Research Summary

I have had a longstanding interest and productive history in the field of tissue remodeling, particularly as it relates to lung disease and have been continuously RO1 funded since 1991. I have also had virtually two research lives. For many years my work primarily focused on proteolytic enzymes. My group cloned and characterized several new members of the cathepsin family and elucidated their roles in bone, lung, and immune disorders. I also pursued basic mechanisms by which proteases and adhesion receptors coordinate cell invasion and extracellular matrix remodeling. We were the first to recognize a physical association between proteases (urokinase) and integrins important to migration and invasion. However, after moving to UCSF I have focused my lab on epithelial biology and in particularly pulmonary fibrosis as a disorder of great, unmet medical need and a logical extension of my prior work in matrix biology. I led in vivo investigations of the role of epithelial mesenchymal transition (EMT) in pulmonary fibrosis and in the course of studying epithelial plasticity we discovered a population of lung epithelial progenitors expressing the integrin alpha6/beta4 capable of regenerative activity in vitro and in vivo in response to major injury. Follow-up studies referenced below led to the discovery that the actual stem/progenitor cells are relatively rare distal airway epithelial subpopulations low in mature lineage markers, identifiable in mice by high levels of the Class I antigen H2K-1, and capable of rapid mobilization, proliferation, and pluripotent differentiation in vivo. In humans we have recently identified Type II cells as much more plastic than that of mice, capable of transdiifferentiation and expansion as metaplastic basal cells after major injury. So, in mice airway progenitors mobilize and migrate into alveoli. In humans, alveolar Type II cells transdifferentiate and execute early lung repair locally. This is a surprising finding that is likely to be a major lab focus for the next several years. My lab now is comprised of mainly PhD trainees and research faculty. We are committed to a mechanistic understanding of the cellular basis of alveolar regeneration after lung injury.

I have trained over 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.

Research Funding

  • February 15, 2020 - January 31, 2027 - Program to promote lung regeneration and block fibrosis , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R35HL150767
  • September 21, 2016 - May 31, 2023 - Epithelial stem/progenitor cells as repair agents in diffuse alveolar damage , Principal Investigator . Sponsor: NIH, Sponsor Award ID: U01HL134766
  • July 15, 2015 - April 30, 2020 - Epithelial Stem/Progenitor Cells in Repair of the Injured Lung , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01HL128484
  • February 1, 2019 - January 31, 2020 - LOXL-2 dependent blockade of TGF Beta1 signaling and lung fibrosis , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01HL142265
  • August 9, 2012 - July 31, 2018 - Targeting epithelial cells to treat pulmonary fibrosis , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P01HL108794
  • January 1, 2012 - December 31, 2016 - Epithelial Progenitor Cells in Lung Repair and Regeneration , Principal Investigator . Sponsor: NIH, Sponsor Award ID: U01HL111054
  • January 1, 1991 - December 31, 2014 - Epithelial Mesenchymal Transition in Pulmonary Fibrosis , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01HL044712
  • July 1, 2007 - May 31, 2013 - Urokinase Receptor Integrin Interactions in Lung Cancer , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01CA125564
  • June 1, 2001 - May 31, 2012 - Role of Elastolytic Cathepsins in Emphysema , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R37HL067204
  • December 1, 2008 - May 31, 2009 - Identification, Isolation, and Reprogramming Alveolar Epithelial Progenitor Cells , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R03HL096269
  • January 1, 1993 - December 31, 2007 - Cysteine Proteases in MHC Class II Antigen Presentation , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01HL048261
  • August 20, 1995 - July 31, 1998 - CATHEPSIN S AND ALZHEIMERS DISEASE , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01AG012959
  • September 30, 1985 - March 31, 1989 - INTERACTION OF HUMAN ALVEOLAR MACROPHAGES WIH FIBRIN , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01HL036548
  • December 1, 1985 - June 30, 1988 - ROLE OF HUMAN ALVEOLAR MACROPHAGES IN EMPHYSEMA , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01HL036563
  • July 1, 1985 - August 31, 1985 - ROLE OF HUMAN ALVEOLAR MACROPHAGES IN EMPHYSEMA , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01HL033945

Education

Tulane University, 1968, Premedical
University of Alabama School of Medicine, M.D., 1972, Medicine

