Vascular Barrier Regulation by PAF, Ceramide, Caveolae, and NO - an Intricate Signaling Network with Discrepant Effects in the Pulmonary and Systemic Vasculature

Abstract

Increased endothelial permeability and vascular barrier failure are hallmarks of inflammatory responses in both the pulmonary and the systemic circulation. Platelet-activating factor (PAF) has been implicated as an important lipid mediator in the formation of pulmonary and extrapulmonary edema. Ostensibly, the PAF-induced signaling pathways in endothelial cells utilize similar structures and molecules including acid sphingomyelinase, ceramide, caveolae, endothelial nitric oxide synthase, and nitric oxide, in pulmonary and systemic microvessels. Yet, the constituents of these signaling pathways act and respond in distinctly different and frequently opposing ways in the lung versus organs of the systemic circulation. By confronting seemingly discrepant findings from the literature, we reconstruct the differential signaling pathways by which PAF regulates edema formation in the systemic and the pulmonary vascular bed, and trace this dichotomy from the level of myosin light chain kinase via the regulation of endothelial nitric oxide synthase and sphingomyelinase signaling to the level of caveolar trafficking. Here, we propose that PAF regulates vascular barrier function in individual organs by opposing signaling pathways that culminate in increased respectively decreased nitric oxide synthesis in the systemic and the pulmonary endothelium. The present review may provide a physiological explanation for the overall disappointing results of previous pharmacological strategies in conditions of generalized barrier failure such as sepsis, and instead advertises the development of organ-specific interventions by targeting the individual composition or trafficking of endothelial caveolae.

The trail to deadly membrane rafts

“…Besides their role in sepsis, hemolytic uremic syndrome, and Wilson's disease [8], sphingomyelinase and ceramide contribute to the pathophysiology of a wide variety of further clinical disorders including lung inflammation, fibrosis and infection [10], cystic fibrosis [11], several cardiovascular diseases [12,13], multiple sclerosis [14], major depression [15], Parkinson's disease [16], Alzheimer's disease [15], and diabetes [17]. In all those conditions, lysosomal pH, activity of acid sphingomyelinase, ceramide production with formation of membrane rafts, and subsequent O 2 − generation may contribute to the underlying pathophysiology.…”

A Metronidazole-Resistant Isolate of Blastocystis spp. Is Susceptible to Nitric Oxide and Downregulates Intestinal Epithelial Inducible Nitric Oxide Synthase by a Novel Parasite Survival Mechanism

“…Nitric oxide (NO) plays multiple functions in the human body, such as maintenance of vascular tone (9), modulation of epithelial barrier function (16), and neurotransmission (38). Generation of nitrosative stress in response to microbes is also an important component of the human cellular defense arsenal (3,6,19).…”

Acid Sphingomyelinase Regulates Platelet Cell Membrane Scrambling, Secretion, and Thrombus Formation

“…Activation of Asm is thus expected to enhance the activation-dependent platelet degranulation and phosphatidylserine translocation by modifying membrane properties. ASM is upregulated or activated by a wide variety of mediators, including thrombin, 37 platelet-activating factor, 30 amyloid, 45,46 and plasminogen activator inhibitor 1. 47 Pathophysiologically, ASM plays a major role in vascular inflammation and the development of atherosclerosis 31 by regulating the release of Weibel-Palade bodies from stimulated endothelial cells.…”

“…16,20 By producing ceramide, ASM may trigger cell membrane scrambling with phosphatidylserine exposure and thus suicidal death of other blood cells, such as erythrocytes. 21,22 ASM activity and ceramide formation thus contribute to the pathophysiology of a wide variety of disorders, including atherosclerosis, [23][24][25] inflammation, fibrosis and infection, 26 cystic fibrosis, [26][27][28] Wilson disease, 22 diabetes mellitus, 29 cardiovascular disease, 30,31 cerebral ischemia, 32 multiple sclerosis 33 major depression, 14 Parkinson disease, 34 and Alzheimer disease. 14 Tricyclic antidepressant medications, such as amitriptyline or fluoxetine, are widely used as experimental functional ASM-inhibitors.…”