, Nelson C, DiMaggio T, Jones N, Matthews H, Lewis KL, Oler AJ, Carlson RJ, Arkwright PD, Hong C, Agama S, Wilson TM, Tucker S, Zhang Y, McElwee JJ, Pao M, Glover SC, Rothenberg ME, Hohman RJ, Stone KD, Caughey GH, Heller T, Metcalfe DD, Biesecker LG, Schwartz LB, Milner JD. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat Genet. 2016 12; 48(12):1564-1569.  View on PubMed
  8. Xu X, Greenland JR, Gotts JE, Matthay MA, Caughey GH. Cathepsin L Helps to Defend Mice from Infection with Influenza A. PLoS One. 2016; 11(10):e0164501.  View on PubMed
  9. Greenland JR, Wong CM, Ahuja R, Wang AS, Uchida C, Golden JA, Hays SR, Leard LE, Rajalingam R, Singer JP, Kukreja J, Wolters PJ, Caughey GH, Tang Q. Donor-Reactive Regulatory T Cell Frequency Increases During Acute Cellular Rejection of Lung Allografts. Transplantation. 2016 10; 100(10):2090-8.  View on PubMed
  10. Nimishakavi S, Raymond WW, Gruenert DC, Caughey GH. Divergent Inhibitor Susceptibility among Airway Lumen-Accessible Tryptic Proteases. PLoS One. 2015; 10(10):e0141169.  View on PubMed
  11. Caughey GH. Mast cell proteases as pharmacological targets. Eur J Pharmacol. 2016 May 05; 778:44-55.  View on PubMed
  12. Raymond WW, Xu X, Nimishakavi S, Le C, McDonald DM, Caughey GH. Regulation of hepatocyte growth factor in mice with pneumonia by peptidases and trans-alveolar flux. PLoS One. 2015; 10(5):e0125797.  View on PubMed
  13. Bose O, Baluk P, Looney MR, Cheng LE, McDonald DM, Caughey GH, Krummel MF. Mast cells present protrusions into blood vessels upon tracheal allergen challenge in mice. PLoS One. 2015; 10(3):e0118513.  View on PubMed
  14. Greenland JR, Xu X, Sayah DM, Liu FC, Jones KD, Looney MR, Caughey GH. Mast cells in a murine lung ischemia-reperfusion model of primary graft dysfunction. Respir Res. 2014 Aug 13; 15:95.  View on PubMed
  15. Sutherland RE, Barry SS, Olsen JS, Salantes DB, Caughey GH, Wolters PJ. Dipeptidyl peptidase I controls survival from Klebsiella pneumoniae lung infection by processing surfactant protein D. Biochem Biophys Res Commun. 2014 Jul 18; 450(1):818-823.  View on PubMed
  16. Xu X, Greenland J, Baluk P, Adams A, Bose O, McDonald DM, Caughey GH. Cathepsin L protects mice from mycoplasmal infection and is essential for airway lymphangiogenesis. Am J Respir Cell Mol Biol. 2013 Sep; 49(3):437-44.  View on PubMed
  17. Chau JY, Tiffany CM, Nimishakavi S, Lawrence JA, Pakpour N, Mooney JP, Lokken KL, Caughey GH, Tsolis RM, Luckhart S. Malaria-associated L-arginine deficiency induces mast cell-associated disruption to intestinal barrier defenses against nontyphoidal Salmonella bacteremia. Infect Immun. 2013 Oct; 81(10):3515-26.  View on PubMed
  18. Raman K, Trivedi NN, Raymond WW, Ganesan R, Kirchhofer D, Verghese GM, Craik CS, Schneider EL, Nimishakavi S, Caughey GH. Mutational tail loss is an evolutionary mechanism for liberating marapsins and other type I serine proteases from transmembrane anchors. J Biol Chem. 2013 Apr 12; 288(15):10588-98.  View on PubMed
  19. Greenland JR, Jones KD, Hays SR, Golden JA, Urisman A, Jewell NP, Caughey GH, Trivedi NN. Association of large-airway lymphocytic bronchitis with bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 2013 Feb 15; 187(4):417-23.  View on PubMed
  20. Nimishakavi S, Besprozvannaya M, Raymond WW, Craik CS, Gruenert DC, Caughey GH. Activity and inhibition of prostasin and matriptase on apical and basolateral surfaces of human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2012 Jul; 303(2):L97-106.  View on PubMed

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