Distribution and significance of the smooth muscle component in polyps of the large intestine

Immunocytochemical staining for alpha smooth muscle actin specifically reveals the distribution of the muscularis mucosae and pericryptal intramucosal smooth muscle fibers in the normal mucosa and polyps of the large intestine. In the latter, the muscular component is hyperplastic, especially in pedunculated polyps, which display a thick "muscular zone" at the top of the stalk. The diagnostic (and prognostic) significance of the distribution pattern of the muscular component in polyps, and in "early invasion" cases, is discussed.     

Immunolocalization of beta catenin in intestinal polyps of Peutz-Jeghers and juvenile polyposis syndromes

AIM: To examine the membranous and nuclear distribution of beta catenin in the epithelial cells of gut polyps from Peutz-Jeghers syndrome and juvenile polyposis in comparison with other types of polyps and tumours. METHODS: Immunohistochemistry for beta catenin and proliferation markers was performed on conventional paraffin sections. Immunohistological staining was carried out on Peutz-Jeghers syndrome polyps from four different families, on juvenile polyposis polyps from two different families, on solitary juvenile polyps, and on hyperplastic polyps. The immunohistochemistry was evaluated qualitatively in relation to defined areas of the polyps. RESULTS: All polyps from the hamartomatous polyposis syndromes (Peutz-Jeghers syndrome and juvenile polyposis) showed nuclear localization of beta catenin in some epithelial cell nuclei. In Peutz-Jeghers syndrome polyps beta catenin positive nuclei were seen at the base of the deep crypt infoldings. In juvenile polyposis polyps and in some solitary juvenile polyps they were found in irregularly distributed cryptal epithelial cells corresponding to the proliferative compartments. Normal mucosa of the gut and hyperplastic polyps of the colon do not show nuclear staining for beta catenin. CONCLUSIONS: The dysregulation of cellular beta catenin distribution is not only a phenomenon of adenoma formation and adenoma progression in the colon--it is at least focally present in polyps of the hamartomatous type and is related to the proliferation zones of these polyps. The nuclear translocation of beta catenin most probably reflects a disturbed beta catenin metabolism. In view of the different functions of beta catenin during development and cell differentiation, the nuclear translocation of beta catenin is likely to be an important factor in enhanced cell proliferation which escapes local control mechanisms.     

Contraction in the smooth muscle cell

This paper advances the hypothesis that the rearrangement of the actin cytoskeleton that takes place during contraction in the SMC is a mechanical reflection of the spatiotemporal pattern of the cell's polarized stimulus. In that sense the cell is responding more like a motile non-muscle cell than like a skeletal muscle cell. The paper reviews how diffusion patterns are generated and modified and suggests how the patterns are detected by the cell and transduced into cytoskeletal movement. Evidence is presented suggesting the actin cytoskeleton is composed of conical-shaped myofibrils (contractile units) measuring half a cell in length and containing filament-free spaces at their centres filled with cell inclusions. It is argued that the SMC contracts by involving variable combinations of the myofibrils in sequence and that the cell takes advantage of that fact to translocate various contractile elements between the myofibrils during contraction, thus economizing on its needs for those elements. Among the elements translocated are thought to be myosin, SR and mitochondria.     

Identification of smooth muscle series elastic component in intact carotid artery.

Experiments were performed to indentify the series elastic component (SEC) in intact dog carotid artery held at in situ length. The vessels were studied during excitation of the muscle with norepinephrine and after metabolic poisoning with potassium cyanide and sodium iodoacetate. Static circumferential stress-strain curves and stress-quick-release stiffness curves were examined to evaluate Maxwell and Voigt model elements. The vessels were studied at 33, 36, and 39 degrees C. Temperature variations altered active stress, but did not alter connective tissue properties or the Maxwell SEC stiffness. The Voigt model SEC stiffness was altered, but this was secondary to changes in active stress. Thus, most of the SEC is separate from the contractile apparatus. Other vessels were treated with elastase, collagenase, or hyaluronidase to digest the connective tissue components of the wall. Hyaluronidase had no effect on mechanics. Elastase and collagenase altered connective tissue properties, but only elastase unequivocally altered SEC stiffness. This analysis indicated 1) that the carotid artery wall is better represented by a Maxwell model than a Voigt model, and 2) that the SEC in intact carotid artery is primarily elastin.     

Peutz-Jeghers syndrome with osseous metaplasia of the intestinal polyps

A cam of Peutz-Jeghers syndrome (PJS) with osseous metaplasia In three of 15 hamartomatous polyps of the small Intestine Is reported. At 35 years of age, the patient was diagnosed as having PJS by cutaneous pigmentation around the mouth and polyposis of the stomach, duodenum and Intestine. Fifty-two polyps of the large intestine were resected, which were Characteristic of those of PJS. Three of them showed adenomatous and carcinomatous changes, but there was no osseous metaplasia in any of the resected polyps. At age 40, he had surgery under the diagnosis of Intestinal obstruction. There were 15 polyps in the resected jejunum. These polyps were also characteristic of those of PJS. Additionally, three of these polyps were accompanied by osseous metaplasia. Histologically, mature bone formation and Calcification were found close to the hyperplastic glands In the submucosa or in the propriate muscle. Malignant transformation was not observed. Osseous metaplasia is extremely rare in benign potyps, and it has not been reported in hamartomatous polyps of PJS to date. The knowledge of this association may be helpful in the clinical diagnosis of this benign lesion in PJS.     

