Faculty ProfilesHarold Chapman, MD
513 Parnassus Ave
San Francisco, CA 94143
The Chapman lab has had a longstanding interest and track record of innovation in the field of tissue remodeling, particularly as it relates to lung disease. For many years my work primarily focused on proteolytic enzymes. My group and I cloned and characterized several new members of the cathepsin family and elucidated their roles in bone, brain, lung, and immune disorders. I also pursued basic mechanisms by which proteases and adhesion receptors coordinate cell invasion and extracellular matrix remodeling and this has led to longstanding interest in integrin signaling. We were the first to recognize the physical and functional connections between integrins and the key cell surface protease, plasminogen activator. After moving from Harvard to UCSF 12 years ago I focused my lab on pulmonary fibrosis as a disorder of great unmet medical need and a logical extension of my prior work in matrix biology. I pioneered the in vivo investigation of the role of epithelial mesenchymal transition (EMT) in pulmonary fibrosis and uncovered mechanistic insight as to how integrins and hypoxia regulate epithelial cell plasticity. These studies have provided a roadmap for defining the role of EMT signaling in human fibrosis and lung cancer. More recently we have extended our studies of epithelial plasticity into the realm of lung stem/progenitor cells and are committed to defining the regenerative potential of the lung after injury.
I have trained approximately twenty PhD and/or MD post-docs who now populate academic departments and pharmaceutical labs. As a physician scientist myself, I have particularly enjoyed the responsibility of motivating and training capable young physicians for careers in disease-oriented research. These now include Division and Department Chairs as well as several independent medicine faculty with successful NIH-funded research programs. My lab now is comprised of mainly PhD trainees and junior faculty and we are committed to understanding and targeting the emerging relationship between hypoxia, EMT, and tissue remodeling during fibrogenesis and cancer progression.
Awards and Honors
Merit Award, National Institute of Health, 2001-2012
American Association of Physicians, 1998
American Society for Clinical Investigation, 1987
Related Web Sites
- Chapman Lab
- Clinical Profile at UCSF Medical Center
- Profile at UCSF Pulmonary and Critical Care Division
In the News
Recent Articles (73)
Zhou Y, Horowitz JC, Naba A, Ambalavanan N, Atabai K, Balestrini J, Bitterman PB, Corley RA, Ding BS, Engler AJ, Hansen KC, Hagood JS, Kheradmand F, Lin QS, Neptune E, Niklason L, Ortiz LA, Parks WC, Tschumperlin DJ, White ES, Chapman HA, Thannickal VJ. Extracellular matrix in lung development, homeostasis and disease. Matrix Biol. 2018 Mar 08.
Wei Y, Kim TJ, Peng DH, Duan D, Gibbons DL, Yamauchi M, Jackson JR, Le Saux CJ, Calhoun C, Peters J, Derynck R, Backes BJ, Chapman HA. Fibroblast-specific inhibition of TGF-ß1 signaling attenuates lung and tumor fibrosis. J Clin Invest. 2017 Oct 02; 127(10):3675-3688.
Xi Y, Kim T, Brumwell AN, Driver IH, Wei Y, Tan V, Jackson JR, Xu J, Lee DK, Gotts JE, Matthay MA, Shannon JM, Chapman HA, Vaughan AE. Local lung hypoxia determines epithelial fate decisions during alveolar regeneration. Nat Cell Biol. 2017 Aug; 19(8):904-914.
McClendon J, Jansing NL, Redente EF, Gandjeva A, Ito Y, Colgan SP, Ahmad A, Riches DWH, Chapman HA, Mason RJ, Tuder RM, Zemans RL. Hypoxia-Inducible Factor 1a Signaling Promotes Repair of the Alveolar Epithelium after Acute Lung Injury. Am J Pathol. 2017 Aug; 187(8):1772-1786.
Kanegai CM, Xi Y, Donne ML, Gotts JE, Driver IH, Amidzic G, Lechner AJ, Jones KD, Vaughan AE, Chapman HA, Rock JR. Persistent Pathology in Influenza-Infected Mouse Lungs. Am J Respir Cell Mol Biol. 2016 10; 55(4):613-615.
Vaughan AE, Brumwell AN, Xi Y, Gotts JE, Brownfield DG, Treutlein B, Tan K, Tan V, Liu FC, Looney MR, Matthay MA, Rock JR, Chapman HA. Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. Nature. 2015 Jan 29; 517(7536):621-5.