Honors & Awards

  • 1972
    Alpha Omega Alpha, University of Alabama School of Medicine
  • 1985-1990
    Career Investigator Award, American Lung Association
  • 1987
    American Society for Clinical Investigation
  • 1998
    American Association of Physicians
  • 2001
    MERIT Award, NIH/NHLBI

Selected Publications

  1. Cohen ML, Brumwell AN, Ho TC, Garakani K, Montas G, Leong D, Ding VW, Golden JA, Trinh BN, Jablons DM, Matthay MA, Jones KD, Wolters PJ, Wei Y, Chapman HA, Le Saux CJ. A fibroblast-dependent TGF-β1/sFRP2 noncanonical Wnt signaling axis promotes epithelial metaplasia in idiopathic pulmonary fibrosis. J Clin Invest. 2024 Jul 09; 134(18).  View on PubMed
  2. Le Saux CJ, Ho TC, Brumwell AM, Kathiriya JJ, Wei Y, Hughes JB, Garakani K, Atabai K, Auyeung VC, Papa FR, Chapman HA. BCL-2 Modulates IRE1α Activation to Attenuate Endoplasmic Reticulum Stress and Pulmonary Fibrosis. Am J Respir Cell Mol Biol. 2024 Apr; 70(4):247-258.  View on PubMed
  3. Cohen ML, Brumwell AN, Che Ho T, Montas G, Golden JA, Jones KD, Wolters PJ, Wei Y, Chapman HA, Le Saux CJ. A fibroblast-dependent TGFβ1/sFRP2 noncanonical Wnt signaling axis underlies epithelial metaplasia in idiopathic pulmonary fibrosis. bioRxiv. 2023 Aug 04.  View on PubMed
  4. Basil MC, Cardenas-Diaz FL, Kathiriya JJ, Morley MP, Carl J, Brumwell AN, Katzen J, Slovik KJ, Babu A, Zhou S, Kremp MM, McCauley KB, Li S, Planer JD, Hussain SS, Liu X, Windmueller R, Ying Y, Stewart KM, Oyster M, Christie JD, Diamond JM, Engelhardt JF, Cantu E, Rowe SM, Kotton DN, Chapman HA, Morrisey EE. Human distal airways contain a multipotent secretory cell that can regenerate alveoli. Nature. 2022 04; 604(7904):120-126.  View on PubMed
  5. Kathiriya JJ, Wang C, Zhou M, Brumwell A, Cassandras M, Le Saux CJ, Cohen M, Alysandratos KD, Wang B, Wolters P, Matthay M, Kotton DN, Chapman HA, Peng T. Human alveolar type 2 epithelium transdifferentiates into metaplastic KRT5+ basal cells. Nat Cell Biol. 2022 01; 24(1):10-23.  View on PubMed
  6. Chapman HA. Nuclear IL-33 as a growth and survival agent within basal cells. J Clin Invest. 2021 10 01; 131(19).  View on PubMed
  7. Bota-Rabassedas N, Banerjee P, Niu Y, Cao W, Luo J, Xi Y, Tan X, Sheng K, Ahn YH, Lee S, Parra ER, Rodriguez-Canales J, Albritton J, Weiger M, Liu X, Guo HF, Yu J, Rodriguez BL, Firestone JJA, Mino B, Creighton CJ, Solis LM, Villalobos P, Raso MG, Sazer DW, Gibbons DL, Russell WK, Longmore GD, Wistuba II, Wang J, Chapman HA, Miller JS, Zong C, Kurie JM. Contextual cues from cancer cells govern cancer-associated fibroblast heterogeneity. Cell Rep. 2021 04 20; 35(3):109009.  View on PubMed
  8. Wei Y, Dong W, Jackson J, Ho TC, Le Saux CJ, Brumwell A, Li X, Klesney-Tait J, Cohen ML, Wolters PJ, Chapman HA. Blocking LOXL2 and TGFβ1 signalling induces collagen I turnover in precision-cut lung slices derived from patients with idiopathic pulmonary fibrosis. Thorax. 2021 07; 76(7):729-732.  View on PubMed
