Molecular Mechanisms of the ATInduced Increase in Endothelial Production of PGI2

To elucidate the precise molecular mechanism(s) by which AT exerts anti-inflammatory activity, we examined the effect of AT on the endothelial production of PGI2 using cultured endothelial cells. However, AT did not directly increase endothelial production of PGI2 in cultured endothe-lial cells. Thus, the mechanism(s) by which AT promotes endothelial release of PGI2 in vivo might involve unknown factors other than endothelial cells.

Capsaicin-sensitive sensory neurons are nociceptive neurons that are activated by a wide variety of noxious physical and chemical stimuli. Since ablation of sensory fibers can result in a marked increase in the severity of inflammation, the sensory neurons have been shown to play a role in the maintenance of tissue integrity by regulating local inflammatory responses. On activation, the sensory neurons release calcitonin gene-related peptide (CGRP) that can increase the endothelial production of PGI2 in vitro. Since various noxious stimuli that activate the sensory neurons to release CGRP are capable of inducing tissue damage, the CGRP-induced increase in endothelial production of PGI2 might contribute to attenuation of local inflammatory responses, thereby reducing the tissue damage. Consistent with this hypothesis, we previously reported that capsaicin-

TNF-a has an important role in the development of the microcirculatory disturbance associated with sepsis or circulatory shock, primarily by activating neutrophils, thereby inducing endothelial cell injury leading to microcirculatory disturbance due to local hemoconcentration, and secondarily by inducing microthrombus formation, which precipitates the preexisting microcirculatory disturbance as described earlier (Figure 2). Thus, inhibition of both neu-trophil activation and microthrombus formation might be important for maintenance of proper microcirculation. AT increases the endothelial production of PGI2 via enhancement of the capsaicin-sensitive sensory neurons. PGI2 is a vasodilator and has a potent inhibitory effect on platelet activation. Since platelet activation and subsequent vasospasms are critical factors in the development of arterial thrombosis, AT might prevent arterial thrombosis by increasing the endothelial production of PGI2 through interaction with heparin-like substances on endothelial cells, contributing to maintenance of proper microcirculation in the arteries (Figure 3). This hypothesis is consistent with the observations that arterial thrombosis, as well as venous thrombosis, are frequently found in patients in a homozygous state with variant AT molecules that do not have heparin affinity. In addition, PGI2 has inhibitory effects on monocytic TNF-a production and neutrophil activation. Activated neutrophils are critically involved in the development of microcircula-tory disturbance in the postcapillary venules due to the

Arteries

Arteries

Enhancement of stimulation nt

Capsaicin-sensitive sensory neurons

Figure 3 Regulation of the microcirculation by antithrombin. AT, antithrombin; TNF-a, tumor necrosis factor-a; CGRP, calci-tonin-gene related peptide; F. Xa, activated form of coagulation factor X; PGI2, prostacyclin.

Veins

Enhancement of stimulation nt

Capsaicin-sensitive sensory neurons

Figure 3 Regulation of the microcirculation by antithrombin. AT, antithrombin; TNF-a, tumor necrosis factor-a; CGRP, calci-tonin-gene related peptide; F. Xa, activated form of coagulation factor X; PGI2, prostacyclin.

increase in microvascular permeability, leading to reduced blood flow resulting from local hemoconcentration. In addition to stasis, activated coagulation factors such as factor Xa are essential for development of venous thrombosis (Figure 3). Thus, AT might prevent thrombus formation by promoting endothelial production of PGI2 in postcapillary venules where activated neutrophil-induced endothelial damage is frequently induced and also in veins by its inherent anticoagulant activity. Thus, both anti-inflammatory and anticoagulant activities of AT might contribute to the maintenance of proper microcirculation.

Was this article helpful?

0 0
Cure Tennis Elbow Without Surgery

Cure Tennis Elbow Without Surgery

Everything you wanted to know about. How To Cure Tennis Elbow. Are you an athlete who suffers from tennis elbow? Contrary to popular opinion, most people who suffer from tennis elbow do not even play tennis. They get this condition, which is a torn tendon in the elbow, from the strain of using the same motions with the arm, repeatedly. If you have tennis elbow, you understand how the pain can disrupt your day.

Get My Free Ebook


Post a comment