Abstract-Development and progression of end-organ damage in hypertension have been associated with increased oxidative stress. Superoxide anion accumulation has been reported in deoxycorticosterone acetate (DOCA)-salt hypertension, in which endothelin-1 plays an important role in cardiovascular damage. We hypothesized that blockade of ET A receptors in DOCA-salt rats would decrease oxidative stress. Key Words: endothelin Ⅲ receptors, endothelin Ⅲ deoxycorticosterone Ⅲ hypertension, arterial Ⅲ oxidative stress R eactive oxygen species (ROS), such as superoxide anion (⅐O 2 Ϫ ), hydrogen peroxide, and peroxynitrite (ONOO Ϫ ), are generated as intermediates in reduction-oxidation reactions. The major source of ROS in the vasculature is the nonmitochondrial NADPH oxidase. Under physiological conditions, ROS production is inactivated by an elaborate cellular and extracellular antioxidant defense system, of which glutathione peroxidase is a major component. In pathological conditions, increased generation of ROS and/or depletion of the antioxidant capacity results in increased bioavailability of ROS, referred to as oxidative stress. 1 There is increasing evidence that oxidative stress plays a pathological role in hypertension. 2 Several recent studies have provided compelling evidence for increased ROS generation in the vascular tissues of hypertensive rats. Enhanced ⅐O 2 Ϫ production has been demonstrated in mesenteric arterioles of SHR in vivo. 3 Likewise, increased ⅐O 2 Ϫ generation has been reported in cultured aortic endothelial cells from SHR compared with WKY. 4 Oxidative stress has been implicated in a variety of other hypertensive models including Angiotensin II (Ang II)-induced hypertension, 5,6 Dahl salt-sensitive hypertension, 7 and in human essential hypertension. 8 By promoting NO inactivation, lipid peroxidation, DNA damage, and protein modification, oxidative stress plays a key role in endothelial dysfunction and end-organ damage. Furthermore, ROS activate many redox-sensitive, growth-related intracellular signaling pathways in vascular smooth muscle and endothelial cells, which is particularly important in altered proliferation and hypertrophy, contributing to vascular remodeling, a characteristic feature of hypertensive disease. 9,10 Cytokines, growth factors, and vasoactive agents such as Ang II regulate the activity and expression of enzymes involved in ROS production. 1 In Ang II-dependent models of hypertension, vascular production of ⅐O 2 Ϫ is increased through activation of vascular NADPH oxidase. 5,6 Indeed,

Arthritis of the knee is the most common type of joint inflammatory disorder and it is associated with pain and inflammation of the joint capsule. Few studies address the effects of the 810-nm laser in such conditions. Here we investigated the effects of low-level laser therapy (LLLT; infrared, 810-nm) in experimentally induced rat knee inflammation. Thirty male Wistar rats (230–250 g) were anesthetized and injected with carrageenan by an intra-articular route. After 6 and 12 h, all animals were killed by CO2 inhalation and the articular cavity was washed for cellular and biochemical analysis. Articular tissue was carefully removed for real-time PCR analysis in order to evaluate COX-1 and COX-2 expression. LLLT was able to significantly inhibit the total number of leukocytes, as well as the myeloperoxidase activity with 1, 3, and 6 J (Joules) of energy. This result was corroborated by cell counting showing the reduction of polymorphonuclear cells at the inflammatory site. Vascular extravasation was significantly inhibited at the higher dose of energy of 10 J. Both COX-1 and 2 gene expression were significantly enhanced by laser irradiation while PGE2 production was inhibited. Low-level laser therapy operating at 810 nm markedly reduced inflammatory signs of inflammation but increased COX-1 and 2 gene expression. Further studies are necessary to investigate the possible production of antiinflammatory mediators by COX enzymes induced by laser irradiation in knee inflammation.

Inflammation contributes to the pathogenesis of chronic kidney disease (CKD). Molecules released by the inflamed injured tissue can activate toll-like receptors (TLRs), thereby modulating macrophage and CD4(+) T-cell activity. We propose that in renal fibrogenesis, M2 macrophages are recruited and activated in a T helper subset 2 cell (T(H)2)-prone inflammatory milieu in a MyD88-dependent manner. Mice submitted to unilateral ureteral ligation (UUO) demonstrated an increase in macrophage infiltration with collagen deposition after 7 d. Conversely, TLR2, TLR4 and MyD88 knockout (KO) mice had an improved renal function together with diminished T(H)2 cytokine production and decreased fibrosis formation. Moreover, TLR2, TLR4 and MyD88 KO animals exhibited less M2 macrophage infiltration, namely interleukin (IL)-10(+) and CD206(+) CD11b(high) cells, at 7 d after surgery. We evaluated the role of a T(H)2 cytokine in this context, and observed that the absence of IL-4 was associated with better renal function, decreased IL-13 and TGF-β levels, reduced arginase activity and a decrease in fibrosis formation when compared with IL-12 KO and wild-type (WT) animals. Indeed, the better renal outcomes and the decreased fibrosis formation were restricted to the deficiency of IL-4 in the hematopoietic compartment. Finally, macrophage depletion, rather than the absence of T cells, led to reduced lesions of the glomerular filtration barrier and decreased collagen deposition. These results provide evidence that future therapeutic strategies against renal fibrosis should be accompanied by the modulation of the M1:M2 and T(H)1:T(H)2 balance, as T(H)2 and M2 cells are predictive of fibrosis toward mechanisms that are sensed by innate immune response and triggered in a MyD88-dependent pathway.

Background and purpose: Recent findings suggest that the noxious gas H2S is produced endogenously, and that physiological concentrations of H2S are able to modulate pain and inflammation in rodents. This study was undertaken to evaluate the ability of endogenous and exogenous H2S to modulate carrageenan-induced synovitis in the rat knee. Experimental approach: Synovitis was induced in Wistar rats by intra-articular injection of carrageenan into the knee joint. Sixty minutes prior to carrageenan injection, the rats were pretreated with indomethacin, an inhibitor of H2S formation (DL-propargylglycine) or an H2S donor [Lawesson's reagent (LR)]. Key results: Injection of carrageenan evoked knee inflammation, pain as characterized by impaired gait, secondary tactile allodynia of the ipsilateral hindpaw, joint swelling, histological changes, inflammatory cell infiltration, increased synovial myeloperoxidase, protein nitrotyrosine residues, inducible NOS (iNOS) activity and NO production. Pretreatment with LR or indomethacin significantly attenuated the pain responses, and all the inflammatory and biochemical changes, except for the increased iNOS activity, NO production and 3-NT. Propargylglycine pretreatment potentiated synovial iNOS activity (and NO production), and enhanced macrophage infiltration, but had no effect on other inflammatory parameters. Conclusions and implications:Whereas exogenous H2S delivered to the knee joint can produce a significant antiinflammatory and anti-nociceptive effect, locally produced H2S exerts little immunomodulatory effect. These data further support the development and use of H2S donors as potential alternatives (or complementary therapies) to the available anti-inflammatory compounds used for treatment of joint inflammation or relief of its symptoms.