Heterogeneity of calcium channels in mast cells and basophils and the possible relevance to pathophysiology of lung diseases: A review

Calcium plays a critical role in the formation and secretion of a wide variety of chemical mediators. Calcium slow-channel blockers,e.g. nifedipine and verapamil, have been shown to inhibit the synthesis of SRS (SRS-A, leukotrienes) in human and guinea pig lung tissue, thromboxane A₂ formation in rat lung and platelet activating factor in human neutrophils. Verapamil and nifedipine also prevent the release of lysosomal enzymes from rabbit and human polymorphonuclear neutrophils. Calcium-channel blockers produce variable inhibitory effects on allergic and nonallergic histamine secretion. Ca⁺⁺-entry blockers also inhibit the Ca⁺⁺ uptake (influx) into mast cells. Many of these inhibitory effects of Ca⁺⁺ antagonists are antagonized by an increased extracellular Ca⁺⁺ ion concentration. The magnitude of the inhibitory influences of Ca⁺⁺-channel blockers on allergic and nonallergic release of chemical mediators appears to depend on the cell source, species, nature and the concentration of the secretory stimuli as well as on the composition and pH of buffers and the concentration of Ca⁺⁺-entry blockers used. The data summarized in this review suggest the existence of a functional heterogeneity of Ca⁺⁺ channels in leukocytes, mast cells and basophils. Interference with the Ca⁺⁺-dependent steps involved in the formation and/or release of chemical mediators appears to be the primary mode of action for Ca⁺⁺-channel blockers in these cells.The differential effects of Ca⁺⁺ antagonists on Ca⁺⁺-dependent activation of phospholipase A₂, 5-lipoxygenase, and calmodulin (or other intracellular Ca⁺⁺-binding proteins) in different cell types (mast cells, basophils, leukocytes, lung tissue, etc.) may explain the variation of their effectiveness in inhibiting the synthesis/release of chemical mediators and antagonizing bronchoconstriction in response to diverse stimuli.During the process of hypersensitization and in immediate hypersensitivity diseases, Ca⁺⁺ homeostasis (uptake, mobilization, distribution, relocation, etc.) may be altered in leukocytes (mast cells, basophils) and lung tissues. The altered Ca⁺⁺ homeostasis could be responsible for the induction of airway hyperreactivity in asthmatics and for hyperreleasability of chemical mediators from leukocytes, mast cells and other cell types.The development of drugs (Ca⁺⁺-channel blockers, antiallergic agents) that are capable of selectively altering Ca⁺⁺-dependent functions in leukocytes (mast cells, basophils, macrophages) and lung tissue in disease staes would offer an attractive alternative and an effective therapeutic approach for obstructive respiratory diseases,e.g. allergic asthma, exercise-induced asthma and a variety of other mediator-dependent allergic disorders.     

Aeroallergen-induced immediate asthmatic responses and late-phase associated pulmonary eosinophilia in the guinea pig: effect of methylprednisolone and mepyramine

Guinea pigs were sensitized by intraperitoneal injection of ovalbumin, 10 micrograms mixed with 100 mg A1(OH)3 in saline. On days 15-30 sensitized guinea pigs were challenged with ovalbumin aerosol (0.5 mg/ml, 30 s, 15 psi) which produced immediate asthmatic responses characterized by dyspnea, convulsions, and some deaths during the first 14 min. Twenty to 24 h later the animals were sacrificed with an overdose of pentobarbital, and lungs, bronchi, and lower trachea were dissected and fixed in 10% neutral buffered formalin. Histopathological examination of randomly coded tissues of the respiratory tract revealed a pulmonary eosinophilic cellular infiltrate in the epithelium/subepithelium of trachea, bronchi, and bronchioles as well as the peribronchial, peribronchiolar, and perivascular areas of the lungs. Oral administration of mepyramine (10 mg/kg) 2 h before aeroallergen challenge provided complete protection against immediate asthmatic responses and prevented deaths during the first 14 min without influencing the late phase associated lung eosinophilic cellular infiltrate. The immediate asthmatic responses were not influenced by methylprednisolone (30 mg/kg) administered orally 24 and 2 h before aeroallergen challenge. Following an additional dose of methylprednisolone 4 h after challenge, there was a significant inhibition of pulmonary eosinophilia (30 mg/kg; -24 h, -2 h, and +4 h). These observations suggest that histamine is the principal mediator of immediate asthma attacks in guinea pigs. Methylprednisolone may be acting by inhibiting the production of eosinophil chemotactic factor of anaphylaxis (platelet-activating factor or leukotriene B4) from the alveolar macrophages, T lymphocytes, and perhaps other cells, thus preventing pulmonary eosinophilia.     

Inhibition of aeroallergen-induced bronchial eosinophilia by azelastine in guinea pigs.

The ability of azelastine to influence allergic bronchial eosinophil infiltration in guinea pigs was studied. Aeroallergen challenge of actively sensitized guinea pigs produces eosinophil infiltration in bronchoalveolar lavage fluid collected 20-24 h after aeroallergen exposure. Azelastine and methylprednisolone, administered orally 2 h before challenge, inhibited eosinophilic infiltration yielding the ED50s of 1.55 and 4.48 mg/kg, respectively. WEB-2086, a platelet-activating factor antagonist (3 mg/kg), and theophylline, a phosphodiesterase inhibitor (30 mg/kg), also suppressed allergic bronchial infiltration of eosinophils by 44%. The data obtained in this study demonstrate that azelastine exerts direct bronchial anti-inflammatory activity in guinea pigs.     

