Acute respiratory failure from acute lung injury is a major clinical problem with substantial mortality and morbidity. The overall objective of this proposal is to test the value of cell-based therapy with mesenchymal stem cells (MSC) for the treatment of experimental acute lung injury and restoring normal lung fluid balance in acute lung injury.
Aim 1 is designed to determine the therapeutic effects of intrapulmonary and intravenous delivery of MSC on pulmonary edema and survival in clinically relevant mouse models of acute lung injury.
Aim 2 will evaluate the mechanisms responsible for the beneficial effects of MSC treatment in the clinically relevant models of pulmonary edema from acute lung injury in mice studied in Aim 1, with a specific focus on the role of interleukin-1 receptor antagonist (IL-1ra) and interleukin-10.
Aim 3 is designed to test the therapeutic and mechanistic effects of allogeneic human MSC on restoring alveolar epithelial fluid transport in an in vitro model of cultured human alveolar epithelial type II cells and in an ex vivo perfused human lung preparation. The proposed studies in Aims 1 and 2 will advance our understanding of the mechanisms by which MSCs reduce lung injury and pulmonary edema as well as advance our knowledge of the biology of MSCs in the setting of acute lung injury in mice.
Aim 3 will translate these findings to the human lung by using cultured monolayers of polarized human alveolar epithelial type II cells and an ex vivo perfused human lung preparation. The results of these experiments will help make it possible to determine whether testing MSCs in patients with acute lung injury is appropriate. The proposed work will also uncover mechanisms by which MSC reduces pulmonary edema from acute lung injury, and these insights will advance the fields of lung fluid balance, pulmonary edema, and acute lung injury. PROJECT NARRATIVE. This research proposal has direct relevance to the clinical problem of acute respiratory failure from pulmonary edema secondary to acute lung injury, a cause of morbidity and mortality in the United States. The proposal will test novel strategies to use cell based therapy for the treatment of experimental acute lung injury including mouse models of lung injury as well as innovative models that use human lung epithelial cells and intact human lungs harvested from brain dead subjects.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL051854-16
Application #
7686827
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
Project Start
1994-12-01
Project End
2013-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
16
Fiscal Year
2009
Total Cost
$386,250
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Gotts, Jeffrey E; Abbott, Jason; Fang, Xiaohui et al. (2017) Cigarette Smoke Exposure Worsens Endotoxin-Induced Lung Injury and Pulmonary Edema in Mice. Nicotine Tob Res 19:1033-1039
Jackson, Megan V; Morrison, Thomas J; Doherty, Declan F et al. (2016) Mitochondrial Transfer via Tunneling Nanotubes is an Important Mechanism by Which Mesenchymal Stem Cells Enhance Macrophage Phagocytosis in the In Vitro and In Vivo Models of ARDS. Stem Cells 34:2210-23
Hendrickson, Carolyn M; Crestani, Bruno; Matthay, Michael A (2015) Biology and pathology of fibroproliferation following the acute respiratory distress syndrome. Intensive Care Med 41:147-50
Greer, Alexandra M; Matthay, Michael A; Kukreja, Jasleen et al. (2014) Accumulation of BDCA1? dendritic cells in interstitial fibrotic lung diseases and Th2-high asthma. PLoS One 9:e99084
Walter, James; Ware, Lorraine B; Matthay, Michael A (2014) Mesenchymal stem cells: mechanisms of potential therapeutic benefit in ARDS and sepsis. Lancet Respir Med 2:1016-26
Gotts, Jeffrey E; Matthay, Michael A (2014) Endogenous and exogenous cell-based pathways for recovery from acute respiratory distress syndrome. Clin Chest Med 35:797-809
Goolaerts, Arnaud; Pellan-Randrianarison, Nadia; Larghero, Jérôme et al. (2014) Conditioned media from mesenchymal stromal cells restore sodium transport and preserve epithelial permeability in an in vitro model of acute alveolar injury. Am J Physiol Lung Cell Mol Physiol 306:L975-85
Rogers, Angela J; McGeachie, Michael; Baron, Rebecca M et al. (2014) Metabolomic derangements are associated with mortality in critically ill adult patients. PLoS One 9:e87538
Ware, L B; Lee, J W; Wickersham, N et al. (2014) Donor smoking is associated with pulmonary edema, inflammation and epithelial dysfunction in ex vivo human donor lungs. Am J Transplant 14:2295-302
McAuley, D F; Curley, G F; Hamid, U I et al. (2014) Clinical grade allogeneic human mesenchymal stem cells restore alveolar fluid clearance in human lungs rejected for transplantation. Am J Physiol Lung Cell Mol Physiol 306:L809-15

Showing the most recent 10 out of 232 publications