Ezetimibe reduces plaque inflammation in a rabbit model of atherosclerosis and inhibits monocyte migration in addition to its lipid-lowering effect.

BACKGROUND AND PURPOSE: Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, might also suppress inflammatory components of atherogenesis. We have studied the effects of ezetimibe on two characteristics of atherosclerotic plaques (infiltrate and fibrosis) and on expression of inflammatory genes in a rabbit model of accelerated atherosclerosis. EXPERIMENTAL APPROACH: Femoral atherosclerosis was induced by a combination of endothelial desiccation and atherogenic diet. Animals were randomized to ezetimibe (0.6 mg x kg(-1) x day(-1)), simvastatin (5 mg x kg(-1) x day(-1)), ezetimibe plus simvastatin or no treatment, still on atherogenic diet. A control group of rabbits received normolipidemic diet. KEY RESULTS: Rabbits fed the normolipidemic diet showed normal plasma lipid levels. Either the normolipidemic diet or drug treatment reduced the intima/media ratio (normolipidemic diet: 22%, ezetimibe: 13%, simvastatin: 27%, ezetimibe + simvastatin: 28%), compared with rabbits with atherosclerosis. Ezetimibe also decreased macrophage content and monocyte chemoattractant protein-1 expression in atherosclerotic lesions. Furthermore, ezetimibe reduced the increased activity of nuclear factor kappaB in peripheral blood leucocytes and plasma C-reactive protein levels in rabbits with atherosclerosis. In THP-1 cells, ezetimibe decreased monocyte chemoattractant protein-1-induced monocyte migration. Importantly, the combination of ezetimibe with simvastatin was associated with a more significant reduction in plaque monocyte/macrophage content and some proinflammatory markers than observed with each drug alone. CONCLUSIONS AND IMPLICATIONS: Ezetimibe had beneficial effects both on atherosclerosis progression and plaque stabilization and showed additional anti-atherogenic benefits when combined with simvastatin. Its effect on monocyte migration provides a potentially beneficial action, in addition to its effects on lipids.

Improving the cadmium-induced centriacinar emphysema model in rats by concomitant anti-oxidant treatment.

1. The aim of the present study was to perform an evolutionary analysis of the morphometrical, biochemical and functional parameters of centriacinar emphysema induced by cadmium chloride (CdCl2) in rats and to determine the effects of concomitant N-acetylcysteine (NAC) administration. 2. Male Wistar rats were instilled orotracheally with either CdCl2 (n = 24) or saline (n = 24). One group of rats, consisting of both CdCl2- and saline-treated rats, was fed a normal diet (n = 24), whereas the other group received NAC (n = 24). 3. Changes in inspiratory capacity (IC), lung compliance (CL), expiratory flow at 75% (F75), forced vital capacity (FVC) and hydroxyproline content were assessed 2, 8, 21 and 45 days after instillation. Polymorphonuclear cells were evaluated 2 and 8 days after instillation and the mean linear intercept (Lm) was determined at 21 and 45 days. 4. Over time, CdCl2 instillation causes several changes that are bound up with centriacinar emphysema. The concomitant administration of NAC to CdCl2-treated rats partially reversed Lm at 21 days compared with CdCl2 alone (115 +/- 2 vs 127 +/- 2, respectively; P < 0.05). However, 45 days after instillation, NAC improved lung function in CdCl2-treated rats compared with that in the saline-treated control group (IC 14.64 vs 15.25, respectively (P = 0.054); FVC 16.94 vs 16.28, respectively (P = 0.052), F75 31.41 vs 32.48, respectively (P = 0.062)). In addition, 45 days after instillation, NAC reduced lung collagen content in both the saline-treated control (100 vs 81% alone and in the presence of NAC, respectively) and CdCL2-treated groups (213 vs 161% alone and in the presence of NAC, respectively). In addition, although the results were not significant, NAC tended to reduce Lm and enhance CL in NAC + CdCl2-treated rats. 5. In conclusion, NAC partially improved emphysematous changes and reduced collagen deposition, which diminished the CdCl2-induced fibrotic component of centriacinar emphysema.

Increased collagen deposition correlated with lung destruction in human emphysema.

