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PubMed1987

Correlation of the carcinogenic potential of di(2-ethylhexyl)phthalate (DEHP) with induced hyperplasia rather than with genotoxic activity.

It has been reported that in a long-term feeding study 12,000 ppm of di(2-ethylhexyl)phthalate (DEHP) in the diet produced hepatocellular carcinomas in male and female F-344 rats while 6000 ppm DEHP produced the same tumor type in male and female B6C3F1 mice. In terms of the actual numbers of animals with tumors DEHP produced a greater response in mice than rats. DEHP and its principal hydrolysis product, mono(2-ethylhexyl)phtalate (MEHP) produce multiple effects in the animal such as liver peroxisomal proliferation and hyperplasia. Accordingly, genotoxicity as DNA repair or unscheduled DNA synthesis (UDS) and cell replication as the percentage of cells undergoing scheduled DNA synthesis (SDS or S phase) were determined in mouse hepatocytes in vitro and in vivo in response to DEHP and MEHP. UDS and SDS were determined by autoradiographic quantitation of [3H]-thymidine incorporation in primary hepatocyte cultures treated directly or isolated from B6C3F1 male mice treated in vivo. No DNA repair was observed in mouse hepatocyte cultures treated with up to 1.0 mM DEHP or 0.5 mM MEHP. No DNA repair was observed in cultures from mice treated with up to 500 mg/kg DEHP 12, 24 or 48 h previously or from animals treated up to 28 days with 6000 ppm DEHP in the diet. At 24 h following treatment with 500 mg/kg DEHP, 3.1% of the hepatocytes were in S phase compared to control values of 0.2%. Administration of DEHP in the diet at 6000 ppm produced 9.2% of the cells in S phase at day 7 with the value returning to control levels by day 14. On day 28 of the feeding study the liver to body weight ratios had almost doubled in the group treated with DEHP compared to controls. No increase in the liver-specific enzyme alanine aminotransferase was seen in the serum following treatment with 500 mg/kg DEHP, indicating that the hyperplasia was due to mitogenic stimulation rather than regenerative hyperplasia in response to cytotoxicity. Increases in the endpoints relating to hyperplasia in response to DEHP were greater in the mouse than those that have been reported in the rat. Thus, the carcinogenic response of DEHP correlates better with induced hyperplasia rather than with genotoxicity.

Alanine Transaminase↗

PubMed1991

Nodular regenerative hyperplasia of the liver: an important cause of portal hypertension in non-cirrhotic patients.

In our hospital over the last 10 years a diagnosis of nodular regenerative hyperplasia was made for 13 patients. Sixty-nine percent of these patients had portal hypertension, representing 27% of all our patients with portal hypertension and a non-cirrhotic liver. Nodular regenerative hyperplasia was the second most frequent cause of portal hypertension in patients without cirrhosis. To make the diagnosis, a reticulin staining of a surgical biopsy is most helpful. However, the characteristic derangement of the liver architecture on histology may still be overlooked. In this study a suggestive relation was found between malignant disease (multiple myeloma, chronic myelogenous leukaemia, Leydig cell tumour and Hodgkin's disease), the use of cytotoxic or immunosuppressive drugs and nodular regenerative hyperplasia. Furthermore, a high rate of symptomatic nodular regenerative hyperplasia was observed in patients following kidney transplantation. Liver function abnormalities developed in these patients after a period ranging from 8 months to 3 years of immunosuppressive- or chemotherapy. These liver function abnormalities were, however, usually mild. Since hepatic encephalopathy is not likely to develop in these patients with nodular regenerative hyperplasia a decompressive shunt operation is a good alternative approach, if not the treatment of choice, for the prevention of recurrent variceal haemorrhage.

Adolescent↗

PubMed1983

Androgen excretion in women with a family history of breast cancer or with epithelial hyperplasia or cancer of the breast.