Rectification in the smooth muscle cell membrane of rabbit aorta.

1. The current-voltage relation of the smooth muscle cell membrane of rabbit aorta was determined by the partition method. 2. No anomalous rectification was observed in any of the following solutions: normal Krebs, Na free choline, Na sulphate, and high K-Na free sulphate. 3. Delayed rectification was seen on application of depolarizing current in both normal Krebs solution and Na free choline solution. 4. High concentration of K made the steady-state current-voltage relation almost linear in a voltage range of about 0 to -20mV. This effect, and steady-state cathodal rectification which was seen in physiological solution, could be explained qualitatively by constant field theory without involving channels capable of anomalous rectification. 5. A slow decrease in K conductance, during application of large and long-lasting hyperpolarizing currents, which occurs in skeletal muscle and is attributed to the tubule system, was never observed in the arteries either in Krebs, Na-free choline, or Na sulphate solution.     

Arterial smooth muscle. A multifunctional mesenchymal cell

In 1968, Professor Robert Wissler published a landmark review on the role of smooth muscle cells in atherogenesis. He suggested that in future studies more attention should be given to the cytologic and metabolic characteristics of these multifunctional mesenchymal cells. This article summarizes some of our studies inspired by these words and indicates a few of the many questions that still need to be addressed. We have shown that smooth muscle cells of different phenotypes from that expressed in normal arterial media exist in regions of diffuse intimal thickenings adjacent to atheroma and also in vessels following injury. Cells of equivalent phenotype can exist in cell culture, and we have shown that they have all the characteristics of smooth muscle in atherogenesis, ie, they proliferate in response to mitogens, readily synthesize increased amounts of extracellular matrix, and accumulate large amounts of lipid. In contrast, smooth muscle cells of the phenotype that normally exists in the unaffected artery do not express these characteristics and their major function is maintenance of vessel tone. Thus a deeper knowledge of the factors that control smooth muscle phenotype is essential to an understanding of the mechanisms underlying the pathogenesis of atherosclerosis.     

Genetic alterations and epithelial dysplasia in juvenile polyposis syndrome and sporadic juvenile polyps.

Juvenile polyps are regarded as hamartomatous polyps and occur in sporadic and familial syndromic settings. There is increased risk of gastrointestinal neoplasia in patients with juvenile polyposis syndrome, but the molecular mechanisms are not known. We therefore studied 78 colorectal juvenile polyposis from 12 patients with juvenile polyps syndrome and 34 sporadic juvenile polyps for epithelial dysplasia and genetic changes associated with colorectal neoplasia. Dysplasia occurred in 31% of syndromic juvenile polyps but not in sporadic juvenile polyps (P < 0.0001). Topographic control of proliferation and expression of the cyclin-dependent kinase inhibitor p21(WAFI/CIP1) seen in native colorectal epithelium was lost in 79% of dysplastic juvenile polyps and in 8% of nondysplastic juvenile polyps (P < 0.000001). Somatic mutations in the adenomatous polyposis coli (APC) gene were demonstrated in 50% of dysplastic juvenile polyps (3 of 6) but not in any of 16 juvenile polyps without dysplasia (P = 0.01). Both sporadic and syndromic juvenile polyps had K-ras mutations (14%) and there was no relationship to dysplasia. p53 gene product overexpression identified by immunohistochemical staining occurred rarely in dysplastic juvenile polyps (2 of 24, 8%). Our results indicate that the multiple genetic alterations involved in usual colorectal neoplasia also play a role in neoplastic transformation of juvenile polyps, predominantly in juvenile polyposis syndrome.     

Elastin synthesis and accumulation in irradiated smooth muscle cell cultures.

Multilayer cultures of neonatal rat aortic smooth muscle cells, which were actively synthesizing elastin, were exposed to gamma-radiation. Elastin synthesis and accumulation was measured as a function of time after irradiation and compared to control (non-irradiated) cultures. Cells exposed to 50 Gy ceased to divide but continued to synthesize and accumulate elastin. The culture morphology suggested that the irradiated cells accumulated an extensive extracellular matrix between their cell layers. Interestingly, the amount of elastin accumulated in the irradiated cultures was nearly the same as in the controls despite the difference in cell number in the two cultures. Thus, on a per cell basis, the elastin accumulation was greater in the irradiated cultures than in the controls.     

