Rapidly changing perspectives about mast cells at mucosal surfaces

Summary: Mast cells (MCs) are major effector cells of immunoglobulin E (IgE)‐mediated allergic inflammation. However, it has become increasingly clear that they also play important roles in diverse physiological and pathological processes. Recent advances have focused on the importance of MCs in both innate and adaptive immune responses and have fostered studies of MCs beyond the myopic focus on allergic reactions. MCs possess a variety of surface receptors and may be activated by inflammatory mediators, IgE, IgG, light chains, complement fragments, proteases, hormones, neuropeptides, and microbial products. Following activation, they produce a plethora of pro‐inflammatory mediators and participate in inflammatory reactions in many organs. This review focuses on the role of MCs in inflammatory reactions in mucosal surfaces with particular emphasis on their role in respiratory and gastrointestinal inflammatory conditions.     

Proteinase-activated receptor 2 activation in the airways enhances antigen-mediated airway inflammation and airway hyperresponsiveness through different pathways

BACKGROUND: Serine proteinases such as mast cell tryptase, trypsin-like enzymes, and certain allergens are important in the pathogenesis of asthma. These proteinases can activate the proteinase-activated receptor (PAR)-2, which has been shown to be upregulated in the airways of patients with asthma. OBJECTIVE: The purpose of this study was to investigate PAR-2 activation in the airways during allergen challenge and its effects on the 2 principle features of asthma, airway inflammation and airway hyperresponsiveness (AHR). METHODS: Proteinase-activated receptor 2 activating peptide SLIGRL-NH2 (PAR-2 activating peptide [ap]) or control peptide LSIGRL-NH2 (PAR-2 control peptide [cp]) was administered alone or in conjunction with ovalbumin intranasally to mice, and AHR and airway inflammation were evaluated. RESULTS: PAR2ap did not induce AHR or airway inflammation in ovalbumin-sensitized mice that had not been challenged with ovalbumin. When administered with ovalbumin, PAR-2ap enhanced AHR and airway inflammation compared with ovalbumin administered alone or with PAR-2cp. The enhanced AHR persisted for 5 days, whereas the enhancement to airway inflammation dissipated. Mice administered PAR-2ap alone during the 5 days after the final antigen challenge demonstrated an additional enhancement to airway inflammation compared with the control animals. PAR-2ap administered with allergen increased TNF and IL-5 mRNA in lung tissue and IL-13 and TNF in bronchoalveolar lavage fluid. CONCLUSION: Exogenous PAR-2 activation in parallel with allergen challenge enhances allergen-mediated AHR and airway inflammation through distinct mechanisms. PAR-2 activation can also enhance established airway inflammation even when dissociated from exposure to allergen. Therefore, PAR-2 activation may play a pathogenic role in the development of AHR and airway inflammation.     

Effect of statins on collagen type I degradation in patients with coronary artery disease and atrial fibrillation

The present study was undertaken to assess the effect of statins on collagen type I degradation and C-reactive protein in patients with coronary artery disease and atrial fibrillation. One hundred six patients with coronary artery disease and atrial fibrillation were studied: 40 (36 men, mean age 72 +/- 8 years) treated with a statin and 66 (48 men, mean age 74 +/- 9 years) not treated with a statin. Serum concentrations of carboxy-terminal telopeptide of collagen type I, an index of collagen type I degradation, and high-sensitivity C-reactive protein were measured in all patients. Carboxy-terminal telopeptide of collagen type I levels were significantly higher (p <0.001) in statin-treated patients (0.64 ng/ml, 95% confidence interval [CI] 0.57 to 0.71) compared with nonstatin-treated patients (0.38 ng/ml, 95% CI 0.31 to 0.44). These changes were independent of cholesterol levels (before or after therapy). Statin-treated patients had significantly lower (p <0.001) C-reactive protein levels (0.25 mg/dl, 95% CI 0.23 to 0.28) compared to statin nonusers (1.1 mg/dl, 95% CI 0.92 to 1.25). In conclusion, this study suggests that therapy with statins in patients with coronary artery disease and atrial fibrillation is associated with an increase in collagen degradation and an attenuation of inflammation, independently of cholesterol lowering.     

Progesterone triggers selective mast cell secretion of 5-hydroxytryptamine

Mast cells are involved in allergic reactions where they secrete numerous mediators in response to immunoglobulin E and antigen. However, they have recently been implicated in neuroinflammatory conditions with a higher prevalence in women, and there have been clinical reports of progesterone anaphylaxis. When tested on purified rat peritoneal mast cells, progesterone alone stimulated release only of 5-hydroxytryptamine (serotonin) in a dose- and time-dependent manner. Serotonin release by progesterone was exceptional because it was not accompanied by histamine release or degranulation and was either augmented or unaffected by drugs which inhibit secretion induced by the classic mast cell secretagogue, compound 48/80. These findings indicate that mast cells are capable of selective serotonin secretion, previously shown only after pretreatment with certain tricyclic drugs, and may be involved in neuroendocrine syndromes.     

