title: Loss of PECAM-1 function impairs alveolarization.
abstract: The final stage of lung development in humans and rodents occurs principally after birth and involves the partitioning of the large primary saccules into smaller air spaces by the inward protrusion of septae derived from the walls of the saccules. Several observations in animal models implicate angiogenesis as critical to this process of alveolarization, but all anti-angiogenic treatments examined to date have resulted in endothelial cell (EC) death. We therefore targeted the function of platelet endothelial cell adhesion molecule, (PECAM-1), an EC surface molecule that promotes EC migration and has been implicated in in vivo angiogenesis. Administration of an anti-PECAM-1 antibody that inhibits EC migration, but not proliferation or survival in vitro, disrupted normal alveolar septation in neonatal rat pups without reducing EC content. Three-dimensional reconstruction of lungs showed that pups treated with a blocking PECAM-1 antibody had remodeling of more proximal branches resulting in large tubular airways. Subsequent studies in PECAM-1-null mice confirmed that the absence of PECAM-1 impaired murine alveolarization, without affecting EC content, proliferation, or survival. Further, cell migration was reduced in lung endothelial cells isolated from these mice. These data suggest that the loss of PECAM-1 function compromises postnatal lung development and provide evidence that inhibition of EC function, in contrast to a loss of viable EC, inhibits alveolarization.
authors.affiliation: Pulmonary, Allergy and Critical Care Division, Department of Medicine, Institute for Medicine and Engineering, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318, USA.
authors.forename: Horace M
authors.initials: HM
authors.lastname: DeLisser
authors.forename: Brian P
authors.initials: BP
authors.lastname: Helmke
authors.forename: Gaoyuan
authors.initials: G
authors.lastname: Cao
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Egan
authors.forename: Darren
authors.initials: D
authors.lastname: Taichman
authors.forename: Melane
authors.initials: M
authors.lastname: Fehrenbach
authors.forename: Aisha
authors.initials: A
authors.lastname: Zaman
authors.forename: Zheng
authors.initials: Z
authors.lastname: Cui
authors.forename: Gopi S
authors.initials: GS
authors.lastname: Mohan
authors.forename: H Scott
authors.initials: HS
authors.lastname: Baldwin
authors.forename: Peter F
authors.initials: PF
authors.lastname: Davies
authors.forename: Rashmin C
authors.initials: RC
authors.lastname: Savani
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D019138:Antibodies, Blocking / Q000008:administration & dosage / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008168:Lung / Q000098:blood supply / Q000254:growth & development* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000098:blood supply / Q000187:drug effects / Q000254:growth & development* / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D042810:Receptor, TIE-1 / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D003907:Dexamethasone; D042810:Receptor, TIE-1