Small airway fibrosis (bronchiolitis obliterans syndrome) is the primary obstacle to long-term survival following lung transplantation. Here, we show the importance of functional microvasculature in the prevention of epithelial loss and fibrosis due to rejection and for the first time, relate allograft microvascular injury and loss of tissue perfusion to immunotherapy-resistant rejection. To explore the role of alloimmune rejection and airway ischemia in the development of fibroproliferation, we used a murine orthotopic tracheal transplant model. We determined that transplants were reperfused by connection of recipient vessels to donor vessels at the surgical anastomosis site. Microcirculation through the newly formed vascular anastomoses appeared partially dependent on VEGFR2 and CXCR2 pathways. In the absence of immunosuppression, the microvasculature in rejecting allografts exhibited vascular complement deposition, diminished endothelial CD31 expression, and absent perfusion prior to the onset of fibroproliferation. Rejecting grafts with extensive endothelial cell injury were refractory to immunotherapy. After early microvascular loss, neovascularization was eventually observed in the membranous trachea, indicating a reestablishment of graft perfusion in established fibrosis. One implication of this study is that bronchial artery revascularization at the time of lung transplantation may decrease the risk of subsequent airway fibrosis.
Ashok N. Babu, Tomohiro Murakawa, Joshua M. Thurman, Edmund J. Miller, Peter M. Henson, Martin R. Zamora, Norbert F. Voelkel, Mark R. Nicolls
Title and authors | Publication | Year |
---|---|---|
Immunomodulation by allograft endothelial cells
Bose S, Do V, Testini C, Jadhav SS, Sailliet N, Kho AT, Komatsu M, Boneschansker L, Kong SW, Wedel J, Briscoe DM |
Frontiers in Transplantation | 2025 |
Targeting CXCR2 signaling in inflammatory lung diseases: neutrophil-driven inflammation and emerging therapies.
Hussain MS, Goyal A, Goyal K, S RJ, Nellore J, Shahwan M, Rekha A, Ali H, Dhanasekaran M, MacLoughlin R, Dua K, Gupta G |
Naunyn-Schmiedeberg's archives of pharmacology | 2025 |
Bronchial anastomotic complications as a microvascular disruption in a mouse model of airway transplantation
Khan MA, Bhusal S, Lau CL, Krupnick AS |
Frontiers in Immunology | 2025 |
Impaired complement regulation drives chronic lung allograft dysfunction after lung transplantation
Kulkarni HS, Tague LK, Calabrese DR, Liao F, Liu Z, Garnica L, Shankar N, Wu X, Kulkarni DH, Bernardt C, Byers D, Chen C, Huang HJ, Witt CA, Hachem RR, Kreisel D, Atkinson JP, Greenland JR, Gelman AE |
bioRxiv | 2024 |
Microvascular Regeneration and Perfusion of Partially Decellularized Tracheal Grafts
Sher AC, Liu L, Izem M, Calyeca J, Meeker MO, Chiang T |
The Laryngoscope | 2024 |
Chronic Graft-Versus-Host Disease: Immune Insights, Therapeutic Advances, and Parallels for Solid Organ Transplantation
Boiko JR, Hill GR |
Transplantation | 2024 |
Regeneration of tracheal neotissue in partially decellularized scaffolds.