Opposing effects of short- and long-term stress on airway inflammation

Between 20% and 35% of subjects with asthma experience asthma exacerbations during periods of stress. The biological mechanisms underlying these exacerbations are not clearly understood, and the role of psychologic factors in the pathophysiology of asthma remains controversial. We investigated the ability of psychologic stress to modulate airway inflammation and airway hyperresponsiveness (AHR) to methacholine in a murine model of asthma. Animals were exposed to a stressor daily for 3 (short-term stress) or 7 (long-term stress) days. After allergen challenge, AHR was assessed through plethysmography, and bronchoalveolar lavage cells were counted as a measure of inflammation. After short-term stress, inflammatory cell number was decreased compared with unstressed animals, whereas levels of interleukin (IL)-6, IL-9, and IL-13 were increased. Administration of a corticosteroid receptor antagonist, before stress, prevented the decrease in inflammatory cell numbers. In contrast, animals stressed for 7 consecutive days showed a significant increase in inflammatory cell numbers, which was independent of the glucocorticoid response, but no change in cytokine levels. AHR was not altered in stressed animals. Our results indicate that repeated exposure to stress over the long term engages different mechanisms than short-term stress and can exacerbate the chronic inflammatory responses of the airway.     

Allergic sensitization enhances anion current responsiveness of murine trachea to PAR-2 activation

Protease-activated receptor 2 (PAR-2) is a G protein-coupled receptor possibly involved in the pathogenesis of asthma. PAR-2 also modulates ion transport in cultured epithelial cells, but these effects in native airways are controversial. The influence of allergic inflammation on PAR-2-induced changes in ion transport has received little attention. Here, we studied immediate changes in transepithelial short circuit current (I _sc) induced by PAR-2 activation in the tracheas of naive and allergic mice. Activation of PAR-2 with an apically added activation peptide (AP) induced a small increase in I _sc, while a much larger increase was observed following basolateral AP addition. In ovalbumin-sensitized and -challenged animals used as a model of allergic airway inflammation, the effect of basolateral AP addition was enhanced. Responses to basolateral AP in both naive and allergic mice were not decreased by blocking sodium absorption with amiloride or CFTR function with CFTR_inh172 but were reduced by the cyclooxygenase inhibitor indomethacin and largely blocked (>80%) by niflumic acid, a calcium-activated chloride channels’ (CaCC) blocker. Allergic mice also showed an enhanced response to ATP and thapsigargin. There was no change in mRNA expression of Par-2 or of the chloride channels Ano1 (Tmem16a) and Bestrophin 2 in tracheas from allergic mice, while mRNA levels of Bestrophin 1 were increased. In conclusion, basolateral PAR-2 activation in the mouse airways led to increased anion secretion through apical CaCC, which was more pronounced in allergic animals. This could be a protective mechanism aimed at clearing allergens and defending against mucus plugging.     

Erythrocyte membrane cholesterol and lipid core growth in a rabbit model of atherosclerosis: Modulatory effects of rosuvastatin

Background

Lipid core expansion is partly responsible for the conversion of a stable atherosclerotic lesion to a rupture-prone plaque. Intraplaque hemorrhage contributes to the accumulation of cholesterol within unstable plaques. In the present study, we investigated, using a rabbit model of atherosclerosis, the extent to which diet-induced increases in cholesterol content of erythrocyte membranes (CEM) contribute to lipid core expansion and the modulatory effect of rosuvastatin use.

Methods and results

Rabbits fed with atherogenic diet (0.75% cholesterol) for 5 months exhibited advanced atherosclerotic lesions (mean plaque area, 0.39 ± 0.03 mm²), and lipid core size was associated with the concentration–time integral (CTI) of CEM levels (r = 0.567, P = 0.004) independent of other established predictors of lipid core size. Further experiments were performed by feeding rabbits atherogenic diet (1% cholesterol) for 3 months, followed by either normal diet or normal diet plus rosuvastatin for the next 3 months. Although no differences were observed in total plaque area between both groups, administration of rosuvastatin was associated with significantly smaller lipid cores, fewer macrophages within the lipid core, less microvessels as well as with lower CTI of CEM levels compared to normal diet alone. Moreover, intraplaque erythrocyte membranes covered a smaller lipid core area in rabbits under rosuvastatin plus normal diet as opposed to rabbits under diet alone.

Conclusions

Increased CEM levels, induced by high-cholesterol diet, are associated with lipid core growth. Ingestion of a potent HMG-CoA reductase inhibitor (rosuvastatin) may decrease CEM levels, and this effect may contribute to regression of the lipid core.