Xu P, Bailey-Bucktrout S, Xi Y, Xu D, Du D, Zhang Q, Xiang W, Liu J, Melton A, Sheppard D, Chapman HA, Bluestone JA, Derynck R. Innate antiviral host defense attenuates TGF-ß function through IRF3-mediated suppression of Smad signaling. Mol Cell. 2014 Dec 18; 56(6):723-37.
Hogan BL, Barkauskas CE, Chapman HA, Epstein JA, Jain R, Hsia CC, Niklason L, Calle E, Le A, Randell SH, Rock J, Snitow M, Krummel M, Stripp BR, Vu T, White ES, Whitsett JA, Morrisey EE. Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function. Cell Stem Cell. 2014 Aug 07; 15(2):123-38.
Grove LM, Southern BD, Jin TH, White KE, Paruchuri S, Harel E, Wei Y, Rahaman SO, Gladson CL, Ding Q, Craik CS, Chapman HA, Olman MA. Urokinase-type plasminogen activator receptor (uPAR) ligation induces a raft-localized integrin signaling switch that mediates the hypermotile phenotype of fibrotic fibroblasts. J Biol Chem. 2014 May 02; 289(18):12791-804.
Blackwell TS, Tager AM, Borok Z, Moore BB, Schwartz DA, Anstrom KJ, Bar-Joseph Z, Bitterman P, Blackburn MR, Bradford W, Brown KK, Chapman HA, Collard HR, Cosgrove GP, Deterding R, Doyle R, Flaherty KR, Garcia CK, Hagood JS, Henke CA, Herzog E, Hogaboam CM, Horowitz JC, King TE, Loyd JE, Lawson WE, Marsh CB, Noble PW, Noth I, Sheppard D, Olsson J, Ortiz LA, O'Riordan TG, Oury TD, Raghu G, Roman J, Sime PJ, Sisson TH, Tschumperlin D, Violette SM, Weaver TE, Wells RG, White ES, Kaminski N, Martinez FJ, Wynn TA, Thannickal VJ, Eu JP. Future directions in idiopathic pulmonary fibrosis research. An NHLBI workshop report. Am J Respir Crit Care Med. 2014 Jan 15; 189(2):214-22.
Xi Y, Tan K, Brumwell AN, Chen SC, Kim YH, Kim TJ, Wei Y, Chapman HA. Inhibition of epithelial-to-mesenchymal transition and pulmonary fibrosis by methacycline. Am J Respir Cell Mol Biol. 2014 Jan; 50(1):51-60.
Shum AK, Alimohammadi M, Tan CL, Cheng MH, Metzger TC, Law CS, Lwin W, Perheentupa J, Bour-Jordan H, Carel JC, Husebye ES, De Luca F, Janson C, Sargur R, Dubois N, Kajosaari M, Wolters PJ, Chapman HA, Kämpe O, Anderson MS. BPIFB1 is a lung-specific autoantigen associated with interstitial lung disease. Sci Transl Med. 2013 Oct 09; 5(206):206ra139.
Yang J, Wheeler SE, Velikoff M, Kleaveland KR, LaFemina MJ, Frank JA, Chapman HA, Christensen PJ, Kim KK. Activated alveolar epithelial cells initiate fibrosis through secretion of mesenchymal proteins. Am J Pathol. 2013 Nov; 183(5):1559-1570.
Matthay MA, Anversa P, Bhattacharya J, Burnett BK, Chapman HA, Hare JM, Hei DJ, Hoffman AM, Kourembanas S, McKenna DH, Ortiz LA, Ott HC, Tente W, Thébaud B, Trapnell BC, Weiss DJ, Yuan JX, Blaisdell CJ. Cell therapy for lung diseases. Report from an NIH-NHLBI workshop, November 13-14, 2012. Am J Respir Crit Care Med. 2013 Aug 01; 188(3):370-5.
Morrisey EE, Cardoso WV, Lane RH, Rabinovitch M, Abman SH, Ai X, Albertine KH, Bland RD, Chapman HA, Checkley W, Epstein JA, Kintner CR, Kumar M, Minoo P, Mariani TJ, McDonald DM, Mukouyama YS, Prince LS, Reese J, Rossant J, Shi W, Sun X, Werb Z, Whitsett JA, Gail D, Blaisdell CJ, Lin QS. Molecular determinants of lung development. Ann Am Thorac Soc. 2013 Apr; 10(2):S12-6.
