Faculty ProfilesGeorge Caughey, MD
90 Medical Center Way
San Francisco, CA 94143
415-221-4810 ext. 6385
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 and Training
|Location||Degree or Training||Specialty||Date|
|University of California, San Francisco||Post-Doc Fellow/Scholar||Medicine|
|University of California, San Francisco||Clinical Pulmonary Fellowship||Medicine|
|Stanford University||Doctor of Medicine||Medicine|
|Pennsylvania Hospital||Residency||Internal Medicine|
Recent Articles (131)
Greenland JR, Sun H, Calabrese D, Chong T, Singer JP, Kukreja J, Hays SR, Golden JA, Caughey GH, Venstrom JM, Rajalingam R. HLA Mismatching Favoring Host-Versus-Graft NK Cell Activity Via KIR3DL1 Is Associated With Improved Outcomes Following Lung Transplantation. Am J Transplant. 2017 Aug; 17(8):2192-2199.
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 Dec; 48(12):1564-1569.
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 Oct; 100(10):2090-8.
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.
Greenland JR, Jewell NP, Gottschall M, Trivedi NN, Kukreja J, Hays SR, Singer JP, Golden JA, Caughey GH. Bronchoalveolar lavage cell immunophenotyping facilitates diagnosis of lung allograft rejection. Am J Transplant. 2014 Apr; 14(4):831-40.
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.
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.
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.
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.
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.
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. J Clin Invest. 2012 Feb; 122(2):748-58.
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. PLoS One. 2011; 6(11):e27564.
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. J Leukoc Biol. 2012 Feb; 91(2):275-84.
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. J Immunol. 2010 Nov 01; 185(9):5360-8.
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. J Allergy Clin Immunol. 2010 May; 125(5):1046-1053.e8.
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. J Allergy Clin Immunol. 2009 Nov; 124(5):1099-105.e1-4.
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. Am J Respir Crit Care Med. 2009 Aug 01; 180(3):203-10.
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. J Immunol. 2009 May 01; 182(9):5770-7.
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. J Biol Chem. 2008 May 16; 283(20):13943-51.
Trivedi NN, Raymond WW, Caughey GH. Chimerism, point mutation, and truncation dramatically transformed mast cell delta-tryptases during primate evolution. J Allergy Clin Immunol. 2008 May; 121(5):1262-8.
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. J Immunol. 2007 Nov 01; 179(9):6072-9.
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. Clin Immunol. 2007 Jun; 123(3):268-71.
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. Gastroenterology. 2007 Jun; 132(7):2422-37.
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. J Exp Med. 2006 Dec 25; 203(13):2907-17.
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. Biol Chem. 2006 Aug; 387(8):1143-6.
Verghese GM, Gutknecht MF, Caughey GH. Prostasin regulates epithelial monolayer function: cell-specific Gpld1-mediated secretion and functional role for GPI anchor. Am J Physiol Cell Physiol. 2006 Dec; 291(6):C1258-70.
Raymond WW, Cruz AC, Caughey GH. Mast cell and neutrophil peptidases attack an inactivation segment in hepatocyte growth factor to generate NK4-like antagonists. J Biol Chem. 2006 Jan 20; 281(3):1489-94.
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. Am J Respir Crit Care Med. 2006 Jan 15; 173(2):219-25.
Xu X, Golden JA, Dolganov G, Jones KD, Donnelly S, Weaver T, Caughey GH. Transcript signatures of lymphocytic bronchitis in lung allograft biopsy specimens. J Heart Lung Transplant. 2005 Aug; 24(8):1055-66.
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. J Pathol. 2005 Jan; 205(1):102-11.
Wolters PJ, Mallen-St Clair J, Lewis CC, Villalta SA, Baluk P, Erle DJ, Caughey GH. Tissue-selective mast cell reconstitution and differential lung gene expression in mast cell-deficient Kit(W-sh)/Kit(W-sh) sash mice. Clin Exp Allergy. 2005 Jan; 35(1):82-8.
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. Am J Physiol Lung Cell Mol Physiol. 2004 Nov; 287(5):L928-35.
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. Am J Physiol Lung Cell Mol Physiol. 2004 Aug; 287(2):L307-17.
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. Biol Chem. 2003 Oct-Nov; 384(10-11):1527-31.
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. J Biol Chem. 2003 Sep 05; 278(36):34517-24.
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. Biochemistry. 2003 Mar 11; 42(9):2616-24.
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. J Biol Chem. 2003 Jan 31; 278(5):3363-71.
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. Am J Physiol Lung Cell Mol Physiol. 2002 Feb; 282(2):L197-206.
