Accession Number : ADA291639

Title :   Mechanisms of Tumor Necrosis Factor/Cachectin (TNFalpha)-Induced Pulmonary Vascular Endothelial Injury.

Descriptive Note : Final rept. Dec 90-Oct 94,

Corporate Author : MARYLAND UNIV BALTIMORE SCHOOL OF MEDICINE

Personal Author(s) : Goldblum, Simeon E.

PDF Url : ADA291639

Report Date : 30 SEP 1994

Pagination or Media Count : 94

Abstract : Diverse forms of severe military injuries can all lead to multiple organ failure (MOF). Prominent components to this life-threatening state include systemic vascular collapse, disseminated intravascular coagulation, and the Adult Respiratory Distress Syndrome (ARDS). One common element to these complications is the presence of endothelial cell (EC) injury or dysfunction. Two candidate mediators of pulmonary vascular EC injury and ARDS include the endogenous mediator tumor necrosis factor-a (TNF-a) and the exogenous factor, bacterial lipopolysaccharide (LPS). In addition, an LPS-induced, EC- derived glycoprotein, SPARC (Secreted Protein Acidic and Rich in Cysteine), regulates EC shape. To better study the mechanisms of TNFa-, LPS-, and SPARC-induced changes in endothelial barrier function, we utilized an in vitro experimental system that precludes hydrostatic pressure changes, granulocyte effector cells, or other nonendothelial-derived host factors. We studied the influence of human rTNFa, E.coli 0111 :B4 LPS, and murine SPARC on the movement of 14C- bovine serum albumin across bovine pulmonary vascular EC monolayers grown to confluence on filter supports mounted in chemotaxis chambers. We also studied whether these three mediators regulated endothelial barrier function through actin reorganzation. We found that TNFa, LPS, and SPARC each induced dose-, time- and temperature dependent increments in transendothelial 14C-BSA flux and that these changes in barrier function were mediated through EC actin depolymerization. The LPS effect was profoundly serum-dependent and this serum requirement could be satisfied by LPS-binding protein as well as soluble CD 14.

Descriptors :   *RESPIRATORY SYSTEM, *NECROSIS, PROPAGATION, MILITARY PERSONNEL, HUMANS, BACTERIA, CELLS, FAILURE, GLYCOPROTEINS, NEOPLASMS, SIGNS AND SYMPTOMS, IN VITRO ANALYSIS, BARRIERS, DOSAGE, SUPPORTS, WOUNDS AND INJURIES, BLOOD SERUM, BOVINES, DEPOLYMERIZATION, CARDIOVASCULAR SYSTEM, CHAMBERS, GRANULOCYTES, CYSTEINE, COLLAPSE, ORGANS(ANATOMY), ENDOTHELIUM, LIPOPOLYSACCHARIDES, SERUM ALBUMIN, HYDROSTATIC PRESSURE, CHEMOTAXIS, BLOOD COAGULATION, MUSCLE PROTEINS.

Subject Categories : Anatomy and Physiology
      Medicine and Medical Research

Distribution Statement : APPROVED FOR PUBLIC RELEASE