Smith KR, Dahl HH, Canafoglia L, Andermann E, Damiano J, Morbin M, Bruni AC, Giaccone G, Cossette P, Saftig P, Grötzinger J, Schwake M, Andermann F, Staropoli JF, Sims KB, Mole SE, Franceschetti S, Alexander NA, Cooper JD, Chapman HA, Carpenter S, Berkovic SF, Bahlo M. Cathepsin F mutations cause Type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis. Hum Mol Genet. 2013 Apr 01; 22(7):1417-23.
Sennino B, Ishiguro-Oonuma T, Wei Y, Naylor RM, Williamson CW, Bhagwandin V, Tabruyn SP, You WK, Chapman HA, Christensen JG, Aftab DT, McDonald DM. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov. 2012 Mar; 2(3):270-87.
Ulsamer A, Wei Y, Kim KK, Tan K, Wheeler S, Xi Y, Thies RS, Chapman HA. Axin pathway activity regulates in vivo pY654-ß-catenin accumulation and pulmonary fibrosis. J Biol Chem. 2012 Feb 10; 287(7):5164-72.
Chapman HA, Li X, Alexander JP, Brumwell A, Lorizio W, Tan K, Sonnenberg A, Wei Y, Vu TH. Integrin a6ß4 identifies an adult distal lung epithelial population with regenerative potential in mice. J Clin Invest. 2011 Jul; 121(7):2855-62.
Borok Z, Whitsett JA, Bitterman PB, Thannickal VJ, Kotton DN, Reynolds SD, Krasnow MA, Bianchi DW, Morrisey EE, Hogan BL, Kurie JM, Walker DC, Radisky DC, Nishimura SL, Violette SM, Noble PW, Shapiro SD, Blaisdell CJ, Chapman HA, Kiley J, Gail D, Hoshizaki D. Cell plasticity in lung injury and repair: report from an NHLBI workshop, April 19-20, 2010. Proc Am Thorac Soc. 2011 Jun; 8(3):215-22.
Marmai C, Sutherland RE, Kim KK, Dolganov GM, Fang X, Kim SS, Jiang S, Golden JA, Hoopes CW, Matthay MA, Chapman HA, Wolters PJ. Alveolar epithelial cells express mesenchymal proteins in patients with idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2011 Jul; 301(1):L71-8.
Zhu S, Gladson CL, White KE, Ding Q, Stewart J, Jin TH, Chapman HA, Olman MA. Urokinase receptor mediates lung fibroblast attachment and migration toward provisional matrix proteins through interaction with multiple integrins. Am J Physiol Lung Cell Mol Physiol. 2009 Jul; 297(1):L97-108.
Liu Y, Chattopadhyay N, Qin S, Szekeres C, Vasylyeva T, Mahoney ZX, Taglienti M, Bates CM, Chapman HA, Miner JH, Kreidberg JA. Coordinate integrin and c-Met signaling regulate Wnt gene expression during epithelial morphogenesis. Development. 2009 Mar; 136(5):843-53.
Kim Y, Kugler MC, Wei Y, Kim KK, Li X, Brumwell AN, Chapman HA. Integrin alpha3beta1-dependent beta-catenin phosphorylation links epithelial Smad signaling to cell contacts. J Cell Biol. 2009 Jan 26; 184(2):309-22.
Kim KK, Wei Y, Szekeres C, Kugler MC, Wolters PJ, Hill ML, Frank JA, Brumwell AN, Wheeler SE, Kreidberg JA, Chapman HA. Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis. J Clin Invest. 2009 Jan; 119(1):213-24.
Tang CH, Hill ML, Brumwell AN, Chapman HA, Wei Y. Signaling through urokinase and urokinase receptor in lung cancer cells requires interactions with beta1 integrins. J Cell Sci. 2008 Nov 15; 121(Pt 22):3747-56.
Wei Y, Tang CH, Kim Y, Robillard L, Zhang F, Kugler MC, Chapman HA. Urokinase receptors are required for alpha 5 beta 1 integrin-mediated signaling in tumor cells. J Biol Chem. 2007 Feb 09; 282(6):3929-39.
