SIGNAL TRANSDUCTION IN PULMONARY ENDOTHELIUM - IMPLICATIONS FOR LUNG VASCULAR DYSFUNCTION

The pulmonary endothelium represents the largest vascular bed in the body and is a natural target for inflammatory processes which can disrupt vascular function. The regulation of bovine and human endothelial cell stimulus- coupling events which lead to prostaglandin synthesis and alteration in barrier function is complex and involves activation of G-protein membrane phospholipases, PKC, and elevation of intracellular Ca2+ (Fig 6). An initial and critical event in endothelial cell activation is the PI-PLC- mediated breakdown of PIP2 generating DAG and IP3. Diacylglycerol and IP3 act as intracellular second messengers in the interior of endothelial cells, thereby producing activation of PKC and raising [Ca2+i] concentrations, respectively. The increase in cytosolic free Ca2+ precedes PLA2 and possibly PLD activity and governs the subsequent release of vasoactive molecules such as EDRF, prostacyclin and other substances. Activation of PLA2 and PLD in response to an agonist, therefore, is likely secondary to stimulation of PIP2-specific PLC activity. Activation of PKC represents an important regulatory control in signal transduction in endothelial cells. Protein kinase C activation exerts multiple effects on agonist-induced modulation of phospholipases via negative feedback inhibition of PLC and positive regulation of PLA2 and PLD. Protein kinase C may be regulating AA release and subsequent PGI2 synthesis possibly by lowering Ca2+ requirements for PLA2 activity. In addition to PLA2, PKC activation in endothelial cells exhibits a positive feedback regulation of PLD stimulation. It is evident that not only agonists such as thrombin but also oxidants like H2O2 activate endothelial cell phospholipases independently of receptor- stimulus coupling. Hydrogen peroxide and other oxidants such as fatty acid hydroperoxide induce activation of PLC, PLA2 and PLD activities in endothelial cells (Fig 5). The exact mechanism of oxidant-mediated activation of the phospholipases is not known but their modulation can alter signal transduction pathways and barrier function. Regulation of PLA2, PLC and PLD and the potential interaction between three different signalling pathways in endothelial cells needs further studies to better understand pulmonary vascular responses to external stimuli. Additional investigation directed at the effect of environmental conditions relevant to the lung vasculature (such as hyperoxia and hypoxia) as well as signalling responsiveness of endothelium derived from pathologic lung tissues would greatly forward understanding of the functional consequences of altered second messenger profiles in vascular wall constituents such as the endothelium.