Urinary testosterone and androstanediol were measured by gas chromatography in four groups of premenopausal subjects: 22 healthy women (control group), 21 healthy women with a family history of breast cancer (familiality group), 39 patients with breast lumps which consisted of ductal or lobular hyperplasia (hyperplasia group) and 18 patients with infiltrating breast carcinoma (carcinoma group). On the basis of normal values found in our laboratory, steroid levels were above normal in 4.5% of the controls, 4.7% of the familiality group, 38.5% of the hyperplasia group (P less than 0.01 vs controls) and 61.1% of the carcinoma group (P less than 0.001 vs control group). The mean testosterone level in the carcinoma group (11.3 +/- 6.78 S.D.) and the mean androstanediol level in the hyperplasia group (47.25 +/- 31.0 S.D.) were significantly higher than those of the control group (testosterone 6.25 +/- 3.48 S.D., androstanediol 32.55 +/- 20.0 S.D.). No significant difference was found in mean testosterone or androstanediol levels between the control group and the familiality group (testerone 5.41 +/- 3.6 S.D., androstanediol 29.38 +/- 15.89 S.D.). We conclude that increased excretion of androgenic steroids is a hormonal abnormality common to breast cancer patients and to patients with breast epithelial hyperplasia, but not to subjects with a family history of carcinoma of the breast.

Adult↗

PubMed1988

Induction of hyperplasia in the bladder epithelium of rats by a dietary excess of acid or base: implications for toxicity/carcinogenicity testing.

In previous studies we observed an increased incidence of hyperplasia in the epithelium of the urinary bladder of rats fed cereal-based stock diet supplemented with 6% monosodium glutamate (MSG) for 3 months. Hyperplasia was not enhanced, however, when 6% MSG was fed in a purified casein diet. Further studies have been conducted to identify the dietary factor that caused the different response with the two diets. Feeding MSG had a marked alkalizing effect on the urine. Rats fed purified diet produced urine of higher acidity than did those fed stock diet, a finding attributed to the greater excess of base in the stock diet. When diets with a considerable excess of cations were fed, urinary pH showed a characteristic pattern of widely differing values during a 24-hr period, with high values (pH greater than or equal to 8] for several hours of darkness, when food intake was high, declining during the day to a minimum at the end of the light period. Hyperplasia of the bladder epithelium was induced not only by feeding MSG, but also by feeding 5% of the alkalizing salt KHCO3, both in purified diet and in stock diet. The epithelial response to an alkalizing substance was prevented by simultaneous feeding of the acidifying salt NH4Cl. These findings indicate that the bladder changes induced by MSG are attributable to its alkalizing properties rather than to MSG per se. Moderate to severe hyperplasia of the bladder epithelium was induced also by feeding 5% NH4Cl in purified diet, a procedure accompanied by a further lowering of urinary pH. These findings showed that hyperplasia of the bladder epithelium of rats can be induced both by acidifying and by alkalizing the urine through manipulation of the acid-base balance of the basal diet. There is thus a possibility that, in carcinogenicity studies, administration of compounds to rats in the form of a salt may lead to erroneous conclusions.

Acid-Base Equilibrium↗

PubMed1992

Induction of reversible urothelial cell hyperplasia in rats by clorsulon, a flukicide with weak carbonic anhydrase inhibitory activity.

Clorsulon, a flukicide registered for use in treating Fasciola hepatica infections in cattle, has induced urinary bladder urothelial cell hyperplasia in rats at oral doses of 30 mg/kg/day or more. Despite previous testing at doses above this threshold, this lesion had not been found in subchronic or chronic toxicity studies in rats. After ruling out the presence of a contaminant as the causative factor in producing this lesion, a study was conducted in which clorsulon increased the pH and altered the electrolyte composition of urine, consistent with its weak carbonic anhydrase inhibitory activity. The acid/base balance of the diet markedly affected the threshold for induction of the urothelial cell hyperplasia: acidification by addition of 5% ammonium chloride to the diet reduced the incidence and severity. In additional studies it was found that the urothelial cell hyperplasia was most pronounced after 1 week of treatment compared with daily exposure for either 5 or 15 wk. The reversibility of the hyperplasia despite continued treatment confirms that the hyperplasia is not a preneoplastic lesion, a conclusion supported by negative studies of carcinogenicity in rodent bioassays of clorsulon and other drugs with carbonic anhydrase inhibitory activity.

