Dr. Caughey received an M.D. from Stanford. After Medicine and Pulmonary subspecialty training at Pennsylvania Hospital and UCSF, he trained in lung research at UCSF’s Cardiovascular Research Institute and at Genentech, joining UCSF’s pulmonary faculty in 1986. He occupies the Julius and Lillian Nadel Endowed Chair and is Chief of the Pulmonary and Critical Care Medicine Section at the San Francisco VA Medical Center. Major activities include laboratory-based research, teaching, inpatient and outpatient clinical consulting, and serving on editorial, administrative, and advisory committees.
Research Interests Extracellular proteases influence the pathology of lung diseases. The lab is interested in the roles of known and novel proteases in normal and diseased lung, emphasizing roles in scarring, ion transport, and anti-bacterial defense. The lab’s traditional focus is on peptidases secreted by mast cells, which are resident inflammatory cells especially abundant in human lung. The lab purified and cloned the major secreted mast cell serine proteases, tryptases and chymases. Achievements include the first cloning of a tryptase and discovery of new functions of these enzymes as peptidases, secretagogues and modulators of muscle tone. With collaborators, the lab identified potent tryptase blockers, one of which prevents allergic bronchoconstriction. These investigations encouraged pharmaceutical development of tryptase inhibitors, trials of which are underway in humans to treat asthma and ulcerative colitis. The lab characterized the multi-gene human tryptase locus, discovering novel genes encoding membrane-anchored (gamma) and truncated (delta) tryptases, as well as major polymorphisms and a widespread inherited deficiency of the alpha isoform. A current thrust of research is investigation of clinical consequences of alpha tryptase deficiency in humans.
Cloning of dog and human chymase genes allowed localization of the latter to a cluster of protease genes on chromosome 14q11.2, a locus linked to asthma susceptibility. Availability of cDNAs and genes led to heterologous expression, crystallization, molecular modeling, mutagenesis, and studies of transcriptional regulation. Additionally, the lab characterized a mouse model lacking chymase activity, facilitating in vivo studies of chymase biology. Work by members of the lab and their collaborators suggests ways in which mast cells influence wound healing, tissue remodeling, fibrosis, and tumorigenesis, which differ from the acute allergic phenomena with which mast cells are traditionally associated. For example, tryptase promotes fibroblast and airway smooth muscle cell growth. These effects provide links between the activation of mast cells and pathological phenomena such as sub-epithelial fibrosis and airway smooth muscle hypertrophy (as seen in asthma) and alveolar scarring (as seen in several types of fibrotic lung disease). Some of these effects are mediated by hydrolysis of G-protein-coupled proteinase-activated receptors (PARs).
Another major subject of research is a group of Type I membrane-anchored serine peptidases expressed by airway epithelium, one which (prostasin) is a major regulator of epithelial Na+ transport and a target for therapeutic inhibition in cystic fibrosis.
Selected Recent Publications Xu X, Golden JA, Dolganov G, Jones KD, Donnelly S, Weaver T, Caughey GH. Transcript signatures of lymphocytic bronchitis in lung allograft biopsies. J Heart Lung Transplant 24:1055-66, 2005
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 KitW-sh/KitW-sh Sash mice. Clin Exp Allergy 35:82-8, 2005
Raymond WW, Sommerhoff CP, Caughey GH. Mastin is a gelatinolytic mast cell peptidase resembling a mini-proteasome. Arch Biochem Biophys 435:311-22, 2005
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 Resp Crit Care Med 173:219-25, 2006.
Raymond WW, Cruz AC, Caughey GH. Mast cell and neutrophil peptidases attack an inactivation segment in hepatocyte growth factory to generate NK4-like antagonists. J Biol Chem 281:1489-94, 2006.
Verghese GM, Gutknecht MF, Caughey GH. Prostasin regulates epithelial monolayer function: cell-specific Gpld1-mediated secretion and role of the GPI anchor. Am J Physiol Cell Physiol291:C1258-70, 2006.
Caughey GH. A pulmonary perspective on GASPIDs: Granule-Associated Serine Peptidases of Immune Defense. Curr Resp Med Rev 2:263-277, 2006.
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 Med203:2907-17,2006.
Planès C and Caughey GH. Regulation of the epithelial Na+ channel by peptidases. Curr Top Dev Biol 78:23-46, 2007.
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 123:268-71, 2007.
Caughey GH. Mast cell tryptases and chymases in inflammation and host defense. Immunol Rev 217:141-154, 2007.
Trivedi NN, Tong Q, Raymond WW, Bhagwandin VJ, Caughey GH. Mast cell tryptases changed rapidly during primate speciation and evolved from g-like transmembrane peptidases in ancestral vertebrates. J Immunol 179:6072-9, 2007.
Trivedi NN, Raymond WW, Caughey GH. Chimerism, point mutation and truncation dramatically transformed mast cell d tryptases during primate evolution. J Allergy Clin Immunol 121:1262-8, 2008.
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 283:13943-51, 2008.
