Mohsen Ibrahim1, Xingan Wang2, Carlos A Puyo3, Alessandro Montecalvo2, Howard J Huang4, Ramsey R Hachem4, Claudio Andreetti5, Cecilia Menna5, Ridong Chen6, Alexander S Krupnick7, Daniel Kreisel7, Erino A Rendina5, Andrew E Gelman8. 1. Department of Surgery, Washington University School of Medicine, St. Louis, Missouri; Department of Thoracic Surgery, Sapienza University, Rome, Italy. 2. Department of Surgery, Washington University School of Medicine, St. Louis, Missouri. 3. Departments of Anesthesia. 4. Medicine. 5. Department of Thoracic Surgery, Sapienza University, Rome, Italy. 6. APT Therapeutics Inc, St. Louis, Missouri. 7. Department of Surgery, Washington University School of Medicine, St. Louis, Missouri; Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri. 8. Department of Surgery, Washington University School of Medicine, St. Louis, Missouri; Department of Thoracic Surgery, Sapienza University, Rome, Italy; Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri. Electronic address: gelmana@wudosis.wustl.edu.
Abstract
BACKGROUND: There is accumulating evidence that extracellular adenosine triphosphate (eATP) promotes many of the underlying mechanisms that exacerbate acute lung injury. However, much of these data are from inbred rodent models, indicating the need for further investigation in higher vertebrates to better establish clinical relevance. To this end we evaluated a human recombinant apyrase therapy in a canine warm pulmonary ischemia-reperfusion injury (IRI) model and measured eATP levels in human lung recipients with or without primary lung graft dysfunction (PGD). METHODS: Warm ischemia was induced for 90 minutes in the left lung of 14 mongrel dogs. Seven minutes after reperfusion, the apyrase APT102 (1 mg/kg, n = 7) or saline vehicle (n = 7) was injected into the pulmonary artery. Arterial blood gases were obtained every 30 minutes up to 180 minutes after reperfusion. Bronchioalveolar lavage fluid (BALF) was analyzed for eATP concentration, cellularity, and inflammatory mediator accumulation. Thirty bilateral human lung transplant recipients were graded for immediate early PGD and assessed for BALF eATP levels. RESULTS: APT102-treated dogs had progressively better lung function and less pulmonary edema during the 3-hour reperfusion period compared with vehicle-treated controls. Protection from IRI was observed, with lower BALF eATP levels, fewer airway leukocytes, and blunted inflammatory mediator expression. Human lung recipients with moderate to severe PGD had significantly higher eATP levels compared with recipients without this injury. CONCLUSIONS: Extracellular ATP accumulates in acutely injured canine and human lungs. Strategies that target eATP reduction may help protect lung recipients from IRI.
BACKGROUND: There is accumulating evidence that extracellular adenosine triphosphate (eATP) promotes many of the underlying mechanisms that exacerbate acute lung injury. However, much of these data are from inbred rodent models, indicating the need for further investigation in higher vertebrates to better establish clinical relevance. To this end we evaluated a human recombinant apyrase therapy in a canine warm pulmonary ischemia-reperfusion injury (IRI) model and measured eATP levels in human lung recipients with or without primary lung graft dysfunction (PGD). METHODS: Warm ischemia was induced for 90 minutes in the left lung of 14 mongrel dogs. Seven minutes after reperfusion, the apyrase APT102 (1 mg/kg, n = 7) or saline vehicle (n = 7) was injected into the pulmonary artery. Arterial blood gases were obtained every 30 minutes up to 180 minutes after reperfusion. Bronchioalveolar lavage fluid (BALF) was analyzed for eATP concentration, cellularity, and inflammatory mediator accumulation. Thirty bilateral human lung transplant recipients were graded for immediate early PGD and assessed for BALF eATP levels. RESULTS: APT102-treated dogs had progressively better lung function and less pulmonary edema during the 3-hour reperfusion period compared with vehicle-treated controls. Protection from IRI was observed, with lower BALF eATP levels, fewer airway leukocytes, and blunted inflammatory mediator expression. Human lung recipients with moderate to severe PGD had significantly higher eATP levels compared with recipients without this injury. CONCLUSIONS: Extracellular ATP accumulates in acutely injured canine and human lungs. Strategies that target eATP reduction may help protect lung recipients from IRI.
