Expression of eicosanoid receptors subtypes and eosinophilic inflammation: implication on chronic rhinosinusitis

BACKGROUND: Eicosanoid receptors are G-protein-coupled receptors playing an important immunomodulatory role in airway diseases. However, there is little information on the expression of these receptors and their link with eosinophilic inflammation in paranasal sinus diseases. We aimed with this study to investigate the tissue expression of leukotrienes and prostaglandin E2 receptors in chronic rhinosinusitis patients and the link of this regulation with eosinophilic inflammation. METHODS: Samples were prepared from nasal tissue of patients with chronic rhinosinusitis without nasal polyps (CRS, n = 11), with nasal polyps (CRS-NP, n = 13) and healthy subjects (Controls, n = 6). mRNA expression of CysLT(1), CysLT(2), BLT(1), BLT(2), E-prostanoid receptors (EP(1), EP(2), EP(3), EP(4)) and sol-IL-5Rα was determined by real-time PCR. Concentrations of PGE2, LTC4/D4/E4, LTB4 and sol-IL-5Rα were determined by ELISA and of ECP by ImmunoCap. Protein expression and tissue localization of eicosanoid receptors and activated eosinophils were evaluated by immunohistochemistry. RESULTS: CysLT(1 )mRNA expression was significantly increased in CRS-NP compared to CRS and controls, and CRS compared to controls, whereas CysLT(2 )mRNA was enhanced in both CRS groups without differences between them. Levels of both receptors correlated to the number of activated eosinophils, sol-IL-5Rα, ECP and LTC(4)/D(4)/E(4 )concentrations in the disease groups. PGE(2 )protein concentrations and prostanoid receptors EP(1 )and EP(3 )were down-regulated in the CRS-NP tissue vs. CRS and controls, whereas EP(2 )and EP(4 )expression was enhanced in CRS and CRS-NP patients vs. controls. No differences in BLT receptors were observed between patients and controls. CONCLUSION: CyLTs receptors are up-regulated in nasal polyp tissue and their expression correlate with eosinophilic inflammation supporting previous results. Eicosanoid receptors mRNA pattern observed suggests that down-regulation of EP(1 )and EP(3 )in CRS-NP and up-regulation EP(2 )and EP(4 )in CRS and CRS-NP groups may have some role in the development of the diseases and their regulation may not be directly linked to eosinophil activation but involve post-transcriptional events mainly related to other inflammatory cell sources

Biphasic effect of extracellular ATP on human and rat airways is due to multiple P2 purinoceptor activation

BACKGROUND: Extracellular ATP may modulate airway responsiveness. Studies on ATP-induced contraction and [Ca(2+)](i )signalling in airway smooth muscle are rather controversial and discrepancies exist regarding both ATP effects and signalling pathways. We compared the effect of extracellular ATP on rat trachea and extrapulmonary bronchi (EPB) and both human and rat intrapulmonary bronchi (IPB), and investigated the implicated signalling pathways. METHODS: Isometric contraction was measured on rat trachea, EPB and IPB isolated rings and human IPB isolated rings. [Ca(2+)](i )was monitored fluorimetrically using indo 1 in freshly isolated and cultured tracheal myocytes. Statistical comparisons were done with ANOVA or Student's t tests for quantitative variables and χ(2 )tests for qualitative variables. Results were considered significant at P < 0.05. RESULTS: In rat airways, extracellular ATP (10(-6)–10(-3 )M) induced an epithelium-independent and concentration-dependent contraction, which amplitude increased from trachea to IPB. The response was transient and returned to baseline within minutes. Similar responses were obtained with the non-hydrolysable ATP analogous ATP-γ-S. Successive stimulations at 15 min-intervals decreased the contractile response. In human IPB, the contraction was similar to that of rat IPB but the time needed for the return to baseline was longer. In isolated myocytes, ATP induced a concentration-dependent [Ca(2+)](i )response. The contractile response was not reduced by thapsigargin and RB2, a P2Y receptor inhibitor, except in rat and human IPB. By contrast, removal of external Ca(2+), external Na(+ )and treatment with D600 decreased the ATP-induced response. The contraction induced by α-β-methylene ATP, a P2X agonist, was similar to that induced by ATP, except in IPB where it was lower. Indomethacin and H-89, a PKA inhibitor, delayed the return to baseline in extrapulmonary airways. CONCLUSION: Extracellular ATP induces a transient contractile response in human and rat airways, mainly due to P2X receptors and extracellular Ca(2+ )influx in addition with, in IPB, P2Y receptors stimulation and Ca(2+ )release from intracellular Ca(2+ )stores. Extracellular Ca(2+ )influx occurs through L-type voltage-dependent channels activated by external Na(+ )entrance through P2X receptors. The transience of the response cannot be attributed to ATP degradation but to purinoceptor desensitization and, in extrapulmonary airways, prostaglandin-dependent PKA activation

Right Hepatectomy in Patients over 70 Years of Age: An Analysis of Liver Function and Outcome.

BACKGROUND: As a consequence of the increase in life expectancy, hepatobiliary surgeons have to deal with an emerging aged population. We aimed to analyze the liver function and outcome after right hepatectomy (RH) in patients over 70 years of age. METHODS: From January 2006 to December 2009, we prospectively collected data of 207 consecutive elective hepatectomies. In patients who had RH, cardiac risk was assessed by a dedicated preoperative workup. Liver failure (LF) was defined by the "fifty-fifty" criteria at postoperative day 5 (POD) and morbidity by the Clavien-Dindo classification. Liver function tests (LFTs) and short-term outcome were retrospectively analyzed in patients over (elderly group, EG) and younger (young group, YG) than 70 years of age. RESULTS: Eighty-seven consecutive RH were performed during the study period. Indication for surgery included 90 % malignancy in 47 % of patients requiring preoperative chemotherapy. ASA grade &gt; 2 (44 vs. 16 %, p = 0.027), ischemic heart disease (17 vs. 5 %, p = 0.076), and preoperative cardiac failure (26 vs. 2 %, p &lt; 0.001) were more frequent in the EG (n = 23) than in the YG (n = 64). Both groups were similar regarding rates of normal liver parenchyma, chemotherapy and intraoperative parameters. The overall morbidity rates were comparable, but the serious complication (grades III-V) rate was relatively higher in the EG (39 vs. 25 %, p = 0.199), particularly in patients with diabetes mellitus (100 vs. 29 %, p = 0.04) and those who had additional nonhepatic surgery (67 vs. 35 %, p = 0.110) and transfusions (44 vs. 30 %, p = 0.523). The 90-day mortality rate was similar (9 % in the EG vs. 3 % in the YG, p = 0.28) and was related to heart failure in the EG. LFTs showed a similar trend from POD 1 to 8, and patients ≥70 years of age had no liver failure. CONCLUSIONS: Age ≥70 years alone is not a contraindication to RH. However, major morbidity is particularly higher in the elderly with diabetes. This high-risk group should be closely monitored in the postoperative course. Liver function is not altered in the elderly patient after RH