Animals↗

PubMed1994

Gingival hyperplasia induced by calcium channel blockers: mode of action.

Gingival hyperplasia is a known side effect in patients treated with diphenylhydantoin, cyclosporin and the calcium channel antagonists. The present study proposes a mechanism by which calcium channel antagonists may induce gingival hyperplasia. The calcium antagonist induces blockage of the aldosterone synthesis in zona glomerulosa of the adrenal cortex since this pathway is calcium-dependent, cyclic nucleotide-independent. This may produce a feedback stimulation of an increase in pituitary secretion of ACTH which affects zona glomerulosa hyperplasia. This hyperplasia is merely related by accumulation of steroid intermediate products (androgens) that are transformed to testosterone because of an increase in 17-alpha-hydroxylase enzyme activity. Elevated levels of testosterone may act on the gingival cells and matrix to produce gingival hyperplasia.

Adrenocorticotropic Hormone↗

PubMed1994

Endometrial hyperplasia: efficacy of a new treatment with a vaginal cream containing natural micronized progesterone.

Seventy-eight premenopausal women affected by benign endometrial hyperplasia (60 simple and 18 complex) were treated from the 10th to the 25th day of the menstrual cycle with a vaginal cream containing 100 mg of natural micronized progesterone in polyethylene glycol base. The treatment lasted 3 months in 58 patients and 6 in the other 16 patients. Four patients were lost from the study. We observed a total of 67 complete regressions (90.5%) of which 58 (78.3%) occurred in the first 3 months and 9 (11.5%) after 6 months of treatment. Simple hyperplasia showed a significantly higher response to treatment in comparison with the complex type (P < 0.001). The most frequent endometrial pattern detected in the patients in whom hyperplasia regressed was of a secretive type. Recurrence of hyperplasia occurred in 1 out of 58 (1.72%) patients at the 3rd month and in 3 out of 49 (6.1%) patients at the 6th month after treatment. There were no significant differences between the two hystological groups in the percentage of recurrence. During treatment we observed a significant reduction of the amount, duration and frequency of the menstrual bleeding. Minimal side-effects were observed. In conclusion, for its effectiveness and safety, vaginal administration of natural micronized progesterone seems to be an interesting approach to benign endometrial hyperplasia, particularly indicated in women also affected by metabolic disorders.

Administration, Intravaginal↗

PubMed2006

Reactive hyperplasia of the oral cavity in Kerman province, Iran: a review of 172 cases.

The purpose of this study was to present the clinical features of reactive hyperplasia among Iranian people. A series of 172 consecutive confirmed cases were studied using the database available at the Department of Oral Medicine, Kerman School of Dentistry. Reactive hyperplasia was classified into five groups: traumatic fibroma, peripheral fibroma with calcification, pyogenic granuloma, peripheral giant cell granuloma, and hyperplasia caused by dentures. Age, sex, site, clinical and radiographic findings, and outcome of treatment were recorded. Ages ranged from 5 to 79 years (mean 36). More women were affected than men (M/F 1:1.5). Pyogenic granuloma (M/F 1:2.2, chi(2)=6.4, p=0.011) and hyperplasia caused by dentures (M/F 1:3.7, chi(2)=10.9, p=0.001) were significantly more common among women. Peripheral giant cell granuloma was more common among men (M/F 1.4:1). Of the 172 cases, 111 (64%) involved the gingiva. Pyogenic granuloma more often affected the maxillary gingiva, while traumatic fibroma, peripheral fibroma with calcification, and peripheral giant cell granuloma, were more common in the mandibular gingiva. Twenty peripheral giant cell granulomas and 23 pyogenic granulomas had ulcers on the surface. A tendency to bleed was common among patients with pyogenic granuloma (n=31) and peripheral fibroma with calcification (n=12). We have confirmed that the clinical features of reactive hyperplasia among Iranians are, for the most part, similar to those reported by other investigators.