Wang B, Huang X, Wolters PJ, Sun J, Kitamoto S, Yang M, Riese R, Leng L, Chapman HA, Finn PW, David JR, Bucala R, Shi GP. Cutting edge: Deficiency of macrophage migration inhibitory factor impairs murine airway allergic responses. J Immunol. 2006 Nov 01; 177(9):5779-84.
Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, Sheppard D, Chapman HA. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A. 2006 Aug 29; 103(35):13180-5.
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.
DeMeo D, Mariani T, Lange C, Lake S, Litonjua A, Celedón J, Reilly J, Chapman HA, Sparrow D, Spira A, Beane J, Pinto-Plata V, Speizer FE, Shapiro S, Weiss ST, Silverman EK. The SERPINE2 gene is associated with chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2006 Aug; 3(6):502.
Ghosh S, Johnson JJ, Sen R, Mukhopadhyay S, Liu Y, Zhang F, Wei Y, Chapman HA, Stack MS. Functional relevance of urinary-type plasminogen activator receptor-alpha3beta1 integrin association in proteinase regulatory pathways. J Biol Chem. 2006 May 12; 281(19):13021-9.
Wang B, Sun J, Kitamoto S, Yang M, Grubb A, Chapman HA, Kalluri R, Shi GP. Cathepsin S controls angiogenesis and tumor growth via matrix-derived angiogenic factors. J Biol Chem. 2006 Mar 03; 281(9):6020-9.
Demeo DL, Mariani TJ, Lange C, Srisuma S, Litonjua AA, Celedon JC, Lake SL, Reilly JJ, Chapman HA, Mecham BH, Haley KJ, Sylvia JS, Sparrow D, Spira AE, Beane J, Pinto-Plata V, Speizer FE, Shapiro SD, Weiss ST, Silverman EK. The SERPINE2 gene is associated with chronic obstructive pulmonary disease. Am J Hum Genet. 2006 Feb; 78(2):253-64.
Kala M, Chen CR, McLachlan SM, Rapoport B, Aliesky H, Chapman HA. Cathepsin S is not crucial to TSHR processing and presentation in a murine model of Graves' disease. Immunology. 2005 Dec; 116(4):532-40.
Kelleher CM, Silverman EK, Broekelmann T, Litonjua AA, Hernandez M, Sylvia JS, Stoler J, Reilly JJ, Chapman HA, Speizer FE, Weiss ST, Mecham RP, Raby BA. A functional mutation in the terminal exon of elastin in severe, early-onset chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 2005 Oct; 33(4):355-62.
Zheng T, Kang MJ, Crothers K, Zhu Z, Liu W, Lee CG, Rabach LA, Chapman HA, Homer RJ, Aldous D, De Sanctis GT, Desanctis G, Underwood S, Graupe M, Flavell RA, Schmidt JA, Elias JA. Role of cathepsin S-dependent epithelial cell apoptosis in IFN-gamma-induced alveolar remodeling and pulmonary emphysema. J Immunol. 2005 Jun 15; 174(12):8106-15.
Wei Y, Czekay RP, Robillard L, Kugler MC, Zhang F, Kim KK, Xiong JP, Humphries MJ, Chapman HA. Regulation of alpha5beta1 integrin conformation and function by urokinase receptor binding. J Cell Biol. 2005 Jan 31; 168(3):501-11.
Sukhova GK, Wang B, Libby P, Pan JH, Zhang Y, Grubb A, Fang K, Chapman HA, Shi GP. Cystatin C deficiency increases elastic lamina degradation and aortic dilatation in apolipoprotein E-null mice. Circ Res. 2005 Feb 18; 96(3):368-75.
DeMeo DL, Celedón JC, Lange C, Reilly JJ, Chapman HA, Sylvia JS, Speizer FE, Weiss ST, Silverman EK. Genome-wide linkage of forced mid-expiratory flow in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2004 Dec 15; 170(12):1294-301.
Pan JH, Sukhova GK, Yang JT, Wang B, Xie T, Fu H, Zhang Y, Satoskar AR, David JR, Metz CN, Bucala R, Fang K, Simon DI, Chapman HA, Libby P, Shi GP. Macrophage migration inhibitory factor deficiency impairs atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation. 2004 Jun 29; 109(25):3149-53.