Vascular smooth muscle cell in atherosclerosis

Vascular smooth muscle cells (VSMCs) exhibit phenotypic and functional plasticity in order to respond to vascular injury. In case of the vessel damage, VSMCs are able to switch from the quiescent ‘contractile’ phenotype to the ‘proinflammatory’ phenotype. This change is accompanied by decrease in expression of smooth muscle (SM)‐specific markers responsible for SM contraction and production of proinflammatory mediators that modulate induction of proliferation and chemotaxis. Indeed, activated VSMCs could efficiently proliferate and migrate contributing to the vascular wall repair. However, in chronic inflammation that occurs in atherosclerosis, arterial VSMCs become aberrantly regulated and this leads to increased VSMC dedifferentiation and extracellular matrix formation in plaque areas. Proatherosclerotic switch in VSMC phenotype is a complex and multistep mechanism that may be induced by a variety of proinflammatory stimuli and hemodynamic alterations. Disturbances in hemodynamic forces could initiate the proinflammatory switch in VSMC phenotype even in pre‐clinical stages of atherosclerosis. Proinflammatory signals play a crucial role in further dedifferentiation of VSMCs in affected vessels and propagation of pathological vascular remodelling.     

Derivatized dextran inhibition of smooth muscle cell proliferation.

Proliferation of vascular smooth muscle cells is postulated to be one of the key events in the pathogenesis of atherosclerosis or during the development of focal glomerular sclerosis. Several studies have suggested that the antiproliferative effects of heparin appear to be regulated by different structural determinants. Our experiments show that dextrans substituted with carboxylic and benzylamide sulphonate groups markedly inhibit the growth of smooth muscle cells in vitro. Studies on the structure-function relationships of these products to their effect on rat aorta smooth muscle cells are reported. The antiproliferative capacity is similar to that of heparin.     

Lipid accumulation in human aortic smooth muscle cell lysosomes.

Lipid deposition is a central feature of the human atherosclerotic lesion. Deficient lysosomal lipolytic activity has been implicated as a pathogenetic factor in atheroma formation. Cytochemical and ultrastructural examination of the abdominal aortas of 2 normal young males, ages 11 and 23, demonstrates lipid accumulation with lysosomes of intact mural smooth muscle cells. This appears to be an early stage in the process which eventually results in an overloading of lysosomes and the formation of lipid-laden foam cells.     

Peutz-Jeghers syndrome with pseudoinvasion of hamartomatous polyps and multiple epithelial neoplasms

The risk of malignant change developing in the hamartomatous polyps in Peutz-Jeghers syndrome is widely held to be negligible. However an association with tumours of the upper gastro-intestinal tract, ovary and other diverse multiple neoplasms is now recognized. Previously reported cases of malignant change in Peutz--Jeghers polyps may represent 'pseudoinvasion' and we report such a case. This was associated with carcinomas of the bile ducts, left tonsil and a papillary adenoma of the pancreatic duct. It lends further support to the view that there may be a genetic predisposition to the development of neoplasms in this condition. Pathologists and clinicians must be aware of this entity of 'pseudoinvasion' in order to avoid unnecessarily radical surgery in Peutz-Jeghers syndrome.     

Regulation of the cell magnesium in vascular smooth muscle

1. The relation between [Mg](o) and the Mg content of the rat tail artery incubated in Ca-free solutions was studied.2. Variation of [Mg](o) in Ca-free Krebs solution between 0.6 and 2.4 mm did not affect the cell Mg. In ATP-depleted arteries, a sizeable fraction of the cell Mg was found to be proportional to [Mg](o).3. An even larger fraction of the cell Mg became proportional to [Mg](o) in metabolically active arteries in which the transmembrane gradient of Na had been dissipated as a result of inhibition of the Na pump. In contrast to the extracellular Mg, the fraction responded to a change in [Mg](o) at a very slow rate. The size of the fraction was reflected in net uptake of Mg if [Mg](o) was higher than 1.2 mm. The rate of the uptake was lowered markedly by external Ca. All the Mg taken up by the cells was extruded again after restoration of the Na gradient.4. The uptake of Mg in Ca-free, ouabain-containing solution took place even if the concomitant swelling of cells was prevented by substitution of isethionate for external Cl.5. Under steady-state conditions and at const. [Mg](o) and [Na](o), [Mg](i) increased with increasing [Na](i).6. The results are consistent with the hypothesis that the outwardly directed Mg pump in rat vascular smooth muscle utilizes the energy released in the course of spontaneous influx of Na.     

FE models of stress-strain states in vascular smooth muscle cell.

The paper deals with problems related to computational modelling of stress-strain states in vascular smooth muscle cells (SMCs). First, motivation for stress-strain analysis of SMCs is presented. Problems of their structure, geometry, constitutive models and initial (stress-free) state are analyzed on the basis of anatomical, histological and physiological knowledge. Various types of computational FE models of SMCs are presented; their constitutive models are identified on the basis of published mechanical tests carried out with SMCs cultured in vitro. Results of two models are presented; the former is a homogeneous model of the cell tension test with hyperelastic constitutive relations of the cell material. The latter model is more complex, it comprehends cortical and deep cytoskeleton, modelled as a tensegrity structure, and homogeneous linear elastic nucleus and remaining cytoplasm; it is used in computational modelling of indentation test. Perspectives, assumptions and limitations of computational modelling of SMCs under physiological load are discussed.