Tan ZH, Dharmadhikari S, Liu L, Yu J, Shontz KM, Stack JT, Breuer CK, Reynolds SD, Chiang T |
npj Regenerative Medicine | 2023 |
Partial decellularization eliminates immunogenicity in tracheal allografts
Tan ZH, Liu L, Dharmadhikari S, Shontz KM, Kreber L, Sperber S, Yu J, Byun WY, Nyirjesy SC, Manning A, Reynolds SD, Chiang T |
Bioengineering & Translational Medicine | 2023 |
Successful Early Neovascularization in Composite Tracheal Grafts
Nyirjesy SC, Yu J, Dharmadhikari S, Liu L, Bergman M, Tan ZH, VanKoevering KK, Chiang T |
Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery | 2023 |
Long-Term Chondrocyte Retention in Partially Decellularized Tracheal Grafts
Bergman M, Harwood J, Liu L, Shontz KM, Chan C, Chiang T |
Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery | 2023 |
Targeting Interleukin-10 Restores Graft Microvascular Supply and Airway Epithelium in Rejecting Allografts
S Kazmi, M Khan, T Shamma, A Altuhami, H Ahmed, A Assiri, D Broering |
International journal of molecular sciences | 2022 |
Successful tracheal regeneration using biofabricated autologous analogues without artificial supports
Hiwatashi S, Iwai R, Nakayama Y, Moriwaki T, Okuyama H |
Scientific Reports | 2022 |
IL-10 Mediated Immunomodulation Limits Subepithelial Fibrosis and Repairs Airway Epithelium in Rejecting Airway Allografts
MA Khan, GA Ashoor, T Shamma, F Alanazi, A Altuhami, S Kazmi, HA Ahmed, AM Assiri, DC Broering |
Cells | 2021 |
Microvasculature in murine tracheal allografts after combined therapy with clopidogrel and everolimus
C Heim, A Kuckhahn, M Ramsperger-Gleixner, MR Nicolls, M Weyand, SM Ensminger |
Interactive Cardiovascular and Thoracic Surgery | 2021 |
Hyperbaric oxygen therapy to prevent central airway stenosis after lung transplantation
BD Kraft, K Mahmood, NP Harlan, MG Hartwig, LD Snyder, HB Suliman, SL Shofer |
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation | 2021 |
Hypoxia-induced complement dysregulation is associated with microvascular impairments in mouse tracheal transplants
MA Khan, T Shamma, S Kazmi, A Altuhami, HA Ahmed, AM Assiri, DC Broering |
Journal of Translational Medicine | 2020 |
Bronchiolitis obliterans syndrome and restrictive allograft syndrome after lung transplantation: why are there two distinct forms of chronic lung allograft dysfunction?
M Sato |
Annals of translational medicine | 2020 |
Deconstructing tissue engineered trachea: Assessing the role of synthetic scaffolds, segmental replacement and cell seeding on graft performance
S Dharmadhikari, L Liu, K Shontz, M Wiet, A White, A Goins, H Akula, J Johnson, SD Reynolds, CK Breuer, T Chiang |
Acta Biomaterialia | 2020 |
Spatial and Temporal Analysis of Host Cells in Tracheal Graft Implantation
A Danielson, L Liu, KM Shontz, H Syed, S Dharmadhikari, SD Reynolds, CK Breuer, T Chiang |
The Laryngoscope | 2020 |
Chemokine signaling axis between endothelial and myeloid cells regulates development of pulmonary hypertension associated with pulmonary fibrosis and hypoxia
AC Oliveira, C Fu, Y Lu, MA Williams, L Pi, ML Brantly, CE Ventetuolo, MK Raizada, B Mehrad, EW Scott, AJ Bryant |
American journal of physiology. Lung cellular and molecular physiology | 2019 |
iPSC-derived MSC therapy induces immune tolerance and supports long-term graft survival in mouse orthotopic tracheal transplants
