Physiological and biochemical markers of alveolar epithelial barrier dysfunction in perfused human lungs

Abstract

Frank JA, Briot R, Lee JW, Ishizaka A, Uchida T, Matthay MA. Physiological and biochemical markers of alveolar epithelial barrier dysfunction in perfused human lungs. Am J Physiol Lung Cell Mol Physiol 293: L52-L59, 2007. First published March 9, 2007; doi:10.1152/ajplung.00256.2006.-To study air space fluid clearance (AFC) under conditions that resemble the clinical setting of pulmonary edema in patients, we developed a new perfused human lung preparation. We measured AFC in 20 human lungs rejected for transplantation and determined the contribution of AFC to lung fluid balance. AFC was then compared with air space and perfusate levels of a biological marker of epithelial injury. The majority of human lungs rejected for transplant had intact basal (75%) and ␤2-adrenergic agonist-stimulated (70%) AFC. For lungs with both basal and stimulated AFC, the basal AFC rate was 19 Ϯ 10%/h, and the ␤2-adrenergic-stimulated AFC rate was 43 Ϯ 13%/h. Higher rates of AFC were associated with less lung weight gain (Pearson coefficient Ϫ0.90, P Ͻ 0.0001). Air space and perfusate levels of the type I pneumocyte marker receptor for advanced glycation end products (RAGE) were threefold and sixfold higher, respectively, in lungs without basal AFC compared with lungs with AFC (P Ͻ 0.05). These data show that preserved AFC is a critical determinant of favorable lung fluid balance in the perfused human lung, raising the possibility that ␤2-agonist therapy to increase edema fluid clearance may be of value for patients with acute lung injury and pulmonary edema. Also, although additional studies are needed, a biological marker of alveolar epithelial injury may be useful clinically in predicting preserved AFC. alveolar epithelial fluid transport; acute lung injury; acute respiratory distress syndrome; lung transplantation; biological markers; pulmonary edema; primary graft failure; air space fluid clearance POSTLUNG TRANSPLANT REPERFUSION PULMONARY EDEMA is a form of acute lung injury that contributes to early mortality in lung transplant patients (6 -8, 37). Acute lung injury is characterized by the loss of alveolar epithelial barrier function, including increased permeability to protein and decreased fluid transport from the air spaces, resulting in pulmonary edema (6 -8, 37). Removal of edema fluid from the air spaces, or distal air space fluid clearance (AFC), is dependent on a transepithelial sodium concentration gradient established by basolateral sodium-potassium ATPase (19,20). The basal rate of alveolar epithelial ion and fluid transport can be increased by ␤ 2 -adrenergic agonists (15,17,20,22). Edema fluid cleared from the distal air spaces into the interstitial space is transported from the lungs primarily by direct absorption into the pulmonary venous circulation, but also by pulmonary lymphatic drainage and clearance into the pleural space (20,30). Lung fluid balance is the sum of edema formation and lung fluid clearance.Data from nonperfused human lungs obtained from donated organs rejected for transplant (39) and from p...

Clinical grade allogeneic human mesenchymal stem cells restore alveolar fluid clearance in human lungs rejected for transplantation

“…Furthermore, in a separate study, lungs rejected for transplant with measurable basal and stimulated fluid clearance had mean basal AFC rates of 19 Ϯ 10%/h and mean stimulated (terbutaline) AFC of 43 Ϯ 13%/h (17). Lungs were included in this study if the lung demonstrated impaired AFC, with lungs included if baseline AFC was Ͻ10%/h and cold ischemia time Ͻ48 h. Based on this criterion, from July 2011 to June 2012, ϳ50% of rejected lungs were eligible.…”

Cell-free hemoglobin promotes primary graft dysfunction through oxidative lung endothelial injury

“…For the experimental preparation (Figure 4), lungs were continuously perfused at 37°C with DMEM containing 5% albumin and 16% (v/v) fresh whole human blood by roller pump to maintain a pulmonary artery pressure of 10-12 mmHg with passive drainage of perfusate through an open left atrium into a reservoir for recirculation (53,54). Lungs were inflated to continuous positive airway pressure (CPAP) of 10 mmHg with either 95% O 2 (FiO 2 = 0.95) or 21% O 2 (FiO 2 = 0.21), and a recruitment maneuver with sustained inflation to 25 mmHg was performed prior to the experiment (53,54). The lung was suspended from a mass transducer for continuous measurement of lung weight as an index of pulmonary edema formation.…”

Therapeutic Potential of Mesenchymal Stem Cells for Severe Acute Lung Injury

“…15 In more recent work, we adapted our ex vivo perfused human lung preparation for studies of ALI to test the effects of MSC therapy. 16 In this study, the right middle lobe was injured with intraalveolar endotoxin (6 mg), resulting in a sharp increase in lung endothelial and epithelial permeability to protein leading to pulmonary edema and a loss of the normal capacity of the alveolar epithelium to remove alveolar fl uid. 17 When the lung was treated 1 h after instilla- .…”