Role of acid-sensing ion channel 3 in sub-acute-phase inflammation

<p>Abstract</p> <p>Background</p> <p>Inflammation-mediated hyperalgesia involves tissue acidosis and sensitization of nociceptors. Many studies have reported increased expression of acid-sensing ion channel 3 (ASIC3) in inflammation and enhanced ASIC3 channel activity with pro-inflammatory mediators. However, the role of ASIC3 in inflammation remains inconclusive because of conflicting results generated from studies of <it>ASIC3 </it>knockout (<it>ASIC3</it>^-/-) or dominant-negative mutant mice, which have shown normal, decreased or increased hyperalgesia during inflammation.</p> <p>Results</p> <p>Here, we tested whether ASIC3 plays an important role in inflammation of subcutaneous tissue of paw and muscle in <it>ASIC3</it>^-/-mice induced by complete Freund's adjuvant (CFA) or carrageenan by investigating behavioral and pathological responses, as well as the expression profile of ion channels. Compared with the <it>ASIC3</it>^+/+controls, <it>ASIC3</it>^-/-mice showed normal thermal and mechanical hyperalgesia with acute (4-h) intraplantar CFA- or carrageenan-induced inflammation, but the hyperalgesic effects in the sub-acute phase (1–2 days) were milder in all paradigms except for thermal hyperalgesia with CFA-induced inflammation. Interestingly, carrageenan-induced primary hyperalgesia was accompanied by an <it>ASIC3</it>-dependent <it>Nav1.9 </it>up-regulation and increase of tetrodotoxin (TTX)-resistant sodium currents. CFA-inflamed muscle did not evoke hyperalgesia in <it>ASIC3</it>^-/-or <it>ASIC3</it>^+/+mice, whereas carrageenan-induced inflammation in muscle abolished mechanical hyperalgesia in <it>ASIC3</it>^-/-mice, as previously described. However, <it>ASIC3</it>^-/-mice showed attenuated pathological features such as less CFA-induced granulomas and milder carrageenan-evoked vasculitis as compared with <it>ASIC3</it>^+/+mice.</p> <p>Conclusion</p> <p>We provide a novel finding that ASIC3 participates in the maintenance of sub-acute-phase primary hyperalgesia in subcutaneous inflammation and mediates the process of granuloma formation and vasculitis in intramuscular inflammation.</p

Expression and function of proton-sensing G-protein-coupled receptors in inflammatory pain

<p>Abstract</p> <p>Background</p> <p>Chronic inflammatory pain, when not effectively treated, is a costly health problem and has a harmful effect on all aspects of health-related quality of life. Despite the availability of pharmacologic treatments, chronic inflammatory pain remains inadequately treated. Understanding the nociceptive signaling pathways of such pain is therefore important in developing long-acting treatments with limited side effects. High local proton concentrations (tissue acidosis) causing direct excitation or modulation of nociceptive sensory neurons by proton-sensing receptors are responsible for pain in some inflammatory pain conditions. We previously found that all four proton-sensing G-protein-coupled receptors (GPCRs) are expressed in pain-relevant loci (dorsal root ganglia, DRG), which suggests their possible involvement in nociception, but their functions in pain remain unclear.</p> <p>Results</p> <p>In this study, we first demonstrated differential change in expression of proton-sensing GPCRs in peripheral inflammation induced by the inflammatory agents capsaicin, carrageenan, and complete Freund's adjuvant (CFA). In particular, the expression of TDAG8, one proton-sensing GPCR, was increased 24 hours after CFA injection because of increased number of DRG neurons expressing TDAG8. The number of DRG neurons expressing both TDAG8 and transient receptor potential vanilloid 1 (TRPV1) was increased as well. Further studies revealed that TDAG8 activation sensitized the TRPV1 response to capsaicin, suggesting that TDAG8 could be involved in CFA-induced chronic inflammatory pain through regulation of TRPV1 function.</p> <p>Conclusion</p> <p>Each subtype of the OGR1 family was expressed differently, which may reflect differences between models in duration and magnitude of hyperalgesia. Given that TDAG8 and TRPV1 expression increased after CFA-induced inflammation and that TDAG8 activation can lead to TRPV1 sensitization, it suggests that high concentrations of protons after inflammation may not only directly activate proton-sensing ion channels (such as TRPV1) to cause pain but also act on proton-sensing GPCRs to regulate the development of hyperalgesia.</p

A Novel Compound C12 Inhibits Inflammatory Cytokine Production and Protects from Inflammatory Injury In Vivo

Inflammation is a hallmark of many diseases. Although steroids and cyclooxygenase inhibitors are main anti-inflammatory therapeutical agents, they may cause serious side effects. Therefore, developing non-steroid anti-inflammatory agents is urgently needed. A novel hydrosoluble compound, C12 (2,6-bis(4-(3-(dimethylamino)-propoxy)benzylidene)cyclohexanone), has been designed and synthesized as an anti-inflammatory agent in our previous study. In the present study, we investigated whether C12 can affect inflammatory processes in vitro and in vivo. In mouse primary peritoneal macrophages, C12 potently inhibited the production of the proinflammatory gene expression including TNF-α, IL-1β, IL-6, iNOS, COX-2 and PGE synthase. The activity of C12 was partly dependent on inhibition of ERK/JNK (but p38) phosphorylation and NF-κB activation. In vivo, C12 suppressed proinflammatory cytokine production in plasma and liver, attenuated lung histopathology, and significantly reduced mortality in endotoxemic mice. In addition, the pre-treatment with C12 reduced the inflammatory pain in the acetic acid and formalin models and reduced the carrageenan-induced paw oedema and acetic acid-increased vascular permeability. Taken together, C12 has multiple anti-inflammatory effects. These findings, coupled with the low toxicity and hydrosolubility of C12, suggests that this agent may be useful in the treatment of inflammatory diseases