MA Khan, F Alanazi, HA Ahmed, T Shamma, K Kelly, MA Hammad, AO Alawad, AM Assiri, DC Broering |
Stem Cell Research & Therapy | 2019 |
Endothelial Hypoxia-Inducible Factor-2α Is Required for the Maintenance of Airway Microvasculature
X Jiang, W Tian, AB Tu, S Pasupneti, E Shuffle, P Dahms, P Zhang, H Cai, TT Dinh, B Liu, C Cain, AJ Giaccia, EC Butcher, MC Simon, GL Semenza, MR Nicolls |
Circulation | 2019 |
Calcineurin inhibitors augment endothelial-to-mesenchymal transition by enhancing proliferation in association with cytokine-mediated activation
CB Woda, S Bruneau, AL Mak, Z Haskova, K Liu, CC Ghosh, DM Briscoe |
Biochemical and Biophysical Research Communications | 2019 |
Airway hypoxia in lung transplantation
S Pasupneti, MR Nicolls |
Current Opinion in Physiology | 2019 |
Bronchus-associated lymphoid tissue-resident Foxp3+ T lymphocytes prevent antibody-mediated lung rejection
Wenjun Li, Jason M Gauthier, Ryuji Higashikubo, Hsi-Min Hsiao, Satona Tanaka, Linh N Vuong, Jon Ritter, Alice Y. Tong, Brian W Wong, Ramsey Hachem, Varun Puri, Ankit Bharat, Alexander Krupnick, Chyi Hsieh, William M. Baldwin III, Francine Kelly, Scott M Palmer, Andrew Gelman, Daniel Kreisel |
Journal of Clinical Investigation | 2018 |
Diagnosis, Pathophysiology and Experimental Models of Chronic Lung Allograft Rejection:
JM Gauthier, D Ruiz-Pérez, W Li, RR Hachem, V Puri, AE Gelman, D Kreisel |
Transplantation | 2018 |
DEPTOR at the Nexus of Cancer, Metabolism, and Immunity
A Caron, DM Briscoe, D Richard, M Laplante |
Physiological reviews | 2018 |
Microhemorrhage-associated tissue iron enhances the risk for Aspergillus fumigatus invasion in a mouse model of airway transplantation
JL Hsu, OV Manouvakhova, KV Clemons, M Inayathullah, AB Tu, RA Sobel, A Tian, H Nazik, VR Pothineni, S Pasupneti, X Jiang, GS Dhillon, H Bedi, J Rajadas, H Haas, L Aurelian, DA Stevens, MR Nicolls |
Science Translational Medicine | 2018 |
C5a Blockade Increases Regulatory T Cell Numbers and Protects Against Microvascular Loss and Epithelial Damage in Mouse Airway Allografts
MA Khan, F Alanazi, HA Ahmed, A Vater, AM Assiri, DC Broering |
Frontiers in immunology | 2018 |
Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop
Vibha Lama, John Belperio, Jason Christie, Souheil El-Chemaly, Michael Fishbein, Andrew Gelman, Wayne Hancock, Shaf Keshavjee, Daniel Kreisel, Victor E. Laubach, Mark Looney, John F. McDyer, Thalachallour Mohanakumar, Rebecca Shilling, Angela Panoskaltsis-Mortari, David S. Wilkes, Jerry Eu, Mark Nicolls |
JCI Insight | 2017 |
A Critical Role for Airway Microvessels in Lung Transplantation
MR Nicolls, GS Dhillon, N Daddi |
American journal of respiratory and critical care medicine | 2016 |
Microvascular injury after lung transplantation:
MR Nicolls, JL Hsu, X Jiang |
Current Opinion in Organ Transplantation | 2016 |
The intragraft microenvironment as a central determinant of chronic rejection or local immunoregulation/tolerance:
J Wedel, H Nakayama, NM Kochupurakkal, J Koch, M Klagsbrun, DR Bielenberg, DM Briscoe |
Current Opinion in Organ Transplantation | 2016 |
T regulatory Cell–mediated Immunotherapy for Solid Organ Transplantation: A Clinical Perspective
MA Khan |
Molecular Medicine | 2016 |
Hypoxic Gene Expression of Donor Bronchi Linked to Airway Complications after Lung Transplantation
BD Kraft, HB Suliman, EC Colman, K Mahmood, MG Hartwig, CA Piantadosi, SL Shofer |