Adolescent↗

PubMed2004

Interposition vein cuff and intimal hyperplasia: an experimental study.

OBJECTIVE: There is some evidence to suggest that prosthetic distal bypass graft patency can be improved, and the risk of intimal hyperplasia diminished, by interposing a distal vein cuff. We studied intimal remodeling in an end-to-side distal prosthetic anastomosis constructed with and without a vein cuff. METHODS: Twenty-four prosthetic bypasses were constructed with (N=12) or without (N=12) a distal vein cuff in 12 pigs. At 10 weeks, the 20 anastomoses and adjacent arteries from the surviving 10 pigs were studied by histology, immunohistochemistry and morphometry. RESULTS: Intimal hyperplasia was significantly less on all zones of the arterial floor and all suture zone of arteries anastomosed with a vein cuff than within arteries anastomosed without a vein cuff (0.11 versus 0.34; p=0.001 and 0.35 versus 1.19; p=0.0001, respectively). Intimal hyperplasia was also more prominent within the vein cuff than within the recipient artery, with or without a vein cuff (1.35 versus 0.38; p=0.0001). CONCLUSION: An interposition vein cuff at the distal anastomosis between a prosthesis and an artery alters the distribution of intimal hyperplasia. By acting as an expansion chamber where intimal hyperplasia can develop harmlessly, the vein cuff may protect the arterial anastomosis from stenosis.

Anastomosis, Surgical↗

PubMed2005

Frequency of pharyngeal reflux in children with adenoid hyperplasia.

OBJECTIVES: The purpose of the study is to investigate whether there is any association between pharyngeal reflux and adenoid hyperplasia by using 24-h esophageal pH monitoring with a dual probe in children. METHODS: The study group consisted of 30 children with adenoid hyperplasia, and the control group consisted of 12 healthy children, studied prospectively. All children underwent 24-h esophageal pH monitoring with a dual probe (distal and proximal esophageal pH monitoring). The results were evaluated by the Measurement and Analysis Software of Medical Measurement System program (Version: 7.2a). RESULTS: In the study group, the frequency of pharyngeal reflux was 46.7% and the gastroesophageal reflux (GER) was 64.5%, while, in the control group, they were 8.3% and 25%, respectively. There was a significant difference between study and control groups for frequencies of pharyngeal reflux and GER. Mean adenoid nasopharyngeal ratio (ANR) was 0.78+/-0.11 in children with adenoid hyperplasia. There was not a significant difference between positive pharyngeal reflux, positive GER and mean ANR (p>0.05). CONCLUSIONS: Children with adenoid hyperplasia had higher frequency of pharyngeal reflux than children at the same age healthy group. These results supported that pharyngeal reflux may play an important role in the etiology of adenoid hyperplasia.

Adenoids↗

PubMed2004

1,25-Dihydroxyvitamin D downregulation of TGFalpha/EGFR expression and growth signaling: a mechanism for the antiproliferative actions of the sterol in parathyroid hyperplasia of renal failure.

Elevated serum levels of parathyroid hormone (PTH) contribute to the increased morbidity and mortality in renal failure patients. Parathyroid gland hyperplasia is a major cause of high serum PTH. The present studies used the rat model of renal failure to address the mechanisms underlying uremia-induced parathyroid hyperplasia and the antiproliferative properties of vitamin D therapy (1,25-dihydroxyvitamin D (1,25(OH)(2)D(3)) or its less calcemic analogs). Enhanced TGFalpha/EGFR co-expression is the major mitogenic signal in uremic parathyroid glands. At early stages of renal failure, vitamin D therapy efficiently counteracts uremia- and high phosphorus-induced hyperplasia by inhibiting the increases in parathyroid-TGFalpha/EGFR co-expression. In established hyperparathyroidism, characterized by highly enhanced-TGFalpha/EGFR co-expression, vitamin D therapy arrests growth by suppressing EGFR-growth signals from the plasma membrane and nuclear EGFR actions as a transactivator of the cyclin D1 gene, an important contributor to parathyroid hyperplasia in humans. In advanced renal failure, reduced-parathyroid vitamin D receptor levels limits the antiproliferative efficacy of vitamin D therapy. However, non-antiproliferative doses of 1,25-dihydroxyvitamin D enhance the anti-EGFR actions of EGFR-tyrosine kinase inhibitors (TKI). In fact, combined 1,25-dihydroxyvitamin D/TKI therapy inhibits parathyroid hyperplasia more efficiently than phosphorus restriction, the most powerful promoter of parathyroid growth arrest available at present.