Modulation of epithelial sodium channel (ENaC) expression in mouse lung infected with Pseudomonas aeruginosa

BACKGROUND: The intratracheal instillation of Pseudomonas aeruginosa entrapped in agar beads in the mouse lung leads to chronic lung infection in susceptible mouse strains. As the infection generates a strong inflammatory response with some lung edema, we tested if it could modulate the expression of genes involved in lung liquid clearance, such as the α, β and γ subunits of the epithelial sodium channel (ENaC) and the catalytic subunit of Na(+)-K(+)-ATPase. METHODS: Pseudomonas aeruginosa entrapped in agar beads were instilled in the lung of resistant (BalB/c) and susceptible (DBA/2, C57BL/6 and A/J) mouse strains. The mRNA expression of ENaC and Na(+)-K(+)-ATPase subunits was tested in the lung by Northern blot following a 3 hours to 14 days infection. RESULTS: The infection of the different mouse strains evoked regulation of α and β ENaC mRNA. Following Pseudomonas instillation, the expression of αENaC mRNA decreased to a median of 43% on days 3 and 7 after infection and was still decreased to a median of 45% 14 days after infection (p < 0.05). The relative expression of βENaC mRNA was transiently increased to a median of 241%, 24 h post-infection before decreasing to a median of 43% and 54% of control on days 3 and 7 post-infection (p < 0.05). No significant modulation of γENaC mRNA was detected although the general pattern of expression of the subunit was similar to α and β subunits. No modulation of α(1)Na(+)-K(+)-ATPase mRNA, the catalytic subunit of the sodium pump, was recorded. The distinctive expression profiles of the three subunits were not different, between the susceptible and resistant mouse strains. CONCLUSIONS: These results show that Pseudomonas infection, by modulating ENaC subunit expression, could influence edema formation and clearance in infected lungs

Spinal afferent neurons projecting to the rat lung and pleura express acid sensitive channels

BACKGROUND: The acid sensitive ion channels TRPV1 (transient receptor potential vanilloid receptor-1) and ASIC3 (acid sensing ion channel-3) respond to tissue acidification in the range that occurs during painful conditions such as inflammation and ischemia. Here, we investigated to which extent they are expressed by rat dorsal root ganglion neurons projecting to lung and pleura, respectively. METHODS: The tracer DiI was either injected into the left lung or applied to the costal pleura. Retrogradely labelled dorsal root ganglion neurons were subjected to triple-labelling immunohistochemistry using antisera against TRPV1, ASIC3 and neurofilament 68 (marker for myelinated neurons), and their soma diameter was measured. RESULTS: Whereas 22% of pulmonary spinal afferents contained neither channel-immunoreactivity, at least one is expressed by 97% of pleural afferents. TRPV1(+)/ASIC3(- )neurons with probably slow conduction velocity (small soma, neurofilament 68-negative) were significantly more frequent among pleural (35%) than pulmonary afferents (20%). TRPV1(+)/ASIC3(+ )neurons amounted to 14 and 10% respectively. TRPV1(-)/ASIC3(+ )neurons made up between 44% (lung) and 48% (pleura) of neurons, and half of them presumably conducted in the A-fibre range (larger soma, neurofilament 68-positive). CONCLUSION: Rat pleural and pulmonary spinal afferents express at least two different acid-sensitive channels that make them suitable to monitor tissue acidification. Patterns of co-expression and structural markers define neuronal subgroups that can be inferred to subserve different functions and may initiate specific reflex responses. The higher prevalence of TRPV1(+)/ASIC3(- )neurons among pleural afferents probably reflects the high sensitivity of the parietal pleura to painful stimuli

The Schroeder paradox or how the state of water affects the moisture transfer through edible films

The objective of this work was to better understand the water permeation through edible films when water is either in its vapour or in its liquid state related to their physico-chemical properties. Film based on iota-carrageenans or sodium alginate, containing or not fat, and encapsulating or not an aroma compound (n-hexanal) have been prepared. Films were conditioned at three different relative humidities, 0%, 43% and 84%. The incorporation of the n-hexanal in both types of biopolymer modifies the mechanical properties of film matrix and has a synergistic effect when associated to fat. Increasing the moisture content induces film plasticization by decreasing the glass transition of the glycerol enriched phase. Only carrageenan displays similar value for the liquid water transfer rate whereas a discrepancy of the behaviour in contact of liquid or vapour was observed for the alginate-based film, confirming the Schroeder paradox due to swelling. (C) 2011 Elsevier Ltd. All rights reserved.We are grateful to the CONACyT of Mexico for their support to author A. Hambleton and Universidad Politecnica de Valencia. Authors also thank Marc Desprairies from Cargill for its advice and council in using hydrocolloids.Hambleton, A.; Perpinan-Saiz, N.; Fabra Rovira, MJ.; Voilley, A.; Debeaufort, F. (2012). The Schroeder paradox or how the state of water affects the moisture transfer through edible films. Food Chemistry. 132(4):1671-1678. doi:10.1016/j.foodchem.2011.03.009S16711678132