American journal of respiratory and critical care medicine | 2016 |
Safety of hyperbaric oxygen therapy for management of central airway stenosis after lung transplant
K Mahmood, BD Kraft, K Glisinski, MG Hartwig, NP Harlan, CA Piantadosi, SL Shofer |
Clinical Transplantation | 2016 |
Simultaneously Targeting Myofibroblast Contractility and Extracellular Matrix Cross-Linking as a Therapeutic Concept in Airway Fibrosis
YC Lin, YK Sung, X Jiang, M Peters-Golden, MR Nicolls |
American Journal of Transplantation | 2016 |
Pathology of diacetyl and 2,3-pentanedione airway lesions in a rat model of obliterative bronchiolitis
GP Flake, DL Morgan |
Toxicology | 2016 |
Aspergillus -related pulmonary diseases in lung transplantation
S Pasupneti, O Manouvakhova, Nicolls, JL Hsu |
Medical Mycology | 2016 |
Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection
Ye Cui, Kaifeng Liu, Maria Elena Monzon, Robert Padera, Hao Wang, Gautam George, Demet Toprak, Elie AbdelNour, Emmanuel D'Agostino, Hilary Goldberg, Mark Perrella, Rosanna Forteza, Ivan Rosas, Gary Visner, Souheil El-Chemaly |
Journal of Clinical Investigation | 2015 |
Chronic allograft rejection: a fresh look
J Wedel, S Bruneau, N Kochupurakkal, L Boneschansker, DM Briscoe |
Current Opinion in Organ Transplantation | 2015 |
Translational implications of endothelial cell dysfunction in association with chronic allograft rejection
S Bruneau, J Wedel, F Fakhouri, H Nakayama, L Boneschansker, D Irimia, KP Daly, DM Briscoe |
Pediatric Nephrology | 2015 |
Targeted complement inhibition and microvasculature in transplants: a therapeutic perspective: A therapeutic perspective of transplants
MA Khan, JL Hsu, AM Assiri, DC Broering |
Clinical & Experimental Immunology | 2015 |
Cyclosporine Does Not Prevent Microvascular Loss in Transplantation but Can Synergize With a Neutrophil Elastase Inhibitor, Elafin, to Maintain Graft Perfusion During Acute Rejection: Elafin Promotes Microvascular Perfusion
X Jiang, TT Nguyen, W Tian, YK Sung, K Yuan, J Qian, J Rajadas, JM Sallenave, NP Nickel, VJ Perez, M Rabinovitch, MR Nicolls |
American Journal of Transplantation | 2015 |
Pericytes, Microvasular Dysfunction, and Chronic Rejection:
M Kloc, JZ Kubiak, XC Li, RM Ghobrial |
Transplantation | 2015 |
The Role of Lysophosphatidic Acid on Airway Epithelial Cell Denudation in a Murine Heterotopic Tracheal Transplant Model:
Y Tando, C Ota, M Yamada, S Kamata, M Yamaya, K Kano, S Okudaira, J Aoki, H Kubo |
Transplantation Direct | 2015 |
Macrophages in solid organ transplantation
X Jiang, W Tian, YK Sung, J Qian, MR Nicolls |
Vascular cell | 2014 |
Complement components as potential therapeutic targets for asthma treatment
MA Khan, MR Nicolls, B Surguladze, I Saadoun |
Respiratory Medicine | 2014 |
Graft microvascular disease in solid organ transplantation
X Jiang, YK Sung, W Tian, J Qian, GL Semenza, MR Nicolls |
Journal of Molecular Medicine | 2014 |
Promotion of airway anastomotic microvascular regeneration and alleviation of airway ischemia by deferoxamine nanoparticles
X Jiang, AV Malkovskiy, W Tian, YK Sung, W Sun, JL Hsu, S Manickam, D Wagh, LM Joubert, GL Semenza, J Rajadas, MR Nicolls |
Biomaterials | 2013 |
Rattus Model Utilizing Selective Pulmonary Ischemia Induces Bronchiolitis Obliterans Organizing Pneumonia:
JC Densmore, PM Jeziorczak, AV Clough, KA Pritchard, B Cummens, M Medhora, A Rao, ER Jacobs |
