George Caughey, MD
Professor Emeritus
Medicine
School of Medicine

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.

• Therapeutic targeting of cathepsin C: from pathophysiology to treatment.
  Pharmacology & therapeutics 2018 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, …
• A shocking diagnosis.
  Journal of hospital medicine 2017 Prabhakaran A, Dhaliwal G, Schilf CR, Caughey GH, Pile J
• Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number.
  Nature genetics 2016 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…
• Cathepsin L Helps to Defend Mice from Infection with Influenza A.
  PloS one 2016 Xu X, Greenland JR, Gotts JE, Matthay MA, Caughey GH
• Donor-Reactive Regulatory T Cell Frequency Increases During Acute Cellular Rejection of Lung Allografts.
  Transplantation 2016 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
• Divergent Inhibitor Susceptibility among Airway Lumen-Accessible Tryptic Proteases.
  PloS one 2015 Nimishakavi S, Raymond WW, Gruenert DC, Caughey GH
• Mast cell proteases as pharmacological targets.
  European journal of pharmacology 2015 Caughey GH
• Regulation of hepatocyte growth factor in mice with pneumonia by peptidases and trans-alveolar flux.
  PloS one 2015 Raymond WW, Xu X, Nimishakavi S, Le C, McDonald DM, Caughey GH
• Mast cells present protrusions into blood vessels upon tracheal allergen challenge in mice.
  PloS one 2015 Bose O, Baluk P, Looney MR, Cheng LE, McDonald DM, Caughey GH, Krummel MF
• Mast cells in a murine lung ischemia-reperfusion model of primary graft dysfunction.
  Respiratory research 2014 Greenland JR, Xu X, Sayah DM, Liu FC, Jones KD, Looney MR, Caughey GH
• Dipeptidyl peptidase I controls survival from Klebsiella pneumoniae lung infection by processing surfactant protein D.
  Biochemical and biophysical research communications 2014 Sutherland RE, Barry SS, Olsen JS, Salantes DB, Caughey GH, Wolters PJ
• Cathepsin L protects mice from mycoplasmal infection and is essential for airway lymphangiogenesis.
  American journal of respiratory cell and molecular biology 2013 Xu X, Greenland J, Baluk P, Adams A, Bose O, McDonald DM, Caughey GH
• Malaria-associated L-arginine deficiency induces mast cell-associated disruption to intestinal barrier defenses against nontyphoidal Salmonella bacteremia.
  Infection and immunity 2013 Chau JY, Tiffany CM, Nimishakavi S, Lawrence JA, Pakpour N, Mooney JP, Lokken KL, Caughey GH, Tsolis RM, Luckhart S
• Mutational tail loss is an evolutionary mechanism for liberating marapsins and other type I serine proteases from transmembrane anchors.
  The Journal of biological chemistry 2013 Raman K, Trivedi NN, Raymond WW, Ganesan R, Kirchhofer D, Verghese GM, Craik CS, Schneider EL, Nimishakavi S, Caughey GH
• Association of large-airway lymphocytic bronchitis with bronchiolitis obliterans syndrome.
  American journal of respiratory and critical care medicine 2012 Greenland JR, Jones KD, Hays SR, Golden JA, Urisman A, Jewell NP, Caughey GH, Trivedi NN
• Activity and inhibition of prostasin and matriptase on apical and basolateral surfaces of human airway epithelial cells.
  American journal of physiology. Lung cellular and molecular physiology 2012 Nimishakavi S, Besprozvannaya M, Raymond WW, Craik CS, Gruenert DC, Caughey GH
• The αvβ6 integrin modulates airway hyperresponsiveness in mice by regulating intraepithelial mast cells.
  The Journal of clinical investigation 2012 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
• Parasitic infection improves survival from septic peritonitis by enhancing mast cell responses to bacteria in mice.
  PloS one 2011 Sutherland RE, Xu X, Kim SS, Seeley EJ, Caughey GH, Wolters PJ
• Strain-dependent induction of neutrophil histamine production and cell death by Pseudomonas aeruginosa.