Cell Division↗

PubMed2004

Locally applied cilostazol suppresses neointimal hyperplasia by inhibiting tenascin-C synthesis and smooth muscle cell proliferation in free artery grafts.

OBJECTIVE: Accumulation of smooth muscle cells and extracellular matrix in the intima of artery bypass grafts induces neointimal hyperplasia, resulting in graft failure. We investigated the inhibitory effect of locally applied cilostazol, an inhibitor of cyclic adenosine monophosphate phosphodiesterase III, on neointimal hyperplasia and the role of tenascin-C synthesis and smooth muscle cell proliferation in free artery grafts. Methods and results We established a distal anastomotic stricture model of free artery graft stenosis using rat abdominal aorta. In this model, neointimal hyperplasia was observed not only in the distal anastomotic site but also in the graft body at postoperative day 14 and was markedly progressed at day 28. Strong expression of tenascin-C was found in the media and neointima of the graft body. When cilostazol was locally administered around the graft using Pluronic gel, neointimal hyperplasia of the graft was significantly suppressed in comparison with gel-treated control graft. The mean neointima/media area ratio was reduced by 86.6% for the graft body and by 75.8% for the distal anastomotic site versus the control. Cilostazol treatment decreased cell proliferation and tenascin-C expression in the neointima. In an in vitro experiment using cultured smooth muscle cells isolated from rat aorta, cilostazol completely suppressed the tenascin-C mRNA expression induced by platelet-derived growth factor-BB. CONCLUSION: A single topical administration of cilostazol may suppress neointimal hyperplasia by inhibiting cell proliferation and tenascin-C synthesis in free artery grafts, presenting the potential for clinical use in vascular surgery.

Administration, Topical↗

PubMed2005

A Gbetagamma inhibitor reduces intimal hyperplasia in aortocoronary saphenous vein grafts.

OBJECTIVE: Approximately 50% of aortocoronary saphenous vein grafts are occluded 10 years after coronary revascularization surgery. Intimal hyperplasia, a critical component in saphenous vein graft failure, is defined by vascular smooth muscle cell proliferation, which is mediated in part by betagamma subunits of heterotrimeric G proteins (G(betagamma)) and downstream effectors such as mitogen-activated protein kinases. A peptide consisting of the carboxyl-terminus of the beta-adrenergic receptor kinase (betaARKct) binds G(betagamma), thereby inhibiting G(betagamma) signaling. Utilizing a recombinant adenovirus containing the coding sequence for the betaARKct peptide (AdbetaARKct), this study investigates whether treatment of the vein graft with AdbetaARKct reduces intimal hyperplasia in a large animal model of aortocoronary saphenous vein graft intimal hyperplasia. METHODS: Twenty-seven dogs (27-32 kg) underwent aortocoronary bypass grafting to the left anterior descending artery using autologous saphenous vein. Vein grafts were treated with saline (n = 8), an empty adenovirus (n = 8), or AdbetaARKct (n = 8). A subset of dogs (n = 3) were sacrificed on postoperative day 7 and betaARKct expression confirmed by Northern blotting. RESULTS: Arteriograms performed on postoperative day 90 confirmed that saphenous vein grafts were patent. At postoperative day 90, AdbetaARKct-treated grafts demonstrated reduced intimal area compared to empty virus and saline treated animals (P < .05). Additionally, AdbetaARKct treatment of isolated vascular smooth muscle cells in vitro inhibited mitogen-activated protein kinase activation and decreased overall vascular smooth muscle cell proliferation. CONCLUSION: This study demonstrates that betaARKct expression in aortocoronary saphenous vein grafts reduces intimal hyperplasia and decreases vascular smooth muscle cell proliferation in vitro via inhibition of G(betagamma)-mediated mitogen-activated protein kinase activation. Modulation of G(betagamma) via betaARKct may represent a novel therapy to reduce intimal hyperplasia and saphenous vein graft failure.