BACKGROUND: To study the relationship between collagen amount and degree of emphysema as assessed by mean linear intercept (Lm) and correlating these with lung function test workup in patients with and without COPD. METHODS: Lung function tests were assessed in 16 smokers or ex-smokers and 1 non-smoker in order to separate them into two groups: COPD (FEV1/FVC lower than 70%) and non-COPD. A piece of lung tissue was used to analyse the collagen amount (HYP) by means of a colorimetric method. Morphometry was assessed to divide patients into two groups according to Lm: Lm > 260 micrometers was considered non-emphysema and Lm < 260 mm mild-emphysema. RESULTS: The non-emphysema group had a mean Lm value of 246.08+/-3.12 micrometers and the mild-emphysema group of 276.29+/-4.26 micrometers. The amount of hydroxyproline was significantly higher in the mild-emphysema group than in the non-emphysema group (7.82+/-0.67 vs. 5.50+/-0.54 microgram/g tissue). There was a clear positive correlation between Lm and HYP (r=0.55) and a negative correlation between Lm and DlCO (R=-0.5092). No correlation was found between the functional test and HYP, nor were there significant differences between COPD and non-COPD patients for Lm and HYP. CONCLUSIONS: Emphysema is associated with collagen deposition in the lungs, and air space size correlates with the amount of lung collagen even when there is no emphysema.

[Autoinflammatory disorders: a new concept in hereditary periodic fever syndromes]. / Trastornos autoinflamatorios: un nuevo concepto en síndromes de fiebre recurrente hereditaria.

At last year the great scientific advances in genetics and molecular biology have led to a bigger knowledge about we nowadays call "Autoinflammatory syndromes", characterized by recurrent inflammatory episodes genetically determined and not mediated by autoimmunity. In this group, they are included the hereditary periodic fever syndromes: familial mediterranean fever (FMF), hyper Ig-D syndrome (HIDS), TNF-receptor-associated periodic syndrome (TRAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), CINCA syndrome. The past 6 year have witnessed the identification of genes causing these diseases. Some of these genes encode proteins with a common domain (PYRIN domain). These protein are part of regulatory pathway of inflammation and apoptosis. The purpose of this article, is to carry out review of the genetic, clinical, molecular and rheumatologic aspect of these syndromes, in part unknown. Although they are not common, they are not absent in our diary clinical practise. Their study and research we will be able to obtain new knowledge that lead us to solve the complex inflammatory process.

N-acetylcysteine prevents cigarette smoke induced small airways alterations in rats.

This study investigated the effect of cigarette smoke exposure and the potential protection N-acetylcysteine (NAC) in rat lungs. Forty-eight rats were exposed to cigarette smoke (CS) for 10 weeks, without (CS group) or with (CS+NAC group) oral intake of NAC 200 mg x rat(-1) x day(-1), or to fresh air (Control). All rat lungs were assessed in terms of lung function, ventilation distribution (nitrogen, helium and sulphur hexafluoride phase III slopes), and morphometry (airway wall thickening of small, medium and large bronchi). The small bronchi, defined as the airways with an internal perimeter <1,000 microm showed significantly thicker airway walls in the CS than in the Control group. By contrast, no airway wall thickening was observed in the CS+NAC group with respect to Control. Except for decreased lung volumes and compliance in CS and CS+NAC groups, which were entirely attributable to smaller body weight gain, lung function was indistinguishable from Control. Phase III slopes were significantly increased only in the CS group. In conclusion, smoke-induced alterations in the rat lungs were reflected in wall thickening of the small bronchi and increased ventilation maldistribution. These smoke-induced morphometric and ventilation distribution alterations were prevented by N-acetylcysteine.

Lung function and ventilation inhomogeneity in rat lungs after allergen challenge.

We studied the early response to ovalbumin challenge in sensitized Brown-Norway rats through its effect on N(2), He, and SF(6) phase III slopes of the single-breath washout and on indexes of lung function. Sensitized rats showed varying degrees of response in terms of pulmonary pressure (PL), with increases ranging between 125 and 225% of baseline. The sensitized rats presented decreased quasistatic compliance, forced vital capacity, and end-expiratory flow, with all three lung function indexes showing a significant negative correlation with corresponding PL values. They also showed significant positive correlations of PL with the N(2), He, and SF(6) phase III slopes, reflecting diffusion-convection-dependent inhomogeneities generated by conformation changes throughout the entire rat lung. In addition, the rats showing the most marked PL increases (>150% baseline PL) also revealed a reversal of the SF(6)-He slope difference because of a more marked SF(6) than He slope increase. This latter finding suggests that the degree of structural heterogeneity during early response is even more marked in the most peripheral rat lung generations.