  Journal of leukocyte biology 2011 Xu X, Zhang H, Song Y, Lynch SV, Lowell CA, Wiener-Kronish JP, Caughey GH
• Mast cell proteases as protective and inflammatory mediators.
  Advances in experimental medicine and biology 2011 Caughey GH
• How immune peptidases change specificity: cathepsin G gained tryptic function but lost efficiency during primate evolution.
  Journal of immunology (Baltimore, Md. : 1950) 2010 Raymond WW, Trivedi NN, Makarova A, Ray M, Craik CS, Caughey GH
• Accumulation of intraepithelial mast cells with a unique protease phenotype in T(H)2-high asthma.
  The Journal of allergy and clinical immunology 2010 Dougherty RH, Sidhu SS, Raman K, Solon M, Solberg OD, Caughey GH, Woodruff PG, Fahy JV
• Mast cell peptidases: chameleons of innate immunity and host defense.
  American journal of respiratory cell and molecular biology 2009 Trivedi NN, Caughey GH
• Human subjects are protected from mast cell tryptase deficiency despite frequent inheritance of loss-of-function mutations.
  The Journal of allergy and clinical immunology 2009 Trivedi NN, Tamraz B, Chu C, Kwok PY, Caughey GH
• Ex vivo sputum analysis reveals impairment of protease-dependent mucus degradation by plasma proteins in acute asthma.
  American journal of respiratory and critical care medicine 2009 Innes AL, Carrington SD, Thornton DJ, Kirkham S, Rousseau K, Dougherty RH, Raymond WW, Caughey GH, Muller SJ, Fahy JV
• Alpha 2-macroglobulin capture allows detection of mast cell chymase in serum and creates a reservoir of angiotensin II-generating activity.
  Journal of immunology (Baltimore, Md. : 1950) 2009 Raymond WW, Su S, Makarova A, Wilson TM, Carter MC, Metcalfe DD, Caughey GH
• Guinea pig chymase is leucine-specific: a novel example of functional plasticity in the chymase/granzyme family of serine peptidases.
  The Journal of biological chemistry 2008 Caughey GH, Beauchamp J, Schlatter D, Raymond WW, Trivedi NN, Banner D, Mauser H, Fingerle J
• Chimerism, point mutation, and truncation dramatically transformed mast cell delta-tryptases during primate evolution.
  The Journal of allergy and clinical immunology 2008 Trivedi NN, Raymond WW, Caughey GH
• Mast cell alpha and beta tryptases changed rapidly during primate speciation and evolved from gamma-like transmembrane peptidases in ancestral vertebrates.
  Journal of immunology (Baltimore, Md. : 1950) 2007 Trivedi NN, Tong Q, Raman K, Bhagwandin VJ, Caughey GH
• Mast cell tryptases and chymases in inflammation and host defense.
  Immunological reviews 2007 Caughey GH
• Tryptase haplotype in mastocytosis: relationship to disease variant and diagnostic utility of total tryptase levels.
  Clinical immunology (Orlando, Fla.) 2007 Akin C, Soto D, Brittain E, Chhabra A, Schwartz LB, Caughey GH, Metcalfe DD
• Protease-activated receptor 2, dipeptidyl peptidase I, and proteases mediate Clostridium difficile toxin A enteritis.
  Gastroenterology 2007 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
• Regulation of the epithelial Na+ channel by peptidases.
  Current topics in developmental biology 2007 Planès C, Caughey GH
• Neutrophil histamine contributes to inflammation in mycoplasma pneumonia.
  The Journal of experimental medicine 2006 Xu X, Zhang D, Zhang H, Wolters PJ, Killeen NP, Sullivan BM, Locksley RM, Lowell CA, Caughey GH
• A Pulmonary Perspective on GASPIDs: Granule-Associated Serine Peptidases of Immune Defense.
  Current respiratory medicine reviews 2006 Caughey GH
• Cathepsins L and S are not required for activation of dipeptidyl peptidase I (cathepsin C) in mice.