  9. Peng DH, Rodriguez BL, Diao L, Chen L, Wang J, Byers LA, Wei Y, Chapman HA, Yamauchi M, Behrens C, Raso G, Soto LMS, Cuentes ERP, Wistuba II, Kurie JM, Gibbons DL. Collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8+ T cell exhaustion. Nat Commun. 2020 09 09; 11(1):4520.  View on PubMed
  10. Strunz M, Simon LM, Ansari M, Kathiriya JJ, Angelidis I, Mayr CH, Tsidiridis G, Lange M, Mattner LF, Yee M, Ogar P, Sengupta A, Kukhtevich I, Schneider R, Zhao Z, Voss C, Stoeger T, Neumann JHL, Hilgendorff A, Behr J, O'Reilly M, Lehmann M, Burgstaller G, Königshoff M, Chapman HA, Theis FJ, Schiller HB. Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis. Nat Commun. 2020 07 16; 11(1):3559.  View on PubMed
  11. Chapman HA, Wei Y, Montas G, Leong D, Golden JA, Trinh BN, Wolters PJ, Le Saux CJ, Jones KD, Hills NK, Foster E, Oldham JM, Linderholm AL, Kotak P, Decaris M, Turner S, Song JW. Reversal of TGFβ1-Driven Profibrotic State in Patients with Pulmonary Fibrosis. N Engl J Med. 2020 03 12; 382(11):1068-1070.  View on PubMed
  12. Kathiriya JJ, Chapman HA. VEGF Drives the Car toward Better Gas Exchange. Dev Cell. 2020 03 09; 52(5):546-547.  View on PubMed
  13. Kathiriya JJ, Brumwell AN, Jackson JR, Tang X, Chapman HA. Distinct Airway Epithelial Stem Cells Hide among Club Cells but Mobilize to Promote Alveolar Regeneration. Cell Stem Cell. 2020 03 05; 26(3):346-358.e4.  View on PubMed
  14. Wiley CD, Brumwell AN, Davis SS, Jackson JR, Valdovinos A, Calhoun C, Alimirah F, Castellanos CA, Ruan R, Wei Y, Chapman HA, Ramanathan A, Campisi J, Jourdan Le Saux C. Secretion of leukotrienes by senescent lung fibroblasts promotes pulmonary fibrosis. JCI Insight. 2019 12 19; 4(24).  View on PubMed
  15. Egia-Mendikute L, Arpa B, Rosell-Mases E, Corral-Pujol M, Carrascal J, Carrillo J, Mora C, Chapman H, Panosa A, Vives-Pi M, Stratmann T, Serreze D, Verdaguer J. B-Lymphocyte Phenotype Determines T-Lymphocyte Subset Differentiation in Autoimmune Diabetes. Front Immunol. 2019; 10:1732.  View on PubMed
  16. LaCanna R, Liccardo D, Zhang P, Tragesser L, Wang Y, Cao T, Chapman HA, Morrisey EE, Shen H, Koch WJ, Kosmider B, Wolfson MR, Tian Y. Yap/Taz regulate alveolar regeneration and resolution of lung inflammation. J Clin Invest. 2019 04 15; 129(5):2107-2122.  View on PubMed
  17. Thamsen M, Ghosh R, Auyeung VC, Brumwell A, Chapman HA, Backes BJ, Perara G, Maly DJ, Sheppard D, Papa FR. Small molecule inhibition of IRE1α kinase/RNase has anti-fibrotic effects in the lung. PLoS One. 2019; 14(1):e0209824.  View on PubMed
  18. Le Saux CJ, Chapman HA. Idiopathic Pulmonary Fibrosis: Cell Death and Inflammation Revisited. Am J Respir Cell Mol Biol. 2018 08; 59(2):137-138.  View on PubMed
  19. Wang C, de Mochel NSR, Christenson SA, Cassandras M, Moon R, Brumwell AN, Byrnes LE, Li A, Yokosaki Y, Shan P, Sneddon JB, Jablons D, Lee PJ, Matthay MA, Chapman HA, Peng T. Expansion of hedgehog disrupts mesenchymal identity and induces emphysema phenotype. J Clin Invest. 2018 10 01; 128(10):4343-4358.  View on PubMed
  20. Kim KK, Sheppard D, Chapman HA. TGF-β1 Signaling and Tissue Fibrosis. Cold Spring Harb Perspect Biol. 2018 04 02; 10(4).  View on PubMed

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