George Caughey, MD

PROF IN RES-HCOMP

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.

Education
Residency, - Internal Medicine, Pennsylvania Hospital
Doctor of Medicine, - Medicine, Stanford University
Clinical Pulmonary Fellowship, - Medicine, University of California, San Francisco
Post-Doc Fellow/Scholar, - Medicine, University of California, San Francisco
Publications

  1. Caughey GH. Update on Mast Cell Proteases as Drug Targets. Immunology and allergy clinics of North America 2023. PMID: 37758413


  2. 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, ?elb 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, Koro?ec 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 advances 2023. PMID: 36170795


  3. 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. 2021. PMID: 34400315


  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 2020. PMID: 31978350


  5. 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. PMID: 31585081


  6. Korkmaz B, Caughey GH, Chapple I, Gauthier F, Hirschfeld J, Jenne DE, Kettritz R, Lalmanach G, Lamort AS, Lauritzen C, Legowska M, Lesner A, Marchand-Adam S, McKaig SJ, Moss C, Pedersen J, Roberts H, Schreiber A, Seren S, Thakkar NS. Therapeutic targeting of cathepsin C: from pathophysiology to treatment. Pharmacology & therapeutics 2018. PMID: 29842917


  7. Prabhakaran A, Dhaliwal G, Schilf CR, Caughey GH, Pile J. A shocking diagnosis. Volume 12 of Issue 2. Journal of hospital medicine 2017. PMID: 28182807


  8. 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. Volume 48 of Issue 12. Nature genetics 2016. PMID: 27749843


  9. Xu X, Greenland JR, Gotts JE, Matthay MA, Caughey GH. Cathepsin L Helps to Defend Mice from Infection with Influenza A. Volume 11 of Issue 10. PloS one 2016. PMID: 27716790


  10. 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. Volume 100 of Issue 10. Transplantation 2016. PMID: 27077597


  11. Nimishakavi S, Raymond WW, Gruenert DC, Caughey GH. Divergent Inhibitor Susceptibility among Airway Lumen-Accessible Tryptic Proteases. Volume 10 of Issue 10. PloS one 2015. PMID: 26485396


  12. Caughey GH. Mast cell proteases as pharmacological targets. Volume 778. European journal of pharmacology 2015. PMID: 25958181


  13. 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. Volume 10 of Issue 5. PloS one 2015. PMID: 25938594


  14. 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. Volume 10 of Issue 3. PloS one 2015. PMID: 25789765


  15. 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. Volume 15. Respiratory research 2014. PMID: 25115556


  16. 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. Volume 450 of Issue 1. Biochemical and biophysical research communications 2014. PMID: 24955853


  17. 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. Volume 49 of Issue 3. American journal of respiratory cell and molecular biology 2013. PMID: 23600672


  18. 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. Volume 81 of Issue 10. Infection and immunity 2013. PMID: 23690397


  19. 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. Volume 288 of Issue 15. The Journal of biological chemistry 2013. PMID: 23447538


  20. 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. Volume 187 of Issue 4. American journal of respiratory and critical care medicine 2012. PMID: 23239157


  21. 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. Volume 303 of Issue 2. American journal of physiology. Lung cellular and molecular physiology 2012. PMID: 22582115


  22. Sugimoto K, Kudo M, Sundaram A, Ren X, Huang K, Bernstein X, Wang Y, Raymond WW, Erle DJ, Abrink M, Caughey GH, Huang X, Sheppard D. The avß6 integrin modulates airway hyperresponsiveness in mice by regulating intraepithelial mast cells. Volume 122 of Issue 2. The Journal of clinical investigation 2012. PMID: 22232213


  23. Sutherland RE, Xu X, Kim SS, Seeley EJ, Caughey GH, Wolters PJ. Parasitic infection improves survival from septic peritonitis by enhancing mast cell responses to bacteria in mice. Volume 6 of Issue 11. PloS one 2011. PMID: 22110673


  24. Xu X, Zhang H, Song Y, Lynch SV, Lowell CA, Wiener-Kronish JP, Caughey GH. Strain-dependent induction of neutrophil histamine production and cell death by Pseudomonas aeruginosa. Volume 91 of Issue 2. Journal of leukocyte biology 2011. PMID: 22075928


  25. Caughey GH. Mast cell proteases as protective and inflammatory mediators. Volume 716. Advances in experimental medicine and biology 2011. PMID: 21713659


  26. Raymond WW, Trivedi NN, Makarova A, Ray M, Craik CS, Caughey GH. How immune peptidases change specificity: cathepsin G gained tryptic function but lost efficiency during primate evolution. Volume 185 of Issue 9. Journal of immunology (Baltimore, Md. : 1950) 2010. PMID: 20889553