Animals↗

PubMed2006

A selective alpha1A-adrenoceptor antagonist inhibits detrusor overactivity in a rat model of benign prostatic hyperplasia.

PURPOSE: Alpha(1)-adrenoceptor antagonists relax the obstructed prostatic urethra and suppress the irritative symptoms frequently observed in patients with benign prostatic hyperplasia. We investigated the effects of 3 alpha(1)-adrenoceptor antagonists on urodynamics in rats with hormone induced benign prostatic hyperplasia to determine which alpha(1)-adrenoceptor subtype selective antagonists would suppress irritative symptoms. MATERIALS AND METHODS: Rats were treated with testosterone and 17beta-estradiol by weekly intramuscular injections. After 4 weeks a pressure flow study was done and the effects of the alpha(1)-adrenoceptor antagonists KMD-3213 silodosin, tamsulosin and prazosin on urodynamics were compared. We especially investigated the involvement of the bladder and prostatic urethra to clarify the mechanism of detrusor overactivity expression. RESULTS: Hormone treatment induced benign prostatic hyperplasia and resulted in detrusor overactivity, as determined by cystometry. Baseline perfusion urethral pressure and the phenylephrine induced increase in it were significantly higher in rats with vs without benign prostatic hyperplasia. Cystometry in hormone treated female rats did not show detrusor overactivity. KMD-3213 decreased detrusor overactivity, similar to other alpha(1)-adrenoceptor antagonists. CONCLUSIONS: These results suggest that an excessive response to sympathetic nerve stimulation, which is mainly mediated via alpha(1A)-adrenoceptor, in the hypertrophied prostate gives rise to detrusor overactivity. Furthermore, the alpha(1A)-adrenoceptor selective antagonist KMD-3213 would be suitable for improving irritative symptoms in patients with benign prostatic hyperplasia.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed2007

A preliminary study of JM-27: a serum marker that can specifically identify men with symptomatic benign prostatic hyperplasia.

PURPOSE: Benign prostatic hyperplasia is a common disease in men that until recently was considered a single disease with varying symptoms. Our recent analysis has revealed that a molecular marker, JM-27, is able to distinguish at the tissue level between highly symptomatic individuals and those with histological disease. The goal of these studies was to determine if a serum based assay to detect JM-27 could distinguish men with different forms of benign prostatic hyperplasia. MATERIALS AND METHODS: A serum based enzyme-linked immunosorbent assay was developed using a novel anti-JM-27 monoclonal antibody. The assay was sensitive, detecting JM-27 at the low ng/ml level within the serum. A quantitative measurement of serum JM-27 levels was performed in 68 patients. The patients consisted of 3 groups of 29 patients with asymptomatic benign prostatic hyperplasia (American Urological Association symptom score of 15 or less), 39 with symptomatic benign prostatic hyperplasia (American Urological Association symptom score 16 to 32) and 17 with confirmed prostate cancer. The assay cutoff was determined after a pilot run of samples and applied prospectively. RESULTS: Using the determined cutoff, serum levels of JM-27 can distinguish between symptomatic and asymptomatic patient sets. The sensitivity and specificity of the assay are 90% and 77%, respectively. The presence of prostate cancer in these men does not appear to alter the marker levels. CONCLUSIONS: The present study is believed to represent the first characterization of a serum based marker for severe benign prostatic hyperplasia.

Antigens, Neoplasm↗

PubMed2004

Perivascular delivery of losartan with surgical fibrin glue prevents neointimal hyperplasia after arterial injury.

