Harold Chapman, MD

Professor

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.
Honors and Awards
  • Merit Award, National Institute of Health, 2001-2012
  • American Association of Physicians, 1998
  • American Society for Clinical Investigation, 1987
Websites
Publications
  1. Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis.
  2. Reversal of TGFß1-Driven Profibrotic State in Patients with Pulmonary Fibrosis.
  3. VEGF Drives the Car toward Better Gas Exchange.
  4. Distinct Airway Epithelial Stem Cells Hide among Club Cells but Mobilize to Promote Alveolar Regeneration.
  5. Secretion of leukotrienes by senescent lung fibroblasts promotes pulmonary fibrosis.
  6. Yap/Taz regulate alveolar regeneration and resolution of lung inflammation.
  7. Small molecule inhibition of IRE1a kinase/RNase has anti-fibrotic effects in the lung.
  8. Idiopathic Pulmonary Fibrosis: Cell Death and Inflammation Revisited.
  9. Expansion of hedgehog disrupts mesenchymal identity and induces emphysema phenotype.
  10. TGF-ß1 Signaling and Tissue Fibrosis.
  11. Fibroblast-specific inhibition of TGF-ß1 signaling attenuates lung and tumor fibrosis.
  12. Local lung hypoxia determines epithelial fate decisions during alveolar regeneration.
  13. Hypoxia-Inducible Factor 1a Signaling Promotes Repair of the Alveolar Epithelium after Acute Lung Injury.
  14. Failure of Alveolar Type 2 Cell Maintenance Links Neonatal Distress with Adult Lung Disease.
  15. Persistent Pathology in Influenza-Infected Mouse Lungs.
  16. Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury.
  17. Innate antiviral host defense attenuates TGF-ß function through IRF3-mediated suppression of Smad signaling.
  18. Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function.
  19. Soluble urokinase-type plasminogen activator receptor in FSGS: stirred but not shaken.
  20. Urokinase-type plasminogen activator receptor (uPAR) ligation induces a raft-localized integrin signaling switch that mediates the hypermotile phenotype of fibrotic fibroblasts.
  21. Future directions in idiopathic pulmonary fibrosis research. An NHLBI workshop report.
  22. Inhibition of epithelial-to-mesenchymal transition and pulmonary fibrosis by methacycline.
  23. BPIFB1 is a lung-specific autoantigen associated with interstitial lung disease.
  24. Activated alveolar epithelial cells initiate fibrosis through secretion of mesenchymal proteins.
  25. Cell therapy for lung diseases. Report from an NIH-NHLBI workshop, November 13-14, 2012.
  26. Molecular determinants of lung development.
  27. Cathepsin F mutations cause Type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis.
  28. Identification of pY654-ß-catenin as a critical co-factor in hypoxia-inducible factor-1a signaling and tumor responses to hypoxia.
  29. Regenerative activity of the lung after epithelial injury.
  30. Epithelial responses to lung injury: role of the extracellular matrix.
  31. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors.
  32. Axin pathway activity regulates in vivo pY654-ß-catenin accumulation and pulmonary fibrosis.
  33. Integrin a6ß4 identifies an adult distal lung epithelial population with regenerative potential in mice.
  34. Cell plasticity in lung injury and repair: report from an NHLBI workshop, April 19-20, 2010.
  35. Toward lung regeneration.
  36. Alveolar epithelial cells express mesenchymal proteins in patients with idiopathic pulmonary fibrosis.
  37. Epithelial-mesenchymal interactions in pulmonary fibrosis.
  38. Urokinase receptor mediates lung fibroblast attachment and migration toward provisional matrix proteins through interaction with multiple integrins.
  39. Coordinate integrin and c-Met signaling regulate Wnt gene expression during epithelial morphogenesis.
  40. Integrin alpha3beta1-dependent beta-catenin phosphorylation links epithelial Smad signaling to cell contacts.
  41. Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis.
  42. Signaling through urokinase and urokinase receptor in lung cancer cells requires interactions with beta1 integrins.
  43. The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor.
  44. Endothelin-1 as initiator of epithelial-mesenchymal transition: potential new role for endothelin-1 during pulmonary fibrosis.
  45. Urokinase receptors are required for alpha 5 beta 1 integrin-mediated signaling in tumor cells.
  46. Cutting edge: Deficiency of macrophage migration inhibitory factor impairs murine airway allergic responses.
  47. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix.
  48. Cathepsins L and S are not required for activation of dipeptidyl peptidase I (cathepsin C) in mice.
  49. The SERPINE2 gene is associated with chronic obstructive pulmonary disease.
  50. Functional relevance of urinary-type plasminogen activator receptor-alpha3beta1 integrin association in proteinase regulatory pathways.
  51. Murine cathepsin F deficiency causes neuronal lipofuscinosis and late-onset neurological disease.
  52. Cathepsin S controls angiogenesis and tumor growth via matrix-derived angiogenic factors.
  53. The SERPINE2 gene is associated with chronic obstructive pulmonary disease.
  54. Endosomal proteases in antigen presentation.
  55. Cathepsin S is not crucial to TSHR processing and presentation in a murine model of Graves' disease.
  56. A functional mutation in the terminal exon of elastin in severe, early-onset chronic obstructive pulmonary disease.
  57. Role of cathepsin S-dependent epithelial cell apoptosis in IFN-gamma-induced alveolar remodeling and pulmonary emphysema.
