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 Soto D, Malmsten C, Blount JL, Muilenberg DJ and Caughey GH. Genetic deficiency of human mast cell a-tryptase. Clin Exp Allergy 32:1000-6, 2002
Reiling KK, Krucinski J, Miercke LJW, Raymond WW, Caughey GH, Stroud RM. Structure of human pro-chymase: a model for the activating transition of granule associated proteases. Biochemistry 42:2616-24, 2003
Raymond WW, Ruggles Waugh S, 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 278:34517-24, 2003
Mallen-St. Clair J, Pham CTN, Villalta SA, Caughey GH, Wolters PJ. Mast cell dipeptidyl peptidase I mediates survival from sepsis. J Clin Invest 113:628-34, 2004
Verghese GM, Tong Z-Y, Bhagwandin V, Caughey GH. Mouse prostasin gene structure, promoter analysis and restricted expression in lung and kidney. Am J Resp Cell Mol Biol 30:519-29, 2004
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 287:L307-17, 2004
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 205:102-11, 2005
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, in press
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, in press