Schmidlin F, Amadesi S, Vidil R, Trevisani M, Martinet N, Caughey G, Tognetto M, Cavallesco G, Mapp C, Geppetti P, Bunnett NW. Expression and function of proteinase-activated receptor 2 in human bronchial smooth muscle. Am J Respir Crit Care Med. 2001 Oct 01; 164(7):1276-81.
Wolters PJ, Pham CT, Muilenburg DJ, Ley TJ, Caughey GH. Dipeptidyl peptidase I is essential for activation of mast cell chymases, but not tryptases, in mice. J Biol Chem. 2001 May 25; 276(21):18551-6.
Brown JK, Jones CA, Rooney LA, Caughey GH. Mast cell tryptase activates extracellular-regulated kinases (p44/p42) in airway smooth-muscle cells: importance of proteolytic events, time course, and role in mediating mitogenesis. Am J Respir Cell Mol Biol. 2001 Feb; 24(2):146-54.
Caughey GH, Raymond WW, Blount JL, Hau LW, Pallaoro M, Wolters PJ, Verghese GM. Characterization of human gamma-tryptases, novel members of the chromosome 16p mast cell tryptase and prostasin gene families. J Immunol. 2000 Jun 15; 164(12):6566-75.
Steinhoff M, Vergnolle N, Young SH, Tognetto M, Amadesi S, Ennes HS, Trevisani M, Hollenberg MD, Wallace JL, Caughey GH, Mitchell SE, Williams LM, Geppetti P, Mayer EA, Bunnett NW. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat Med. 2000 Feb; 6(2):151-8.
Wolters PJ, Laig-Webster M, Caughey GH. Dipeptidyl peptidase I cleaves matrix-associated proteins and is expressed mainly by mast cells in normal dog airways. Am J Respir Cell Mol Biol. 2000 Feb; 22(2):183-90.
Steinhoff M, Corvera CU, Thoma MS, Kong W, McAlpine BE, Caughey GH, Ansel JC, Bunnett NW. Proteinase-activated receptor-2 in human skin: tissue distribution and activation of keratinocytes by mast cell tryptase. Exp Dermatol. 1999 Aug; 8(4):282-94.
Corvera CU, Déry O, McConalogue K, Gamp P, Thoma M, Al-Ani B, Caughey GH, Hollenberg MD, Bunnett NW. Thrombin and mast cell tryptase regulate guinea-pig myenteric neurons through proteinase-activated receptors-1 and -2. J Physiol. 1999 Jun 15; 517 ( Pt 3):741-56.
Coussens LM, Raymond WW, Bergers G, Laig-Webster M, Behrendtsen O, Werb Z, Caughey GH, Hanahan D. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. 1999 Jun 01; 13(11):1382-97.
Ma Y, Longley BJ, Wang X, Blount JL, Langley K, Caughey GH. Clustering of activating mutations in c-KIT's juxtamembrane coding region in canine mast cell neoplasms. J Invest Dermatol. 1999 Feb; 112(2):165-70.
Suzuki H, Caughey GH, Gao XP, Rubinstein I. Mast cell chymase-like protease(s) modulates Escherichia coli lipopolysaccharide-induced vasomotor dysfunction in skeletal muscle in vivo. J Pharmacol Exp Ther. 1998 Mar; 284(3):1156-64.
Auchampach JA, Jin X, Wan TC, Caughey GH, Linden J. Canine mast cell adenosine receptors: cloning and expression of the A3 receptor and evidence that degranulation is mediated by the A2B receptor. Mol Pharmacol. 1997 Nov; 52(5):846-60.
Fang KC, Raymond WW, Blount JL, Caughey GH. Dog mast cell alpha-chymase activates progelatinase B by cleaving the Phe88-Gln89 and Phe91-Glu92 bonds of the catalytic domain. J Biol Chem. 1997 Oct 10; 272(41):25628-35.
Corvera CU, Déry O, McConalogue K, Böhm SK, Khitin LM, Caughey GH, Payan DG, Bunnett NW. Mast cell tryptase regulates rat colonic myocytes through proteinase-activated receptor 2. J Clin Invest. 1997 Sep 15; 100(6):1383-93.
Brown JK, Tyler CL, Jones CA, Ruoss SJ, Hartmann T, Caughey GH. Tryptase, the dominant secretory granular protein in human mast cells, is a potent mitogen for cultured dog tracheal smooth muscle cells. Am J Respir Cell Mol Biol. 1995 Aug; 13(2):227-36.
Brown JK, Jones CA, Tyler CL, Ruoss SJ, Hartmann T, Caughey GH. Tryptase-induced mitogenesis in airway smooth muscle cells. Potency, mechanisms, and interactions with other mast cell mediators. Chest. 1995 Mar; 107(3 Suppl):95S-96S.