Intrapulmonary gas mixing in panacinar- and centriacinar-induced emphysema in rats.

We studied ventilation distribution using the single-breath washout technique in rats with two types of induced emphysema: panacinar-like (by instilled elastase) and centriacinar-like (by inhaled CdCl2 combined with oral intake of beta-aminopropionitrile). Morphologically, panacinar and centriacinar groups presented a similar degree of airspace enlargement, which was irregularly distributed and also accompanied by fibrosis only in the centriacinar group. In terms of mechanical properties, the centriacinar group presented lower end-expiratory flows and lower compliance than the panacinar group. The ventilation distribution patterns were also different between both groups. Single-breath washout phase III slopes, reflecting mainly diffusion-convection-dependent inhomogeneities in rat lungs, were largest in the centriacinar group. The SF6-He slope difference, which was reversed in both emphysema groups with respect to the control group, could be attributed mainly to He slope changes in the panacinar group and to SF6 slope changes in the centriacinar group. In addition, the respective He and SF6 slope decrease as a function of end-inspiratory breath-hold time, was only different from the control group in the centriacinar group. The observed ventilation distribution patterns can be explained by interacinar elastic changes in the panacinar group and severe interacinar structural alterations in the centriacinar group.

Endothelin-1 expression during early response after antigen challenge in brown-norway rats.

The objective of this study is to investigate if endothelin-1 (ET-1) gene expression changes during the early response phase following antigen challenge. We used sensitized Brown-Norway rats known to develop an early airway response after antigen challenge. After ovalbumin challenge, sensitized rats presented an early response, characterized by an increase in pulmonary pressure (209+/-14.53%,P<0. 01) and diminished functional parameters (inspiratory capacity, forced vital capacity (FVC) and expiratory flow at 75% of FVC), compared to their respective basal values. ET-1 mRNA expression was assessed by reverse transcription and polymerase chain reaction using specific primers for prepro-ET-1. A group of unsensitized rats was used as control. ET-1 expression was significantly enhanced in sensitized rats during the early response (290+/-62%,P<0.01) compared to the control group. In conclusion, antigen challenge induces an activation of ET-1 gene expression during the early response in Brown-Norway rats, suggesting a contribution of this protein to the development of bronchoconstriction.

[Assessment of the effect of a 5-alpha-reductase inhibitor on cultured explants of human prostate]. / Valoración de la acción de un inhibidor de la 5-alpha-reductasa sobre cultivos de explantes de próstata humana.

For the present work, cultures of hyperplastic human prostate explants were performed to evaluate the "in vitro" response of a 5-alpha reductase inhibitor-finasteride. Explants were cultured over a nine-week period in RPMI-1640 media supplemented with Penicillin-Streptomycin 4% and Fetal Bovine Serum 10%. Cultures were divided into one control group, one with testosterone added (1.25 x 10(4) micrograms/ml) and one which received testosterone (1.25 x 10(-4) micrograms/ml) plus finasteride (0,0038 mg/ml). Control explants showed involutive changes throughout the experience, which occurred later in those treated with testosterone and earlier and more marked in the case of finasteride. The testosterone-treated group showed intense positivity for PSA, a marker which reveals specific tissular functions, which remained uniformed in the control group through the entire experiment, and decreased gradually in the finasteride group. In summary, according to our work, culture of organs would be a useful tool for an in vitro evaluation of the hyperplastic human prostate response to the action of the 5-alpha reductase inhibitor, finasteride.

[Comparative ultrastructural study of the epithelial stromal junction in the prostatic gland]. / Estudio ultraestructural comparado de los E.S.J. en la glándula prostática.

In this paper, the authors carry out a comparative study of the structures adjacent to the alveolar periphery of the prostate-glands of men, dogs and bulls. In the three cases an E.S.J. (Epithelial-Stromal-Junction) similar to that described in the mammary gland and characterized in the first two cases by the existence of four, ultrastruct strata, consisting of the basal lamina, the somas of the adjacent fibroblasts and their cytoplasmic expansions as well as the arrangement of the intercellular, collagen microfibrils, was found to exist in this gland. In the case of the bovine prostate gland, the structural organization of the E.S.J. was basically characterized by the structural arrangement of the collagen microfibrils. The structures described constitute models on which to base future research on the hyperplastic and neoplastic processes of the prostate gland.