  58. Cathepsin S is required for murine autoimmune myasthenia gravis pathogenesis.
  59. Regulation of alpha5beta1 integrin conformation and function by urokinase receptor binding.
  60. Cystatin C deficiency increases elastic lamina degradation and aortic dilatation in apolipoprotein E-null mice.
  61. Transient role for CD1d-restricted natural killer T cells in the formation of atherosclerotic lesions.
  62. Genome-wide linkage of forced mid-expiratory flow in chronic obstructive pulmonary disease.
  63. Macrophage migration inhibitory factor deficiency impairs atherosclerosis in low-density lipoprotein receptor-deficient mice.
  64. The transforming growth factor-beta1 (TGFB1) gene is associated with chronic obstructive pulmonary disease (COPD).
  65. Cathepsins as transcriptional activators?
  66. Familial aggregation of FEF(25-75) and FEF(25-75)/FVC in families with severe, early onset COPD.
  67. Proteases, extracellular matrix, and cancer: a workshop of the path B study section.
  68. Disorders of lung matrix remodeling.
  69. Distinct ligand binding sites in integrin alpha3beta1 regulate matrix adhesion and cell-cell contact.
  70. Mast cell cathepsins C and S control levels of carboxypeptidase A and the chymase, mouse mast cell protease 5.
  71. Matrilysin-dependent elastolysis by human macrophages.
  72. Genome-wide linkage analysis of bronchodilator responsiveness and post-bronchodilator spirometric phenotypes in chronic obstructive pulmonary disease.
  73. Deficiency of the cysteine protease cathepsin S impairs microvessel growth.
  74. Urokinase receptor and integrin interactions.
  75. 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.
  76. Future research directions in idiopathic pulmonary fibrosis: summary of a National Heart, Lung, and Blood Institute working group.
  77. 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.
  78. Substrate specificity of schistosome versus human legumain determined by P1-P3 peptide libraries.
  79. Genomewide linkage analysis of quantitative spirometric phenotypes in severe early-onset chronic obstructive pulmonary disease.
  80. Genome-wide linkage analysis of severe, early-onset chronic obstructive pulmonary disease: airflow obstruction and chronic bronchitis phenotypes.
  81. Adenovirally mediated expression of urokinase receptor binding site on integrin alpha-chain blocks adhesion and migration of human lung fibroblasts.
  82. Random peptide bacteriophage display as a probe for urokinase receptor ligands.
  83. Regulation of CD1 function and NK1.1(+) T cell selection and maturation by cathepsin S.
  84. Urokinase receptors promote beta1 integrin function through interactions with integrin alpha3beta1.
  85. Protease crosstalk with integrins: the urokinase receptor paradigm.
  86. Expression of cathepsins B and S in the progression of prostate carcinoma.
  87. Interferon gamma induction of pulmonary emphysema in the adult murine lung.
  88. Gender-related differences in severe, early-onset chronic obstructive pulmonary disease.
  89. Importance of lysosomal cysteine proteases in lung disease.
  90. Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase- and cathepsin-dependent emphysema.
  91. Simple modifications of the serpin reactive site loop convert SCCA2 into a cysteine proteinase inhibitor: a critical role for the P3' proline in facilitating RSL cleavage.
  92. Protease injury in the development of COPD: Thomas A. Neff Lecture.
  93. Identification of a urokinase receptor-integrin interaction site. Promiscuous regulator of integrin function.
  94. Role for cathepsin F in invariant chain processing and major histocompatibility complex class II peptide loading by macrophages.
  95. Early endosomal maturation of MHC class II molecules independently of cysteine proteases and H-2DM.
  96. Nonproteolytic role for the urokinase receptor in cellular migration in vivo.
  97. Cathepsins and compartmentalization in antigen presentation.
  98. Proteases involved in MHC class II antigen presentation.
  99. Cathepsin S controls the trafficking and maturation of MHC class II molecules in dendritic cells.
  100. Cystatin C deficiency in human atherosclerosis and aortic aneurysms.
  101. Role of urokinase receptor and caveolin in regulation of integrin signaling.
  102. A Fas pathway to pulmonary fibrosis.
  103. A role for caveolin and the urokinase receptor in integrin-mediated adhesion and signaling.
  104. Cathepsin S required for normal MHC class II peptide loading and germinal center development.
  105. Human cathepsin F. Molecular cloning, functional expression, tissue localization, and enzymatic characterization.
  106. Fc epsilon receptor I on dendritic cells delivers IgE-bound multivalent antigens into a cathepsin S-dependent pathway of MHC class II presentation.
  107. Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells.
  108. Cathepsin S activity regulates antigen presentation and immunity.
  109. Genetic epidemiology of severe, early-onset chronic obstructive pulmonary disease. Risk to relatives for airflow obstruction and chronic bronchitis.
  110. Cross-class inhibition of the cysteine proteinases cathepsins K, L, and S by the serpin squamous cell carcinoma antigen 1: a kinetic analysis.
