Protons: small stimulants of capsaicin-sensitive sensory nerves

The data reviewed in this article suggest that protons should no longer be considered simply as an unwanted by-product of anaerobic respiration that results from either an accumulation of inflammatory cells or a reduced oxygenated blood supply during ischaemia. A fall in extracellular pH can stimulate a subpopulation of sensory nerves by activation of ion channels. The available evidence indicates that most, if not all, of the activated neurones are also stimulated by capsaicin, and that protons and capsaicin share a common mechanism of neuronal activation. A proton should be viewed as a mediator that elicits a protective response with reflex cardiovascular and respiratory responses, which modulate systemic blood flow, and with the local release of sensory neuropeptides, which vasodilates the microvasculature and stimulates extravasation.     

Alpha,beta-unsaturated aldehydes in cigarette smoke release inflammatory mediators from human macrophages

Smoking cigarettes is the major risk factor for chronic obstructive pulmonary disease (COPD). COPD is a condition associated with chronic pulmonary inflammation, characterized by macrophage activation, neutrophil recruitment, and cell injury. Many substances contained in cigarette smoke, including reactive oxygen species (ROS), have been proposed to be responsible for the inflammatory process of COPD. However, this issue remains unsettled. By gas chromatography/mass spectrometry (GC/MS) we show that acrolein and crotonaldehyde, two alpha,beta-unsaturated aldehydes, are contained in aqueous cigarette smoke extract (CSE) at micromolar concentrations and mimic CSE in evoking the release of the neutrophil chemoattractant IL-8 and of the pleiotropic inflammatory cytokine TNF-alpha from the human macrophagic cell line U937. In addition, acrolein (10-30 microM) released IL-8 also from cultured human alveolar macrophages and THP-1 macrophagic cells. 4-hydroxy-2-nonenal (30-100 microM), an endogenous alpha,beta-unsaturated aldehyde that is abundant in lungs of patients with COPD, stimulated the release of IL-8 from U937 cells, whereas the saturated aldehyde, acetaldehyde, was ineffective. CSE-evoked IL-8 release was remarkably (> 80%) inhibited by N-acetyl-cysteine (0.1-3 mM) or glutathione monoethyl ester (1-3 mM). Both compounds, by forming covalent adducts (Michael adducts), completely removed unsaturated aldehydes from CSE. Our data demonstrate that alpha,beta-unsaturated aldehydes are major mediators of cigarette smoke-induced macrophage activation, and suggest that they might contribute to pulmonary inflammation associated with cigarette smoke.     

Angiotensin-converting enzyme gene polymorphism may influence blood loss in a geriatric population undergoing total hip arthroplasty

OBJECTIVES: To evaluate how angiotensin-converting enzyme (ACE) gene polymorphism is associated with perioperative blood loss in hip arthroplasty in a geriatric population. DESIGN: A case-control study of subjects consecutively undergoing total hip arthroplasty. SETTING: A department of orthopedic surgery in Italy. PARTICIPANTS: One hundred five patients, mean age +/- standard deviation 68.6 +/- 10.4, undergoing total hip arthroplasty. MEASUREMENTS: ACE gene polymorphism was analyzed using polymerase chain reaction. Decrement of hemoglobin (Hb) and hematocrit (Ht) was calculated as the difference between the preoperative and the lowest postoperative value, measured 1, 2, and 3 days after surgery. Total blood loss was calculated as the sum of intra- and postoperative blood loss. RESULTS: Patients carrying the deletion homozygous and insertion/deletion heterozygous genotypes of the ACE gene show a higher decrement of Hb (P <.01) and Ht (P <.01) and higher total blood loss (P <.007) after hip surgery than subjects carrying the insertion (II) homozygous. The role of ACE gene polymorphism seems hypertension independent. Logistic regression analysis showed that II genotype reduces total blood loss. CONCLUSIONS: This is the largest study evaluating the distribution of ACE gene genotypes in patients undergoing hip arthroplasty and the first investigating the association between bleeding and ACE gene polymorphism. Our data suggest that II genotype is associated with lower total blood loss.     

Protease-activated receptor-2 stimulates angiogenesis and accelerates hemodynamic recovery in a mouse model of hindlimb ischemia

Proteinase-activated receptors (PAR-2) are expressed by the cardiovascular system and mediate vasodilation, plasma protein extravasation, and endothelial cell proliferation, all regarded as essential steps for neovascularization. We investigated the angiogenic action of PAR-2 signaling in vivo. The effect of the PAR-2 activating peptide (PAR-2AP, SLIGRL-NH2) was assessed in the absence of ischemia, and the therapeutic potential of PAR-2AP and the PAR-2 agonist trypsin (at 300 and 1.5 nmol IM daily for 21 days, respectively) was also tested in mice subjected to unilateral limb ischemia. PAR-2AP increased capillarity in normoperfused adductor skeletal muscles, whereas neither the vehicle of the PAR2-AP nor the PAR-2 reverse peptide (PAR-2RP, LRGILS-NH2) did produce any effect. In addition, both PAR-2AP and trypsin enhanced reparative angiogenic response to limb ischemia, an effect that was not produced by PAR-2RP or the vehicle of PAR-2 agonists. Potentiation of reparative angiogenesis by PAR-2AP or trypsin resulted in an accelerated hemodynamic recovery and enhanced limb salvage. In conclusions, our study is the first to demonstrate the angiogenic potential of PAR-2 stimulation in vivo. If similar effects occur in humans, PAR-2AP agonists could have some therapeutic potential for the treatment of tissue ischemia.     

