Research Plan: Our studies have established that impaired alveolar epithelial fluid clearance is associated with a higher mortality in patients with acute lung injury. During the first cycle of this award, we published several studies that markedly increased our understanding of the mechanisms that impair alveolar epithelial function in clinical acute lung injury (see Progress Report). Additional studies are needed to increase our understanding of the biological mechanisms that impair alveolar epithelial fluid clearance in clinical lung injury and to test therapeutic strategies that may increase the clearance of alveolar edema fluid and accelerate the resolution of lung injury.
In Aim 1, we will use pulmonary edema fluid and plasma from critically ill patients with acute lung injury to study the mechanisms that mediate an increase in protein permeability and a decrease in vectorial fluid transport across cultured human alveolar epithelial type 11 cells that form tight monolayers grown in an air-liquid interface. Controls will be done with edema fluid and plasma from patients with cardiogenic pulmonary edema.
In Aim 2, we will collect samples of pulmonary edema fluid and plasma from patients with early acute lung injury to (1) measure alveolar fluid clearance, (2) biological markers of lung epithelial and endothelial injury, and (3) clinical measurements of lung function to assess the biologic and physiologic mechanisms that contribute to impaired alveolar fluid clearance in clinical lung injury.
In Aim 3, we will use our novel preparation of perfused human lungs harvested from brain dead donors to measure lung endothelial and epithelial permeability and alveolar epithelial fluid clearance in order to test the effect of clinically relevant therapeutic strategies (very low tidal volume (3 ml/kg), high frequency ventilation, dopamine, interleukin-1 receptor antagonist, and growth factors) on lung fluid balance over 4-8 hours. In summary, the integrated studies of biochemical, physiological and clinical measurements in plasma and pulmonary edema fluid in critically ill patients in Aim 2 will generate new insights into the mechanisms that impair alveolar epithelial fluid clearance in clinical acute lung injury. The studies in Aims 1 and 3 studies will provide innovative, novel approaches that use human alveolar type II cells and human lungs to study the mechanisms of alveolar epithelial injury as well as to test the potential value of several clinically relevant therapeutic strategies in pre-clinical studies.

Public Health Relevance

Our prior work has shown that patients with acute lung injury who have impaired fluid clearance from the lung are at increased risk of death. The current studies are designed to better understand the molecular mechanisms of impaired fluid clearance and to test new treatments in an isolated lung model of acute lung injury, with the ultimate goal of developing better treatments for patients with acute lung injury.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Harabin, Andrea L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
Zip Code
Zinter, Matt S; Orwoll, Benjamin E; Spicer, Aaron C et al. (2017) Incorporating Inflammation into Mortality Risk in Pediatric Acute Respiratory Distress Syndrome. Crit Care Med 45:858-866
Laffey, John G; Matthay, Michael A (2017) Fifty Years of Research in ARDS. Cell-based Therapy for Acute Respiratory Distress Syndrome. Biology and Potential Therapeutic Value. Am J Respir Crit Care Med 196:266-273
Agrawal, Pankaj B; Wang, Ruobing; Li, Hongmei Lisa et al. (2017) The Epithelial Sodium Channel Is a Modifier of the Long-Term Nonprogressive Phenotype Associated with F508del CFTR Mutations. Am J Respir Cell Mol Biol 57:711-720
Xi, Ying; Kim, Thomas; Brumwell, Alexis N et al. (2017) Local lung hypoxia determines epithelial fate decisions during alveolar regeneration. Nat Cell Biol 19:904-914
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
Sapru, Anil; Liu, Kathleen D; Wiemels, Joseph et al. (2016) Association of common genetic variation in the protein C pathway genes with clinical outcomes in acute respiratory distress syndrome. Crit Care 20:151
Ward, Shan L; Quinn, Carson M; Valentine, Stacey L et al. (2016) Poor Adherence to Lung-Protective Mechanical Ventilation in Pediatric Acute Respiratory Distress Syndrome. Pediatr Crit Care Med 17:917-923
Moazed, Farzad; Burnham, Ellen L; Vandivier, R William et al. (2016) Cigarette smokers have exaggerated alveolar barrier disruption in response to lipopolysaccharide inhalation. Thorax 71:1130-1136
Kangelaris, Kirsten Neudoerffer; Ware, Lorraine B; Matthay, Michael A et al. (2016) The authors reply. Crit Care Med 44:e769-70
Hendrickson, Carolyn M; Howard, Benjamin M; Kornblith, Lucy Z et al. (2016) The acute respiratory distress syndrome following isolated severe traumatic brain injury. J Trauma Acute Care Surg 80:989-97

Showing the most recent 10 out of 150 publications