  111. Endosomal proteolysis and MHC class II function.
  112. Identification of high-affinity binding sites for the insulin sensitizer rosiglitazone (BRL-49653) in rodent and human adipocytes using a radioiodinated ligand for peroxisomal proliferator-activated receptor gamma.
  113. Plasminogen activators, integrins, and the coordinated regulation of cell adhesion and migration.
  114. Degradation of mouse invariant chain: roles of cathepsins S and D and the influence of major histocompatibility complex polymorphism.
  115. Plasmin and plasminogen activator inhibitor type 1 promote cellular motility by regulating the interaction between the urokinase receptor and vitronectin.
  116. Structure and chromosomal assignment of the human cathepsin K gene.
  117. Emerging roles for cysteine proteases in human biology.
  118. Mac-1 (CD11b/CD18) and the urokinase receptor (CD87) form a functional unit on monocytic cells.
  119. Regulation of integrin function by the urokinase receptor.
  120. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency.
  121. Mechanisms of pertussis toxin-induced myelomonocytic cell adhesion: role of Mac-1(CD11b/CD18) and urokinase receptor (CD87).
  122. Essential role for cathepsin S in MHC class II-associated invariant chain processing and peptide loading.
  123. Lysosomal processing of amyloid precursor protein to A beta peptides: a distinct role for cathepsin S.
  124. Urokinase receptor is a multifunctional protein: influence of receptor occupancy on macrophage gene expression.
  125. The lysosomal cysteine protease, cathepsin S, is increased in Alzheimer's disease and Down syndrome brain. An immunocytochemical study.
  126. Molecular cloning of human cathepsin O, a novel endoproteinase and homologue of rabbit OC2.
  127. Identification of the urokinase receptor as an adhesion receptor for vitronectin.
  128. The role of thiol proteases in tissue injury and remodeling.
  129. Reversible cellular adhesion to vitronectin linked to urokinase receptor occupancy.
  130. Human cathepsin S: chromosomal localization, gene structure, and tissue distribution.
  131. Human alveolar macrophages have 15-lipoxygenase and generate 15(S)-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid and lipoxins.
  132. Cytokines induce urokinase-dependent adhesion of human myeloid cells. A regulatory role for plasminogen activator inhibitors.
  133. Molecular cloning and expression of human alveolar macrophage cathepsin S, an elastinolytic cysteine protease.
  134. A serine esterase released by human alveolar macrophages is closely related to liver microsomal carboxylesterases.
  135. Cigarette smoking induces an elastolytic cysteine proteinase in macrophages distinct from cathepsin L.
  136. An autocrine role for urokinase in phorbol ester-mediated differentiation of myeloid cell lines.
  137. Role of enzyme receptors and inhibitors in regulating proteolytic activities of macrophages.
  138. Alveolar macrophage urokinase receptors localize enzyme activity to the cell surface.
  139. Developmental expression of plasminogen activator inhibitor type 1 by human alveolar macrophages. Possible role in lung injury.
  140. Uptake of extracellular enzyme by a novel pathway is a major determinant of cathepsin L levels in human macrophages.
  141. Depressed bronchoalveolar urokinase activity in patients with adult respiratory distress syndrome.
  142. Identification of cystatin C, a cysteine proteinase inhibitor, as a major secretory product of human alveolar macrophages in vitro.
  143. Synthesis and processing of cathepsin L, an elastase, by human alveolar macrophages.
  144. Association between alveolar macrophage plasminogen activator activity and indices of lung function in young cigarette smokers.
  145. Role of enzymes mediating thrombosis and thrombolysis in lung disease.
  146. In vitro assay of extracellular matrix elastin degradation.
  147. Role of plasminogen activator in degradation of extracellular matrix protein by live human alveolar macrophages.
  148. Abnormalities in pathways of alveolar fibrin turnover among patients with interstitial lung disease.
  149. Elastinolytic activity of human cathepsin L.
  150. A fibrinolytic inhibitor of human alveolar macrophages. Induction with endotoxin.
  151. Characterization of a macrophage-derived plasminogen-activator inhibitor. Similarities with placental urokinase inhibitor.
  152. Human alveolar macrophages synthesize factor VII in vitro. Possible role in interstitial lung disease.
  153. Comparison of live human neutrophil and alveolar macrophage elastolytic activity in vitro. Relative resistance of macrophage elastolytic activity to serum and alveolar proteinase inhibitors.
  154. Co-operation between plasmin and elastase in elastin degradation by intact murine macrophages.
  155. Degradation of fibrin and elastin by intact human alveolar macrophages in vitro. Characterization of a plasminogen activator and its role in matrix degradation.
  156. Coordinate expression of macrophage procoagulant and fibrinolytic activity in vitro and in vivo.
  157. Macrophage fibrinolytic activity: identification of two pathways of plasmin formation by intact cells and of a plasminogen activator inhibitor.
  158. Modulation of plasminogen activator secretion by activated macrophages: influence of serum factors and correlation with tumoricidal potential.
  159. Ontogeny of Peyer's patches and immunoglobulin-containing cells in pigs.