Alveolar Endothelium

The vascular endothelium is the first barrier encountered by fluid or inflammatory cells tracking from the vasculature to the alveoli. Endothelial barrier function is an essential and tightly regulated process that ensures proper compartmentalization of the vascular and interstitial spaces while allowing for the diffusive exchange of small molecules and controlled trafficking of macromolecules and immune cells [36]. Failure of endothelial barrier integrity results in excessive leakage of fluid and proteins from the vasculature into the airspace. The loss of barrier integrity can be a consequence of neutrophil activity, in which they accumulate in the microcirculation of the lung, become activated, and subsequently degranulate and release several toxic mediators, including reactive oxygen species (ROS), proteases, proinflammatory cytokines, and procoagulant molecules. Injury done by neutrophils and their intracellular products may increase vascular permeability by altering focal adhesions, transmembrane integrins, and the cytoskeleton of endothelial cells. Further inflammatory mediators, despite neutrophils, can act directly on the lung capillaries, resulting in increased expression of chemokines and cell surface molecules that are important for leukocyte adhesion [35, 49]. Furthermore, injury to the endothelial barrier may be mediated by bacterial or viral products, independently of the effects of activated leukocytes. For example, toxins produced by Pseudomonas aeruginosa and Staphylococcus aureus break down the endothelial barrier as well as the epithelial barrier [12, 66]. Not only NF-kB pathway inflammatory mediators but also specific transmembrane tyrosine kinases from endothelial cells (Tie-2) play an important role in ARDS pathophysiology. Their ligands Angpt-1 and Angpt-2, with nanomolar affinity, can have opposing effects on endothelial cell function. Angpt-1 is largely synthesized and secreted by periendothelial cells and platelets, whereas Angpt-2 is synthesized in the endothelium, where preformed protein is stored for rapid release in granules called Weibel-Palade bodies [15]. The N-terminal region of Angpt-1 may even promote local adherence to the extracellular matrix [61], leading to a high tissue concentration despite low circulating levels. In sepsis, ARDS, and related conditions, circulating Angpt-1 appears to be suppressed [48]. In addition, the magnitude of Angpt-1 decline tends to be two- to threefold or less, compared with the 5- to 20-fold increase in circulating Angpt-2 observed in sepsis or ARDS. Circulating Angpt-2 concentrations have a much broader dynamic range than Angpt-1. In 2006, Parikh et al. reported 10- to 20-fold elevations of circulating Angpt-2 levels in individuals with severe sepsis at the time of ICU admission as compared with patients with uncomplicated sepsis and hospitalized healthy subjects. The authors noted that subjects with severe sepsis developed higher peak Angpt-2 concentrations than those with uncomplicated sepsis and further observed that individuals with impaired lung gas exchange had higher peak Angpt-2 values than those with normal gas exchange [69]. In single-center and multicenter cohort studies, Angpt-2 was a robust indicator of extrapulmonary ARDS [8]. The induction of Angpt-2 clearly precedes adverse outcomes, a point strongly illustrated in an emergency department-based study of 270 adults with suspected infection in whom circulating Angpt-2 measured within the first hour of hospitalization predicted inpatient mortality, with an area under the receiver operator characteristic (ROC) curve of 0.91 [10]. On comparison of several relevant biomarkers, Angpt-2 was the only one capable of predicting the severity, monitoring the course, and prognosticating the outcome of late-onset ARDS in febrile critically ill patients, irrespective of underlying risk factor [23].