OBJECTIVE: Long-term success of revascularization procedures is limited by recurrent stenosis, a reduction in vascular lumen area that results from neointimal hyperplasia. Inhibitors of the renin-angiotensin system, such as losartan, have potential to prevent recurrent stenosis; however, to date, efficacy has not been demonstrated in either animal models or human beings. While we have previously reported that treatment with a satisfactory dose may be an important element in obtaining efficacy, oral delivery cannot achieve the required concentration. We therefore tested the ability of losartan to restrict neointimal hyperplasia after local delivery of an elevated dose in a fibrin glue. METHODS: The porcine saphenous artery was subjected to balloon angioplasty. Losartan (25 micromol/mL) was applied directly to the adventitial surface of the injured vessel after mixing with 1.0 mL of Tisseel. Neointimal formation was quantified after 14 days with morphometry, and immunologic staining was used to monitor expression of proteins associated with cell proliferation, migration, and phenotypic modulation. RESULTS: A statistically significant decrease of 82% (n = 5) in neointimal area was obtained with losartan, and cell proliferation, as defined by proliferating cell nuclear antigen (PCNA) expression, was inhibited by 97%. Reduced cyclin A expression in losartan-treated vessels confirmed that cell cycle progression was blocked; however, the presence of cytokeratin 8 and tenascin in the media and neointima of injured vessels, regardless of treatment, suggested that losartan does not restrict phenotypic modulation. Inhibition of MT1-MMP (MMP-14) expression by losartan indicated that this inhibitor likely suppresses cell migration as well. CONCLUSIONS: These data demonstrate that losartan can effectively prevent recurrent stenosis when delivered locally with a fibrin glue such as Tisseel. Our results also indicate that losartan may operate by interfering with the expression of proteins required for cell cycle progression and migration. CLINICAL RELEVANCE: Release of angiotensin II in response to vascular injury may promote neointimal hyperplasia, because this hormone can stimulate smooth muscle cell proliferation and migration. This study demonstrates that local application of an angiotensin receptor antagonist, losartan, to the site of injury can effectively prevent neointimal hyperplasia after balloon angioplasty. Application of losartan to the perivascular surface of the injured vessel in a surgical fibrin glue enabled delivery of a dose that exceeds the maximum attainable, via a systemic delivery route. The glue also served as a depot from which the drug was slowly released over time. Treatment with losartan may be a viable approach for controlling neointimal hyperplasia at locations (eg, grafts) that are accessible during a surgical procedure.

Administration, Topical↗

PubMed2005

Rapamycin-coated expanded polytetrafluoroethylene bypass grafts exhibit decreased anastomotic neointimal hyperplasia in a porcine model.