Celedón JC, Lange C, Raby BA, Litonjua AA, Palmer LJ, DeMeo DL, Reilly JJ, Kwiatkowski DJ, Chapman HA, Laird N, Sylvia JS, Hernandez M, Speizer FE, Weiss ST, Silverman EK. The transforming growth factor-beta1 (TGFB1) gene is associated with chronic obstructive pulmonary disease (COPD). Hum Mol Genet. 2004 Aug 01; 13(15):1649-56.
DeClerck YA, Mercurio AM, Stack MS, Chapman HA, Zutter MM, Muschel RJ, Raz A, Matrisian LM, Sloane BF, Noel A, Hendrix MJ, Coussens L, Padarathsingh M. Proteases, extracellular matrix, and cancer: a workshop of the path B study section. Am J Pathol. 2004 Apr; 164(4):1131-9.
Zhang F, Tom CC, Kugler MC, Ching TT, Kreidberg JA, Wei Y, Chapman HA. Distinct ligand binding sites in integrin alpha3beta1 regulate matrix adhesion and cell-cell contact. J Cell Biol. 2003 Oct 13; 163(1):177-88.
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.
Palmer LJ, Celedón JC, Chapman HA, Speizer FE, Weiss ST, Silverman EK. Genome-wide linkage analysis of bronchodilator responsiveness and post-bronchodilator spirometric phenotypes in chronic obstructive pulmonary disease. Hum Mol Genet. 2003 May 15; 12(10):1199-210.
Stüve O, Youssef S, Slavin AJ, King CL, Patarroyo JC, Hirschberg DL, Brickey WJ, Soos JM, Piskurich JF, Chapman HA, Zamvil SS. The role of the MHC class II transactivator in class II expression and antigen presentation by astrocytes and in susceptibility to central nervous system autoimmune disease. J Immunol. 2002 Dec 15; 169(12):6720-32.
Crystal RG, Bitterman PB, Mossman B, Schwarz MI, Sheppard D, Almasy L, Chapman HA, Friedman SL, King TE, Leinwand LA, Liotta L, Martin GR, Schwartz DA, Schultz GS, Wagner CR, Musson RA. Future research directions in idiopathic pulmonary fibrosis: summary of a National Heart, Lung, and Blood Institute working group. Am J Respir Crit Care Med. 2002 Jul 15; 166(2):236-46.
Wu ZQ, Shen Y, Khan AQ, Chu CL, Riese R, Chapman HA, Kanagawa O, Snapper CM. The mechanism underlying T cell help for induction of an antigen-specific in vivo humoral immune response to intact Streptococcus pneumoniae is dependent on the type of antigen. J Immunol. 2002 Jun 01; 168(11):5551-7.
Mathieu MA, Bogyo M, Caffrey CR, Choe Y, Lee J, Chapman H, Sajid M, Craik CS, McKerrow JH. Substrate specificity of schistosome versus human legumain determined by P1-P3 peptide libraries. Mol Biochem Parasitol. 2002 Apr 30; 121(1):99-105.
Silverman EK, Palmer LJ, Mosley JD, Barth M, Senter JM, Brown A, Drazen JM, Kwiatkowski DJ, Chapman HA, Campbell EJ, Province MA, Rao DC, Reilly JJ, Ginns LC, Speizer FE, Weiss ST. Genomewide linkage analysis of quantitative spirometric phenotypes in severe early-onset chronic obstructive pulmonary disease. Am J Hum Genet. 2002 May; 70(5):1229-39.
Silverman EK, Mosley JD, Palmer LJ, Barth M, Senter JM, Brown A, Drazen JM, Kwiatkowski DJ, Chapman HA, Campbell EJ, Province MA, Rao DC, Reilly JJ, Ginns LC, Speizer FE, Weiss ST. Genome-wide linkage analysis of severe, early-onset chronic obstructive pulmonary disease: airflow obstruction and chronic bronchitis phenotypes. Hum Mol Genet. 2002 Mar 15; 11(6):623-32.
Zhu S, Gladson CL, Stewart J, White KE, Chapman HA, Olman MA. Adenovirally mediated expression of urokinase receptor binding site on integrin alpha-chain blocks adhesion and migration of human lung fibroblasts. Chest. 2002 Mar; 121(3 Suppl):34S-35S.
Fong S, Doyle MV, Goodson RJ, Drummond RJ, Stratton JR, McGuire L, Doyle LV, Chapman HA, Rosenberg S. Random peptide bacteriophage display as a probe for urokinase receptor ligands. Biol Chem. 2002 Jan; 383(1):149-58.