The association of Hospital Medicare beneficiary payer-mix,national quality rankings and outcomes following hepatopancreatic surgery

IntroductionWe sought to determine the impact of payer-mix on post-operative outcomes among Medicare beneficiaries following hepatopancreatic surgery.MethodsMedicare beneficiaries who underwent hepatopancreatic surgery were identified. Hospital quality markers were obtained from the Hospital General Information dataset. Hospitals were dichotomized (low/average vs. high) based on Medicare patient days versus all patient days irrespective of payer type.ResultsHigh Medicare patient-mix hospitals were more likely to be ranked higher than the national average relative to safety of care (29.4% vs. 38.1%) and timeliness of care (15.4% vs. 26.3%) versus low burden Medicare hospitals (both p < 0.001). However, Medicare beneficiaries who had hepatopancreatic surgery at a high Medicare patient-mix hospital were at higher risk of a complication (OR = 1.13, 95%CI 1.04–1.22), and death within 30-days (OR = 1.37, 95%CI 1.23–1.53) following surgery.ConclusionWhile hospitals caring for higher numbers of Medicare beneficiaries generally performed better on CMS quality indicators, these rankings did not equate to improved post-operative outcomes.     

Disparities in NCCN Guideline Compliant Care for Resectable Cholangiocarcinoma at Minority-Serving Versus Non-Minority-Serving Hospitals

Annals of Surgical Oncology - Racial/ethnic disparities in cancer outcomes may relate to variations in receipt of National Comprehensive Cancer Network (NCCN)&nbsp;guideline&nbsp;compliant...     

ASO Visual Abstract: Impact of Race/Ethnicity and County-Level Vulnerability on Receipt of Surgery Among Older Medicare Beneficiaries Diagnosed with Early Pancreatic Cancer

Annals of Surgical Oncology -     

Mucolytic activity of azelastine in mice and rats

The mucolytic activity of azelastine, an antiallergic/antiasthmatic drug, in mice and rats was investigated. The oral administration of test compounds 30 min before phenol red i.p. injection stimulated dye secretion in the trachea of mice. The resulting oral ED₅₀'s (mg/kg) were: azelastine, 0.16; salbutamol, 2.5;N-acetylcysteine, 61.8;S-Carboxymethyl-l-cysteine, <100; bromhexine, >100; and potassium iodide, 200. In rats, several drugs stimulated secretion of fluorescein sodium (FINa) in the tracheobronchial lumen. The resulting oral ED₅₀'s (mg/kg) were: azelastine, 0.33; terbutaline, 0.3; salbutamol, 0.89; andS-carboxymethyl-l-cysteine, 56.8. Terfenadine and diphenhydramine (1–10 mg/kg, p.o.) did not stimulate tracheal secretion in rats and mice. The mucolytic activity of azelastine may contribute to its overall effectiveness, including antitussive activity in asthmatics. Finally, this activity seems to be dissociated from its H₁-histamine receptor blocking activity.     

ASO Author Reflections: Minority-Serving Hospitals are Associated with Lower Likelihood of Providing NCCN Guideline Compliant Care to Patients with Resectable Cholangiocarcinoma

Annals of Surgical Oncology -     

Association of rs1568885, rs1813443 and rs4411591 polymorphisms with anti-TNF medication response in Greek patients with Crohn’s disease

AIM:To investigate the correlation between rs1568885,rs1813443 and rs4411591 polymorphisms and response to infliximab in a cohort of Greek patients with Crohn’s disease(CD).METHODS:One hundred and twenty-six patients diagnosed with CD based on standard clinical,endoscopic,radiological,and pathological criteria were enrolled in this study at the Gastroenterology Unit of the 2nd Department of Surgery and at the Colorectal Unit of the1st Department of Propaedeutic Surgery.Infliximab at a dose of 5 mg/kg was administered intravenously at weeks 0,2,6 and then every 8 wk.Clinical and serological responses were assessed using the HarveyBradshaw Index and serum C-reactive protein(CRP)levels,respectively,and the endoscopic response was evaluated by ileocolonoscopy performed at baseline and after 12-20 wk of therapy.The changes in endoscopic appearance compared to baseline were classified into four categories,and patients were classified as responders and non-responders.Genomic DNA from whole peripheral blood was extracted and genotyping was performed by allele-specific polymerase chain reactions.χ2test with Yate’s correction based on the S-Plus was used to compare the genotype frequencies.RESULTS:Eighty patients(63.49%)were classified as complete and 32(25.39%)as partial responders to infliximab,while 14(11.11%)were primary non-responders.No correlation was found between response to infliximab and patients’characteristics such as age,gender and disease duration.There was consistency between Harvey-Bradshaw index scores and serum CRP levels.The TT genotype of the rs1568885 polymorphism was significantly related to partial response(P=0.024)and resistance to infliximab(P=0.007)while the AT genotype was more frequent in partial responders(P=0.035)and in primary non-responders(P=0.032).Regarding rs1813443,the CC genotype was found to be associated with partial response(P=0.005)and primary resistance(P=0.002)to infliximab while no association was found between the rs4411591 polymorphism and the clinical response to infliximab.CONCLUSION:Based on our results,the rs1568885and rs1813443 polymorphisms are associated with clinical and biochemical response to infliximab in Greek patients with Crohn’s disease.