Shock | 2013 |
Targeting complement component 5a promotes vascular integrity and limits airway remodeling
MA Khan, C Maasch, A Vater, S Klussmann, J Morser, LL Leung, C Atkinson, S Tomlinson, PS Heeger, MR Nicolls |
Proceedings of the National Academy of Sciences | 2013 |
Tie2-dependent VHL knockdown promotes airway microvascular regeneration and attenuates invasive growth of Aspergillus fumigatus
X Jiang, JL Hsu, W Tian, K Yuan, M Olcholski, VJ Perez, GL Semenza, MR Nicolls |
Journal of Molecular Medicine | 2013 |
Loss of Basal Cells Precedes Bronchiolitis Obliterans–Like Pathological Changes in a Murine Model of Chlorine Gas Inhalation
EG O’Koren, BL Hogan, MD Gunn |
American journal of respiratory cell and molecular biology | 2013 |
Aspergillus fumigatus invasion increases with progressive airway ischemia
JL Hsu, MA Khan, RA Sobel, X Jiang, KV Clemons, TT Nguyen, DA Stevens, M Martinez, MR Nicolls |
PloS one | 2013 |
Complement-mediated microvascular injury leads to chronic rejection.
Khan MA, Nicolls MR |
Advances in experimental medicine and biology | 2013 |
Targeting the intragraft microenvironment and the development of chronic allograft rejection
O Dormond, M Dufour, T Seto, S Bruneau, DM Briscoe |
Human Immunology | 2012 |
Key Features of the Intragraft Microenvironment that Determine Long-Term Survival Following Transplantation
S Bruneau, CB Woda, KP Daly, L Boneschansker, NG Jain, N Kochupurakkal, AG Contreras, T Seto, DM Briscoe |
Frontiers in immunology | 2012 |
CXCR2: From Bench to Bedside
A Stadtmann, A Zarbock |
Frontiers in immunology | 2012 |
New methods for monitoring dynamic airway tissue oxygenation and perfusion in experimental and clinical transplantation
MA Khan, G Dhillon, X Jiang, YC Lin, MR Nicolls |
American journal of physiology. Lung cellular and molecular physiology | 2012 |
Adenovirus-mediated HIF-1α gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection
Xinguo Jiang, Mohammed Khan, Wen Tian, Joshua Beilke, Ramesh Natarajan, Jon Kosek, Merv Yoder, Gregg L. Semenza, Mark Nicolls |
Journal of Clinical Investigation | 2011 |
Chronic Lung Allograft Rejection and Airway Microvasculature: Is HIF-1 the Missing Link?
David Wilkes |
Journal of Clinical Investigation | 2011 |
CD4 + T Cells and Complement Independently Mediate Graft Ischemia in the Rejection of Mouse Orthotopic Tracheal Transplants
MA Khan, X Jiang, G Dhillon, J Beilke, VM Holers, C Atkinson, S Tomlinson, MR Nicolls |
Circulation research | 2011 |
A novel liposome-based therapy to reduce complement-mediated injury in revascularized tissues
L Goga, SB Pushpakumar, G Perez-Abadia, P Olson, G Anderson, CV Soni, JH Barker, C Maldonado |
The Journal of surgical research | 2010 |
Bronchial blood supply after lung transplantation without bronchial artery revascularization
MR Nicolls, MR Zamora |
Current Opinion in Organ Transplantation | 2010 |
Lung Transplant Airway Hypoxia
GS Dhillon, MR Zamora, JE Roos, D Sheahan, RR Sista, PV der Starre, D Weill, MR Nicolls |
American journal of respiratory and critical care medicine | 2010 |
Immunobiology of Chronic Lung Allograft Dysfunction: New Insights from the Bench and Beyond
RA Shilling, DS Wilkes |
American Journal of Transplantation | 2009 |
Every allograft needs a silver lining
Alan G. Contreras and David M. Briscoe |
Journal of Clinical Investigation | 2007 |