  Biological chemistry 2006 Mallen-St Clair J, Shi GP, Sutherland RE, Chapman HA, Caughey GH, Wolters PJ
• Prostasin regulates epithelial monolayer function: cell-specific Gpld1-mediated secretion and functional role for GPI anchor.
  American journal of physiology. Cell physiology 2006 Verghese GM, Gutknecht MF, Caughey GH
• Tryptase genetics and anaphylaxis.
  The Journal of allergy and clinical immunology 2006 Caughey GH
• Mast cell and neutrophil peptidases attack an inactivation segment in hepatocyte growth factor to generate NK4-like antagonists.
  The Journal of biological chemistry 2005 Raymond WW, Cruz AC, Caughey GH
• Mast cells protect mice from Mycoplasma pneumonia.
  American journal of respiratory and critical care medicine 2005 Xu X, Zhang D, Lyubynska N, Wolters PJ, Killeen NP, Baluk P, McDonald DM, Hawgood S, Caughey GH
• Transcript signatures of lymphocytic bronchitis in lung allograft biopsy specimens.
  The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 2005 Xu X, Golden JA, Dolganov G, Jones KD, Donnelly S, Weaver T, Caughey GH
• Mastin is a gelatinolytic mast cell peptidase resembling a mini-proteasome.
  Archives of biochemistry and biophysics 2005 Raymond WW, Sommerhoff CP, Caughey GH
• Mast cell tryptase may modulate endothelial cell phenotype in healing myocardial infarcts.
  The Journal of pathology 2005 Somasundaram P, Ren G, Nagar H, Kraemer D, Mendoza L, Michael LH, Caughey GH, Entman ML, Frangogiannis NG
• Prostasin, a membrane-anchored serine peptidase, regulates sodium currents in JME/CF15 cells, a cystic fibrosis airway epithelial cell line.
  American journal of physiology. Lung cellular and molecular physiology 2004 Tong Z, Illek B, Bhagwandin VJ, Verghese GM, Caughey GH
• Matrix metalloproteinase-2 and -9 expression increases in Mycoplasma-infected airways but is not required for microvascular remodeling.
  American journal of physiology. Lung cellular and molecular physiology 2004 Baluk P, Raymond WW, Ator E, Coussens LM, McDonald DM, Caughey GH
• Mast cell dipeptidyl peptidase I mediates survival from sepsis.
  The Journal of clinical investigation 2004 Mallen-St Clair J, Pham CT, Villalta SA, Caughey GH, Wolters PJ
• Mast cell cathepsins C and S control levels of carboxypeptidase A and the chymase, mouse mast cell protease 5.
  Biological chemistry 2003 Henningsson F, Wolters P, Chapman HA, Caughey GH, Pejler G
• Mouse prostasin gene structure, promoter analysis, and restricted expression in lung and kidney.
  American journal of respiratory cell and molecular biology 2003 Verghese GM, Tong ZY, Bhagwandin V, 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.
  The Journal of biological chemistry 2003 Raymond WW, Ruggles SW, Craik CS, Caughey GH
• Structure of human pro-chymase: a model for the activating transition of granule-associated proteases.
  Biochemistry 2003 Reiling KK, Krucinski J, Miercke LJ, Raymond WW, Caughey GH, Stroud RM
• Building a better heparin.
  American journal of respiratory cell and molecular biology 2003 Caughey GH
• Structure and activity of human pancreasin, a novel tryptic serine peptidase expressed primarily by the pancreas.
  The Journal of biological chemistry 2002 Bhagwandin VJ, Hau LW, Mallen-St Clair J, Wolters PJ, Caughey GH
• New developments in the genetics and activation of mast cell proteases.
  Molecular immunology 2002 Caughey GH
• Lys40 but not Arg143 influences selectivity of angiotensin conversion by human alpha-chymase.
  Biochimica et biophysica acta 2002 Muilenburg DJ, Raymond WW, Wolters PJ, Caughey GH
• Tryptase's potent mitogenic effects in human airway smooth muscle cells are via nonproteolytic actions.
  American journal of physiology. Lung cellular and molecular physiology 2002 Brown JK, Jones CA, Rooney LA, Caughey GH, Hall IP