Liposome-Entrapped γ-Aminobutyric Acid Inhibits Isoniazid-Induced Epileptogenic Activity in Rats

Sprague-Dawley rats with interictal and ictal spike activity induced by intraperitoneally injected isoniazid (INH) were treated, 5 min before or 30 min later, with liposome-entrapped gamma-aminobutyric acid (GABA) (LEG) or GABA or phosphatidylserine. Crossover injections were given in random sequence and INH alone ws also injected in every animal as a control. LEG inhibited either seizures or interictal spikes in both groups. No decrease of epileptogenic activity was seen after GABA or phosphatidylserine treatment alone. It is suggested that LEG could contribute to the reconstitution of the GABA pool decreased by INH.     

Clinical significance of lympho vascular space involvement and lymph node micrometastases in early-stage cervical cancer: a retrospective case-control surgico-pathological study

OBJECTIVE: Several studies have shown that lympho vascular space involvement (LVSI) and lymph node micrometastases (LNmM) may be risk factors for recurrence in early-stage cervical cancer with no apparent lymph node metastases. We performed a retrospective case-control study to reassess whether the presence of lymph node micrometastases and LVSI is predictive of subsequent recurrence following surgical resection of early-stage cervical cancer. METHODS: In a series of 292 patients diagnosed with early cervical cancer and treated by the same surgical procedure (laparoscopic-vaginal radical hysterectomy) during the same time period, two paired series were selected. The first series consisted of 26 cases who recurred in a median time of 36.8 months and the second series were 26 cases matched for age, histological sub-type, surgico-pathological stage and maximal tumor diameter, who did not recur after a median follow-up of 122 months. Sections taken from the hysterectomy specimens were reassessed for LVSI. All the lymph node blocks which have initially been considered as uninvolved were submitted to serial sectioning. Immunohistochemical staining using anti-cytokeratins AE1 and AE3 was used for identifying LNmM. RESULTS: LVSI was twice more frequent and LNmM ten-fold more frequent in the group of patients who recurred: 20/26 (77%) versus 9/26 (35%) and 11/26 (42%) versus 1/26 (4%) respectively. The relative risk of recurrence is 2.64 (1.67-5.49, P < 0.01) in the presence of LVSI and 2.44 (1.58-3.78, P < 0.01) in the presence of LNmM. All the patients with LNmM were LVSI positive. At bivariate analysis, the true LNmM (deposits more than 200 um in size) was the only independent risk factor. CONCLUSIONS: LNmM is an important risk factor of tumor recurrence in patients with early cervical cancer with no apparent lymph node metastases. LNmM seems to occur only in LVSI positive tumors. These data may lead to improve management of early-stage cervical cancer to reduce the risk of recurrence in those cases.     

Effect of Calcium Entry Blockade on ethanol-induced changes in bronchomotor tone

Summary The effect of various Calcium Entry Blockers (CEBs; nifedipine, flunarizine, diltiazem, verapamil) on ethanol-induced bronchoconstriction was studied in normal healthy volunteers. Nifedipine and diltiazem inhibited the bronchoconstriction and verapamil and flunarizine had no effect. The data favour the general hypothesis of differential tissue sensitivity to the various CEBs. The activity of CEBs on bronchomotor tone may be of therapeutic value in patients in whom bronchodilator activity is recommended in addition to the cardiovascular action.     

Hydrogen sulfide causes vanilloid receptor 1-mediated neurogenic inflammation in the airways

Hydrogen sulfide (H(2)S) is described as a mediator of diverse biological effects, and is known to produce irritation and injury in the lung following inhalation. Recently, H(2)S has been found to cause contraction in the rat urinary bladder via a neurogenic mechanism. Here, we studied whether sodium hydrogen sulfide (NaHS), used as donor of H(2)S, produces responses mediated by sensory nerve activation in the guinea-pig airways. NaHS evoked an increase in neuropeptide release in the airways that was significantly attenuated by capsaicin desensitization and by the transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine. In addition, NaHS caused an atropine-resistant contraction of isolated airways, which was completely prevented by capsaicin desensitization. Furthermore, NaHS-induced contraction was reduced by TRPV1 antagonism (ruthenium red, capsazepine and SB366791), and was abolished by pretreatment with the combination of tachykinin NK(1) (SR140333) and NK(2) (SR48968) receptor antagonists. In anesthetized guinea-pigs, intratracheal instillation of NaHS increased the total lung resistance and airway plasma protein extravasation. These two effects were reduced by TRPV1 antagonism (capsazepine) and tachykinin receptors (SR140333 and SR48968) blockade. Our results provide the first pharmacological evidence that H(2)S provokes tachykinin-mediated neurogenic inflammatory responses in guinea-pig airways, and that this effect is mediated by stimulation of TRPV1 receptors on sensory nerves endings. This novel mechanism may contribute to the irritative action of H(2)S in the respiratory system.