  27. Dougherty RH, Sidhu SS, Raman K, Solon M, Solberg OD, Caughey GH, Woodruff PG, Fahy JV. Accumulation of intraepithelial mast cells with a unique protease phenotype in T(H)2-high asthma. Volume 125 of Issue 5. The Journal of allergy and clinical immunology 2010. PMID: 20451039


  28. Trivedi NN, Caughey GH. Mast cell peptidases: chameleons of innate immunity and host defense. Volume 42 of Issue 3. American journal of respiratory cell and molecular biology 2009. PMID: 19933375


  29. Trivedi NN, Tamraz B, Chu C, Kwok PY, Caughey GH. Human subjects are protected from mast cell tryptase deficiency despite frequent inheritance of loss-of-function mutations. Volume 124 of Issue 5. The Journal of allergy and clinical immunology 2009. PMID: 19748655


  30. Innes AL, Carrington SD, Thornton DJ, Kirkham S, Rousseau K, 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. Volume 180 of Issue 3. American journal of respiratory and critical care medicine 2009. PMID: 19423716


  31. Raymond WW, Su S, Makarova A, Wilson TM, Carter MC, Metcalfe DD, Caughey GH. Alpha 2-macroglobulin capture allows detection of mast cell chymase in serum and creates a reservoir of angiotensin II-generating activity. Volume 182 of Issue 9. Journal of immunology (Baltimore, Md. : 1950) 2009. PMID: 19380825


  32. Caughey GH, Beauchamp J, Schlatter D, Raymond WW, Trivedi NN, Banner D, Mauser H, Fingerle J. Guinea pig chymase is leucine-specific: a novel example of functional plasticity in the chymase/granzyme family of serine peptidases. Volume 283 of Issue 20. The Journal of biological chemistry 2008. PMID: 18353771


  33. Trivedi NN, Raymond WW, Caughey GH. Chimerism, point mutation, and truncation dramatically transformed mast cell delta-tryptases during primate evolution. Volume 121 of Issue 5. The Journal of allergy and clinical immunology 2008. PMID: 18325577


  34. Trivedi NN, Tong Q, Raman K, Bhagwandin VJ, Caughey GH. Mast cell alpha and beta tryptases changed rapidly during primate speciation and evolved from gamma-like transmembrane peptidases in ancestral vertebrates. Volume 179 of Issue 9. Journal of immunology (Baltimore, Md. : 1950) 2007. PMID: 17947681


  35. Caughey GH. Mast cell tryptases and chymases in inflammation and host defense. Volume 217. Immunological reviews 2007. PMID: 17498057


  36. Akin C, Soto D, Brittain E, Chhabra A, Schwartz LB, Caughey GH, Metcalfe DD. Tryptase haplotype in mastocytosis: relationship to disease variant and diagnostic utility of total tryptase levels. Volume 123 of Issue 3. Clinical immunology (Orlando, Fla.) 2007. PMID: 17449330


  37. Cottrell GS, Amadesi S, Pikios S, Camerer E, Willardsen JA, Murphy BR, Caughey GH, Wolters PJ, Coughlin SR, Peterson A, Knecht W, Pothoulakis C, Bunnett NW, Grady EF. Protease-activated receptor 2, dipeptidyl peptidase I, and proteases mediate Clostridium difficile toxin A enteritis. Volume 132 of Issue 7. Gastroenterology 2007. PMID: 17570216


  38. Planès C, Caughey GH. Regulation of the epithelial Na+ channel by peptidases. Volume 78. Current topics in developmental biology 2007. PMID: 17338914


  39. Xu X, Zhang D, Zhang H, Wolters PJ, Killeen NP, Sullivan BM, Locksley RM, Lowell CA, Caughey GH. Neutrophil histamine contributes to inflammation in mycoplasma pneumonia. Volume 203 of Issue 13. The Journal of experimental medicine 2006. PMID: 17158962


  40. Caughey GH. A Pulmonary Perspective on GASPIDs: Granule-Associated Serine Peptidases of Immune Defense. Volume 2 of Issue 39. Current respiratory medicine reviews 2006. PMID: 18516248


  41. Mallen-St Clair J, Shi GP, Sutherland RE, Chapman HA, Caughey GH, Wolters PJ. Cathepsins L and S are not required for activation of dipeptidyl peptidase I (cathepsin C) in mice. Volume 387 of Issue 8. Biological chemistry 2006. PMID: 16895486


  42. Verghese GM, Gutknecht MF, Caughey GH. Prostasin regulates epithelial monolayer function: cell-specific Gpld1-mediated secretion and functional role for GPI anchor. Volume 291 of Issue 6. American journal of physiology. Cell physiology 2006. PMID: 16822939


  43. Caughey GH. Tryptase genetics and anaphylaxis. Volume 117 of Issue 6. The Journal of allergy and clinical immunology 2006. PMID: 16751005