Authors: Maria T Kuipers; Hamid Aslami; John R Janczy; Koenraad F van der Sluijs; Alexander P J Vlaar; Esther K Wolthuis; Goda Choi; Joris J T H Roelofs; Richard A Flavell; Fayyaz S Sutterwala; Paul Bresser; Jaklien C Leemans; Tom van der Poll; Marcus J Schultz; Catharina W Wieland Journal: Anesthesiology Date: 2012-05 Impact factor: 7.892
Authors: Nicolas Riteau; Pamela Gasse; Louis Fauconnier; Aurélie Gombault; Marion Couegnat; Lizette Fick; Jean Kanellopoulos; Valérie F J Quesniaux; Sylvain Marchand-Adam; Bruno Crestani; Bernhard Ryffel; Isabelle Couillin Journal: Am J Respir Crit Care Med Date: 2010-06-03 Impact factor: 21.405
Authors: Jason D Christie; Scarlett Bellamy; Lorraine B Ware; David Lederer; Denis Hadjiliadis; James Lee; Nancy Robinson; A Russell Localio; Keith Wille; Vibha Lama; Scott Palmer; Jonathan Orens; Ann Weinacker; Maria Crespo; Ejigaehu Demissie; Stephen E Kimmel; Steven M Kawut Journal: J Heart Lung Transplant Date: 2010-07-22 Impact factor: 10.247
Authors: Junhee Seok; H Shaw Warren; Alex G Cuenca; Michael N Mindrinos; Henry V Baker; Weihong Xu; Daniel R Richards; Grace P McDonald-Smith; Hong Gao; Laura Hennessy; Celeste C Finnerty; Cecilia M López; Shari Honari; Ernest E Moore; Joseph P Minei; Joseph Cuschieri; Paul E Bankey; Jeffrey L Johnson; Jason Sperry; Avery B Nathens; Timothy R Billiar; Michael A West; Marc G Jeschke; Matthew B Klein; Richard L Gamelli; Nicole S Gibran; Bernard H Brownstein; Carol Miller-Graziano; Steve E Calvano; Philip H Mason; J Perren Cobb; Laurence G Rahme; Stephen F Lowry; Ronald V Maier; Lyle L Moldawer; David N Herndon; Ronald W Davis; Wenzhong Xiao; Ronald G Tompkins Journal: Proc Natl Acad Sci U S A Date: 2013-02-11 Impact factor: 11.205
Authors: William A Altemeier; W Conrad Liles; Ana Villagra-Garcia; Gustavo Matute-Bello; Robb W Glenny Journal: PLoS One Date: 2013-10-11 Impact factor: 3.240
Authors: René J Robles; Samiran Mukherjee; Marta Vuerich; Anyan Xie; Rasika Harshe; Peter J Cowan; Eva Csizmadia; Yan Wu; Alan C Moss; Ridong Chen; Simon C Robson; Maria Serena Longhi Journal: J Crohns Colitis Date: 2020-07-09 Impact factor: 9.071
Authors: Davide Scozzi; Mohsen Ibrahim; Fuyi Liao; Xue Lin; Hsi-Min Hsiao; Ramsey Hachem; Laneshia K Tague; Alberto Ricci; Hrishikesh S Kulkarni; Howard J Huang; Seiichiro Sugimoto; Alexander S Krupnick; Daniel Kreisel; Andrew E Gelman Journal: Am J Transplant Date: 2019-01-25 Impact factor: 8.086
Authors: Harika Vemulapalli; Samara Albayati; Viren C Patwa; Douglas G Tilley; Alexander Y Tsygankov; Elisabetta Liverani Journal: J Cell Commun Signal Date: 2019-12-05 Impact factor: 5.782
Authors: Andrew E Gelman; Andrew J Fisher; Howard J Huang; Maher A Baz; Ciara M Shaver; Thomas M Egan; Micheal S Mulligan Journal: J Heart Lung Transplant Date: 2017-07-24 Impact factor: 10.247
Authors: Ashish K Sharma; Eric J Charles; Yunge Zhao; Adishesh K Narahari; Pranav K Baderdinni; Miranda E Good; Ulrike M Lorenz; Irving L Kron; Douglas A Bayliss; Kodi S Ravichandran; Brant E Isakson; Victor E Laubach Journal: Am J Physiol Lung Cell Mol Physiol Date: 2018-05-10 Impact factor: 5.464