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All rights reserved. http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/dc/elements/1.1/title BEL Framework Large Corpus Document http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/pav/authoredBy http://www.tkuhn.ch/bel2nanopub/RAutvyIb0-EtbrLDk9J2w2KBFmZisC8Swc5Lgcr8yPOsk#_3 http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/pav/version 1.4 http://www.tkuhn.ch/bel2nanopub/RAutvyIb0-EtbrLDk9J2w2KBFmZisC8Swc5Lgcr8yPOsk#_2 http://www.w3.org/ns/prov#value PULMONARY VASCULAR BARRIER REGULATION: OVERVIEW Despite recent therapeutic advances, inflammatory pulmonary conditions such as acute lung injury, acute respiratory distress syndrome, and sepsis continue to result in high rates of patient morbidity and mortality (3). Centrally involved in the pathogenesis of these processes and now recognized as a cardinal feature of inflammation, increased vascular permeability contributes to the profound pathophysiological derangements observed in these disorders. Because of the enormous surface area of the pulmonary vasculature, the pulmonary endothelium, which functions as a semipermeable cellular barrier between the vascular compartment and the interstitium, is particularly sensitive to the dynamic features of barrier regulation. Endothelial barrier properties are not uniform throughout the pulmonary vasculature, with greater macromolecule diffusion in postcapillary venules compared with pulmonary arterioles in whole lung models (91, 96, 118), whereas cultured microvascular endothelial cells (ECs) exhibit tenfold higher barrier properties than macrovascular EC as measured by electrical resistance across monolayers (13). Although the precise mechanisms that regulate this variability in segmental barrier function are unknown, barrier regulatory components such as Ca2+ signaling pathways and differences in content and regulation of barrier protective cAMP are likely involved (21, 80, 135). The integrity of the pulmonary EC monolayer is a critical requirement for preservation of pulmonary function, with two general pathways described for the movement of fluid, macromolecules, and leukocytes into the interstitium and subsequently the alveolar air spaces. The transcellular pathway utilizes a tyrosine kinase-dependent, gp60-mediated transcytotic albumin route, whose regulation and function are unclear but which may serve to uncouple protein and fluid permeability (103, 127, 143). However, there is general consensus that the primary mode of fluid and transendothelial leukocyte trafficking occurs by the paracellular pathway (Fig. 1), whose essential role in endothelial permeability has been well supported by an impressive body of research, including electron microscopy studies (69, 102), which demonstrate the formation of paracellular gaps at sites of active inflammation within the vasculature. View larger version (134K): [in this window] [in a new window] Fig. 1. Paracellular route of pulmonary inflammation. Under basal conditions, endothelial cells (ECs) of the pulmonary vasculature form a semipermeable barrier that restricts the flow of luminal contents into the alveolar air spaces. The important roles of flow and platelets/platelet-derived phospholipids in maintaining these intact intercellular junctions are becoming increasingly recognized (52, 147, 166, 167). During inflammation, the endothelium is activated by biophysical alterations (stretch or increased shear) or by stimuli such as thrombin, tumor necrosis factor (TNF), and/or reactive oxygen species to form paracellular gaps. In concert with a break in the EC barrier, fluid, proteins, and polymorphonuclear neutrophils (PMNs) flow into the alveoli to produce pulmonary edema via this paracellular route. Mechanistic approaches designed to understand EC paracellular gap formation and barrier function have revealed the complexity of these processes; however, several valuable paradigms have been developed. One useful model describes paracellular gap formation as regulated by the balance of competing contractile forces, which generate centripetal tension, and adhesive cell-cell and cell-matrix tethering forces, which together regulate cell shape changes (53). As outlined in Fig. 2, both competing forces in this model are intimately linked to the actin-based endothelial cytoskeleton by a variety of actin-binding proteins that are critical to both tensile force generation as well a... http://www.tkuhn.ch/bel2nanopub/RAutvyIb0-EtbrLDk9J2w2KBFmZisC8Swc5Lgcr8yPOsk#_2 http://www.w3.org/ns/prov#wasQuotedFrom http://www.ncbi.nlm.nih.gov/pubmed/11568129 http://www.tkuhn.ch/bel2nanopub/RAutvyIb0-EtbrLDk9J2w2KBFmZisC8Swc5Lgcr8yPOsk#_3 http://www.w3.org/2000/01/rdf-schema#label Selventa http://www.tkuhn.ch/bel2nanopub/RAutvyIb0-EtbrLDk9J2w2KBFmZisC8Swc5Lgcr8yPOsk#assertion http://www.w3.org/ns/prov#hadPrimarySource http://www.ncbi.nlm.nih.gov/pubmed/11568129 http://www.tkuhn.ch/bel2nanopub/RAutvyIb0-EtbrLDk9J2w2KBFmZisC8Swc5Lgcr8yPOsk#assertion http://www.w3.org/ns/prov#wasDerivedFrom http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://www.tkuhn.ch/bel2nanopub/RAutvyIb0-EtbrLDk9J2w2KBFmZisC8Swc5Lgcr8yPOsk#assertion http://www.w3.org/ns/prov#wasDerivedFrom http://www.tkuhn.ch/bel2nanopub/RAutvyIb0-EtbrLDk9J2w2KBFmZisC8Swc5Lgcr8yPOsk#_2 http://www.tkuhn.ch/bel2nanopub/RAutvyIb0-EtbrLDk9J2w2KBFmZisC8Swc5Lgcr8yPOsk#pubinfo http://www.tkuhn.ch/bel2nanopub/RAutvyIb0-EtbrLDk9J2w2KBFmZisC8Swc5Lgcr8yPOsk http://purl.org/dc/terms/created 2014-07-03T14:29:58.264+02:00 http://www.tkuhn.ch/bel2nanopub/RAutvyIb0-EtbrLDk9J2w2KBFmZisC8Swc5Lgcr8yPOsk http://purl.org/pav/createdBy http://orcid.org/0000-0001-6818-334X http://www.tkuhn.ch/bel2nanopub/RAutvyIb0-EtbrLDk9J2w2KBFmZisC8Swc5Lgcr8yPOsk http://purl.org/pav/createdBy http://orcid.org/0000-0002-1267-0234