  44. Raymond WW, Cruz AC, Caughey GH. Mast cell and neutrophil peptidases attack an inactivation segment in hepatocyte growth factor to generate NK4-like antagonists. Volume 281 of Issue 3. The Journal of biological chemistry 2005. PMID: 16303761


  45. Xu X, Zhang D, Lyubynska N, Wolters PJ, Killeen NP, Baluk P, McDonald DM, Hawgood S, Caughey GH. Mast cells protect mice from Mycoplasma pneumonia. Volume 173 of Issue 2. American journal of respiratory and critical care medicine 2005. PMID: 16210667


  46. Xu X, Golden JA, Dolganov G, Jones KD, Donnelly S, Weaver T, Caughey GH. Transcript signatures of lymphocytic bronchitis in lung allograft biopsy specimens. Volume 24 of Issue 8. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 2005. PMID: 16102441


  47. Raymond WW, Sommerhoff CP, Caughey GH. Mastin is a gelatinolytic mast cell peptidase resembling a mini-proteasome. Volume 435 of Issue 2. Archives of biochemistry and biophysics 2005. PMID: 15708374


  48. Somasundaram P, Ren G, Nagar H, Kraemer D, Mendoza L, Michael LH, Caughey GH, Entman ML, Frangogiannis NG. Mast cell tryptase may modulate endothelial cell phenotype in healing myocardial infarcts. Volume 205 of Issue 1. The Journal of pathology 2005. PMID: 15586361


  49. Tong Z, Illek B, Bhagwandin VJ, Verghese GM, Caughey GH. Prostasin, a membrane-anchored serine peptidase, regulates sodium currents in JME/CF15 cells, a cystic fibrosis airway epithelial cell line. Volume 287 of Issue 5. American journal of physiology. Lung cellular and molecular physiology 2004. PMID: 15246975


  50. Baluk P, Raymond WW, Ator E, Coussens LM, McDonald DM, Caughey GH. Matrix metalloproteinase-2 and -9 expression increases in Mycoplasma-infected airways but is not required for microvascular remodeling. Volume 287 of Issue 2. American journal of physiology. Lung cellular and molecular physiology 2004. PMID: 15075248


  51. Mallen-St Clair J, Pham CT, Villalta SA, Caughey GH, Wolters PJ. Mast cell dipeptidyl peptidase I mediates survival from sepsis. Volume 113 of Issue 4. The Journal of clinical investigation 2004. PMID: 14966572


  52. Henningsson F, Wolters P, Chapman HA, Caughey GH, Pejler G. Mast cell cathepsins C and S control levels of carboxypeptidase A and the chymase, mouse mast cell protease 5. Volume 384 of Issue 10-11. Biological chemistry 2003. PMID: 14669996


  53. Verghese GM, Tong ZY, Bhagwandin V, Caughey GH. Mouse prostasin gene structure, promoter analysis, and restricted expression in lung and kidney. Volume 30 of Issue 4. American journal of respiratory cell and molecular biology 2003. PMID: 12959947


  54. Raymond WW, Ruggles SW, Craik CS, Caughey GH. Albumin is a substrate of human chymase. Prediction by combinatorial peptide screening and development of a selective inhibitor based on the albumin cleavage site. Volume 278 of Issue 36. The Journal of biological chemistry 2003. PMID: 12815038


  55. Reiling KK, Krucinski J, Miercke LJ, Raymond WW, Caughey GH, Stroud RM. Structure of human pro-chymase: a model for the activating transition of granule-associated proteases. Volume 42 of Issue 9. Biochemistry 2003. PMID: 12614156


  56. Caughey GH. Building a better heparin. Volume 28 of Issue 2. American journal of respiratory cell and molecular biology 2003. PMID: 12540478


  57. Bhagwandin VJ, Hau LW, Mallen-St Clair J, Wolters PJ, Caughey GH. Structure and activity of human pancreasin, a novel tryptic serine peptidase expressed primarily by the pancreas. Volume 278 of Issue 5. The Journal of biological chemistry 2002. PMID: 12441343


  58. Caughey GH. New developments in the genetics and activation of mast cell proteases. Volume 38 of Issue 16-18. Molecular immunology 2002. PMID: 12217407


  59. Muilenburg DJ, Raymond WW, Wolters PJ, Caughey GH. Lys40 but not Arg143 influences selectivity of angiotensin conversion by human alpha-chymase. Volume 1596 of Issue 2. Biochimica et biophysica acta 2002. PMID: 12007614


  60. Brown JK, Jones CA, Rooney LA, Caughey GH, Hall IP. Tryptase's potent mitogenic effects in human airway smooth muscle cells are via nonproteolytic actions. Volume 282 of Issue 2. American journal of physiology. Lung cellular and molecular physiology 2002. PMID: 11792624