Damage-associated molecular patterns (DAMPs) include endogenous intracellular molecules released by activated or necrotic cells and extracellular matrix (ECM) molecules that are upregulated upon injury or degraded following tissue damage. DAMPs are vital danger signals that alert our immune system to tissue damage upon both infectious and sterile insult. DAMP activation of Toll-like receptors (TLRs) induces inflammatory gene expression to mediate tissue repair. However, DAMPs have also been implicated in diseases where excessive inflammation plays a key role in pathogenesis, including rheumatoid arthritis (RA), cancer, and atherosclerosis. TLR activation by DAMPs may initiate positive feedback loops where increasing tissue damage perpetuates pro-inflammatory responses leading to chronic inflammation. Here we explore the current knowledge about distinct signalling cascades resulting from self TLR activation. We also discuss the involvement of endogenous TLR activators in disease and highlight how specifically targeting DAMPs may yield therapies that do not globally suppress the immune system.

Dampening inflammation by modulating tlr signalling

http://hub.hku.hk/bitstream/10722/226382/1/content.pdf

Vascular nitric oxide: Beyond eNOS

Regulation of retinal blood flow in health and disease

It is now more than 15 years since the molecular structures of the major prostanoid receptors were elucidated. Since then, substantial progress has been achieved with respect to distribution and function, signal transduction mechanisms, and the design of agonists and antagonists ( ). This review systematically details these advances. More recent developments in prostanoid receptor research are included. The DP2 receptor, also termed CRTH2, has little structural resemblance to DP1 and other receptors described in the original prostanoid receptor classification. DP2 receptors are more closely related to chemoattractant receptors. Prostanoid receptors have also been found to heterodimerize with other prostanoid receptor subtypes and nonprostanoids. This may extend signal transduction pathways and create new ligand recognition sites: prostacyclin/thromboxane A2 heterodimeric receptors for 8- epi -prostaglandin E2, wild-type/alternative (alt4) heterodimers for the prostaglandin FP receptor for bimatoprost and the prostamides. It is anticipated that the 15 years of research progress described herein will lead to novel therapeutic entities.

https://pharmrev.aspetjournals.org/content/pharmrev/63/3/471.full.pdf

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

Bioactive Benzofuran derivatives: A review

Stimulation of prostanoid IP and EP2 receptors dilates retinal arterioles and increases retinal and choroidal blood flow in rats

Attenuation of nitric oxide- and prostaglandin-independent vasodilation of retinal arterioles induced by acetylcholine in streptozotocin-treated rats.

Structural and functional changes in retinal vasculature induced by retinal ischemia-reperfusion in rats.

Ocular pathologic angiogenesis is a causative factor for retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. In the present study, we examined the effects of rapamycin and everolimus, inhibitors of mammalian target of rapamycin (mTOR), on retinal pathologic angiogenesis in mice with oxygen-induced retinopathy (OIR), an animal model of proliferative ischemic retinopathy. Mice were exposed to 80% oxygen from postnatal day (P) 7 to P10, and were then brought into room air and subcutaneously injected with rapamycin and everolimus. The neovascular tufts, the size of the central avascular zone, and the immunoreactivity for phosphorylated ribosomal protein S6 (pS6), a downstream indicator of mTOR activity, were evaluated in flat-mounted retinas. Retinal neovascular tufts and vascular growth in the avascular zone were observed in P15 mice with OIR. In addition, intense immunoreactivity for pS6 was detected in the neovascular tufts and in endothelial cells located at the vascular-avascular border. Both rapamycin and everolimus reduced the extent of retinal neovascular tufts and pS6 immunoreactivity, but they also increased the size of the avascular zone. Thus, activation of the mTOR pathway in endothelial cells contributes to retinal pathologic angiogenesis, and mTOR inhibitors that target proliferating endothelial cells are promising candidates as anti-angiogenic agents for the treatment of vasoproliferative retinal diseases.

/pdf/anti-angiogenic-effects-of-mammalian-target-of-rapamycin-1tvo2vyltc.pdf

Anti-angiogenic Effects of Mammalian Target of Rapamycin Inhibitors in a Mouse Model of Oxygen-Induced Retinopathy

The aim of this study was to examine whether stimulation of β3-adrenoceptors dilates rat retinal blood vessels and how diabetes affects the vasodilator responses. Images of ocular fundus were captured with an original high-resolution digital fundus camera in vivo. The retinal vascular responses were evaluated by measuring diameter of retinal blood vessels contained in the digital images. Both systemic blood pressure and heart rate (HR) were continuously recorded. The β3-adrenoceptor agonist CL316243 (0.3–10 μg/kg/min, i.v.) increased diameter of retinal arterioles (at 10 μg/kg/min, a 31% increase) and decreased mean blood pressure (at 10 μg/kg/min, a 21% decrease) in a dose-dependent manner. CL316243 produced a small but significant increase in HR (at 10 μg/kg/min, a 9% increase). Both SR59230A (1 mg/kg, i.v.) and L-748337 (50 μg/kg, i.v.), β3-adrenoceptor antagonists, significantly prevented CL316243-induced retinal vasodilator responses. Similar observations were made with another β3-adrenoceptor agonist, BRL37344. The β2-adrenoceptor agonist salbutamol also increased diameter of retinal arterioles (at 10 μg/kg/min, a 43% increase), whereas the drug produced greater decrease in blood pressure (at 10 μg/kg/min, a 46% decrease) and increase in HR (at 10 μg/kg/min, a 16% increase), compared with β3-adrenoceptor agonists. The retinal vasodilator responses to CL316243 and BRL37344 observed under blockade of β1/β2-adrenoceptors with propranolol (2 mg/kg, i.v. bolus followed by 100 μg/kg/min infusion) were unaffected 2 weeks after induction of diabetes by the combination of streptozotocin treatment and d-glucose feeding. On the other hand, the vasodilator responses to salbutamol of retinal arterioles were significantly reduced in diabetic rats. These results suggest that stimulation of β3-adrenoceptors causes the vasodilation of retinal arterioles in vivo and the vasodilator responses are unaffected at the early stage of diabetes.

Asami Mori

Papers

Stimulation of prostanoid IP and EP2 receptors dilates retinal arterioles and increases retinal and choroidal blood flow in rats

Attenuation of nitric oxide- and prostaglandin-independent vasodilation of retinal arterioles induced by acetylcholine in streptozotocin-treated rats.

Structural and functional changes in retinal vasculature induced by retinal ischemia-reperfusion in rats.

Anti-angiogenic Effects of Mammalian Target of Rapamycin Inhibitors in a Mouse Model of Oxygen-Induced Retinopathy

Pharmacological evidence for the presence of functional β3-adrenoceptors in rat retinal blood vessels