Caughey GH, Schaumberg TH, Zerweck EH, Butterfield JH, Hanson RD, Silverman GA, Ley TJ. The human mast cell chymase gene (CMA1): mapping to the cathepsin G/granzyme gene cluster and lineage-restricted expression. Genomics. 1993 Mar; 15(3):614-20.
Caughey GH, Raymond WW, Bacci E, Lombardy RJ, Tidwell RR. Bis(5-amidino-2-benzimidazolyl)methane and related amidines are potent, reversible inhibitors of mast cell tryptases. J Pharmacol Exp Ther. 1993 Feb; 264(2):676-82.
Hartmann T, Ruoss SJ, Raymond WW, Seuwen K, Caughey GH. Human tryptase as a potent, cell-specific mitogen: role of signaling pathways in synergistic responses. Am J Physiol. 1992 May; 262(5 Pt 1):L528-34.
Vanderslice P, Ballinger SM, Tam EK, Goldstein SM, Craik CS, Caughey GH. Human mast cell tryptase: multiple cDNAs and genes reveal a multigene serine protease family. Proc Natl Acad Sci U S A. 1990 May; 87(10):3811-5.
Tam EK, Franconi GM, Nadel JA, Caughey GH. Protease inhibitors potentiate smooth muscle relaxation induced by vasoactive intestinal peptide in isolated human bronchi. Am J Respir Cell Mol Biol. 1990 May; 2(5):449-52.
Vanderslice P, Craik CS, Nadel JA, Caughey GH. Molecular cloning of dog mast cell tryptase and a related protease: structural evidence of a unique mode of serine protease activation. Biochemistry. 1989 May 16; 28(10):4148-55.
Franconi GM, Graf PD, Lazarus SC, Nadel JA, Caughey GH. Mast cell tryptase and chymase reverse airway smooth muscle relaxation induced by vasoactive intestinal peptide in the ferret. J Pharmacol Exp Ther. 1989 Mar; 248(3):947-51.
Sigal E, Grunberger D, Craik CS, Caughey GH, Nadel JA. Arachidonate 15-lipoxygenase from human leukocytes: purification and structural homology to other mammalian lipoxygenases. Adv Prostaglandin Thromboxane Leukot Res. 1989; 19:156-9.
Forsberg LS, Lazarus SC, Seno N, DeVinney R, Caughey GH, Gold WM. Dog mastocytoma proteoglycans: occurrence of heparin and oversulfated chondroitin sulfates, containing trisulfated disaccharides, in three cell lines. Biochim Biophys Acta. 1988 Dec 15; 967(3):416-28.
Caughey GH, Viro NF, Calonico LD, McDonald DM, Lazarus SC, Gold WM. Chymase and tryptase in dog mastocytoma cells: asynchronous expression as revealed by enzyme cytochemical staining. J Histochem Cytochem. 1988 Aug; 36(8):1053-60.
Sigal E, Grunberger D, Craik CS, Caughey GH, Nadel JA. Arachidonate 15-lipoxygenase (omega-6 lipoxygenase) from human leukocytes. Purification and structural homology to other mammalian lipoxygenases. J Biol Chem. 1988 Apr 15; 263(11):5328-32.
Caughey GH, Viro NF, Lazarus SC, Nadel JA. Purification and characterization of dog mastocytoma chymase: identification of an octapeptide conserved in chymotryptic leukocyte proteinases. Biochim Biophys Acta. 1988 Jan 29; 952(2):142-9.
Sigal E, Grunberger D, Cashman JR, Craik CS, Caughey GH, Nadel JA. Arachidonate 15-lipoxygenase from human eosinophil-enriched leukocytes: partial purification and properties. Biochem Biophys Res Commun. 1988 Jan 15; 150(1):376-83.
Caughey GH, Viro NF, Ramachandran J, Lazarus SC, Borson DB, Nadel JA. Dog mastocytoma tryptase: affinity purification, characterization, and amino-terminal sequence. Arch Biochem Biophys. 1987 Nov 01; 258(2):555-63.
Varsano S, Basbaum CB, Forsberg LS, Borson DB, Caughey G, Nadel JA. Dog tracheal epithelial cells in culture synthesize sulfated macromolecular glycoconjugates and release them from the cell surface upon exposure to extracellular proteinases. Exp Lung Res. 1987; 13(2):157-84.
Borson DB, Corrales R, Varsano S, Gold M, Viro N, Caughey G, Ramachandran J, Nadel JA. Enkephalinase inhibitors potentiate substance P-induced secretion of 35SO4-macromolecules from ferret trachea. Exp Lung Res. 1987; 12(1):21-36.
Caughey G, Wong H, Gamsu G, Golden J. Nonbronchoscopic bronchoalveolar lavage for the diagnosis for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Chest. 1985 Nov; 88(5):659-62.