OBJECTIVE: We tested the hypothesis that rapamycin coated onto, and eluted from, expanded polytetrafluoroethylene (ePTFE) grafts would diminish neointimal hyperplasia in a porcine model. METHODS: Rapamycin (also called sirolimus) was coated onto the luminal surface of 6-mm-internal-diameter thin-walled ePTFE grafts by using an adhesive polymer that allows timed release of the drug. An adhesive polymer that allows timed release of rapamycin from ePTFE was developed with commercially available chemicals and applied on 6-mm ePTFE grafts. Graft integrity was characterized by scanning electron microscopy, and rapamycin levels were quantified by using high-performance liquid chromatography. Twenty-two mongrel pigs were randomized into three groups: untreated ePTFE (n = 6), adhesive-only coated ePTFE (n = 6), or adhesive- and rapamycin-coated ePTFE (n = 10). End-to-side unilateral aortoiliac bypasses were performed by using 6-mm-internal-diameter ePTFE grafts and standardized anastomotic lengths. Unilateral end-to-side aortoiliac ePTFE grafts (6-mm internal diameter) were inserted by using polypropylene sutures, 6-0 proximally and 7-0 distally; all anastomoses were 12 mm long. All animals received aspirin (325 mg orally) daily. All animals were given oral aspirin (325 mg) daily beginning on the day before surgery. At 28 days, the animals were killed, and the grafts were explanted in continuity with the adjacent aortic cuff and the outflow iliac artery. Variables compared between groups included graft patency, distal anastomotic length and cross-sectional narrowing, and intimal thickness at the arterial-graft junction indexed to the adjacent graft thickness. Microscopic analysis was performed with hematoxylin and eosin and Masson trichrome stains on paraffin sections. A pathologist blinded to experimental groups graded sections for collagen deposition, neointima formation, inflammatory cellular infiltrates, medial necrosis, and aneurysmal degeneration. RESULTS: All animals survived until they were killed without clinical evidence of limb ischemia or graft infection. Preplanned t tests in the context of one-way analysis of variance showed no difference in outcome measures between the untreated ePTFE and adhesive-only coated ePTFE groups; therefore, they were combined in further comparisons with the adhesive- and rapamycin-coated ePTFE group. The Rapamycine eluting expanded polytetrafluoroethylene group had longer anastomoses (85.6% vs 60.6% of the initial anastomotic length maintained; P < .0001) and less cross-sectional narrowing in the outflow graft (16.2% vs 28.5%; P = .0007) when compared with the other two groups by using two-tailed Student t tests. There was no evidence of medial necrosis or aneurysmal degeneration. All patent grafts had complete endothelialization on hematoxylin and eosin sections. Rapamycin was detectable and quantifiable in the arterial wall at 28 days after implantation. CONCLUSIONS: Rapamycin can be coated onto and eluted from ePTFE by using a nonionic polymer and a simple coating technique. At 4 weeks after implantation, the rapamycin-eluting ePTFE grafts demonstrate gross, pathologic, and morphometric features of diminished neointimal hyperplasia when compared with non-drug-eluting ePTFE. Four weeks after implantation in a porcine model, rapamycin-eluting ePTFE grafts demonstrated gross, pathologic, and morphometric features of diminished neointimal hyperplasia when compared with untreated and adhesive-only coated ePTFE grafts. CLINICAL RELEVANCE: Rapamycin-eluting ePTFE grafts decrease neointimal hyperplasia in a porcine model. Further studies are needed to evaluate whether patency will be improved. Rapamycin-eluting ePTFE grafts may allow the use of prosthetic grafts in situations in which autologous vein is unavailable and in which neointimal hyperplasia is pronounced, such as in small-diameter (<6-mm) vessels typical of infrapopliteal interventions.

Anastomosis, Surgical↗

PubMedDate not supplied

Antegrade iliac artery stent implantation for the temporal and spatial examination of stent-induced neointimal hyperplasia and alterations in regional fluid dynamics.

INTRODUCTION: Neointimal hyperplasia remains an important problem after stent implantation. Previous investigations examining vascular responses to stent implantation and effects of drugs have used a retrograde deployment approach that may inadvertently alter the local fluid dynamics surrounding the stent. We present a model of antegrade iliac artery stent implantation that facilitates the analysis of stent-induced alterations in neointimal hyperplasia and wall shear stress in vivo. METHODS: Stent delivery catheters were inserted through the left carotid artery in anesthetized rabbits (n=37). Catheters were advanced under fluoroscopic guidance to the distal iliac arteries, where the stent was deployed. Hemotoxylin and eosin (H&E) staining of unstented and stented vascular sections was performed 21 days after implantation. RESULTS: Selective unilateral stent implantation was successful in 32 of 37 rabbits. No histological abnormalities were observed in the aorta, contralateral unstented iliac, or distal femoral arteries. Neointimal hyperplasia was localized to the stented region. DISCUSSION: The model of stent implantation was relatively easy to perform and produced selective neointimal hyperplasia within the stented region without evidence of damage, cellular proliferation, or flow disruption in the surrounding normal arterial vessels. The model will allow detailed examination of the influence of stent implantation on indices of wall shear stress, neointimal hyperplasia, the mechanisms of cellular proliferation in vivo, and their modification by drugs.

Animals↗