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Biomedical subjects

H W Schnaper

Publications and source records attributed to H W Schnaper.

At least 55 records · Page 3Linked to original sources
PubMed1993

Type IV collagenase(s) and TIMPs modulate endothelial cell morphogenesis in vitro.

It has been proposed that proteases are important in endothelial cell behavior. We examined the contribution of the gelatinase/type IV collagenase system in an in vitro model of endothelial differentiation. Human umbilical vein endothelial cells rapidly align and form networks of tubes when cultured on a basement membrane preparation, Matrigel. Zymograms of culture supernates demonstrate a 72-kD and a 92-kD gelatinase activity; the cells produce most of the 72-kD gelatinase, whereas the 92-kD activity is derived entirely from the Matrigel. Addition of antibodies against type IV gelatinase/collagenase decreases the area of the tube network. Both tissue inhibitors of metalloproteinases, TIMP-1 and TIMP-2, similarly decrease tube formation when added to cultures. Conversely, exogenous recombinant 72-kD gelatinase increases tube-forming activity. The effects of the anti-gelatinase antibodies and the TIMPs are not additive. Inhibition by either antibodies or TIMPs is greatest when they are added at culture initiation, suggesting that the protease activity is important in the early steps of morphogenesis. However, culture of the cells on Matrigel does not increase early expression of mRNA for the 72-kD gelatinase. Expression of message for the enzyme actually decreases during the course of the assay, while transcription of mRNAs for TIMPs increases, further supporting the concept that collagenases facilitate an early event in tube formation. These data demonstrate that gelatinase/type IV collagenase activity is important in endothelial cell morphogenesis on Matrigel, and suggest a role for collagenases in formation of new capillaries in vivo.

Amino Acid Sequence↗
PubMed1993

Human T lymphocytes synthesize the 92 kDa type IV collagenase (gelatinase B).

In order for T cells to exit the circulatory system, traverse the endothelial basement membrane, and arrive in target tissues, these cells must attach to and degrade basement membrane proteins. 12-O-tetradecanoylphorbol-13-acetate (TPA) has been shown to stimulate lymphoid cell adhesion to basement membrane components. We have used TPA to study the ability of human lymphoid cells to secrete type IV collagenases, enzymes capable of degrading basement membrane proteins. Here, we found that human primary T cells and H-9 lymphoid cells synthesize the 92 kDa type IV collagenase (gelatinase B) and TPA stimulates the synthesis and secretion of this protease. Peak TPA-stimulated gelatinase B secretion and mRNA accumulation were observed 9 hours after TPA treatment, while the peak adhesion to type IV collagen was observed only 3 hours after TPA treatment. The protein kinase C inhibitor, H-7, inhibited TPA-stimulated gelatinase B secretion. Both the primary T cells and H-9 lymphoid cells also expressed the mRNA for the tissue inhibitor of metalloproteinase-1 (TIMP-1). These data demonstrate that TPA-stimulated lymphoid cells adhere to type IV collagen and subsequently synthesize and secrete gelatinase B and TIMP-1. We conclude that lymphoid cell extravasation may involve cellular employment of adhesion mechanisms prior to degradation of the matrix, which is similar to the process of extravasation used by metastatic cells.

Animals↗
PubMed1993

Regulation of cell function by extracellular matrix.

The extracellular matrix (ECM) provides structural support and adhesive substrates for the body tissues. Recent advances in our understanding of the biology of matrix indicate that the ECM also plays a significant role in regulating the behavior of cells. Matrix proteins engender changes in cell shape and movement, bind growth factors, and facilitate cell-cell and cell-matrix interactions. Matrix-induced differentiation results from multiple stimuli that include: tensile forces on the cell, cytokine- or growth factor-mediated stimulation, and interaction with bioactive domains of matrix glycoproteins. Because these signals are important determinants of cell behavior, pharmacological manipulation of cell-matrix interactions may offer a valuable new approach to disease treatment.

Animals↗
PubMed1993

The laminins: a family of basement membrane glycoproteins important in cell differentiation and tumor metastases.

Laminins are a family of basement membrane-derived glycoproteins that are very biologically active with a number of diverse cell types. The response of the cells is dependent on the cell type and various cell-specific intracellular events are activated. Multiple active sites on laminin and cellular receptors have been described. Both laminin and the synthetic peptides that define the active sites may have important clinical uses. For example, the neurite-promoting peptides may be useful in vivo in regeneration studies because of their potent activity with neural cells and their lack of antigenicity. Also, peptides, such as YIGSR, that inhibit angiogenesis are potentially useful for treating the vascularization of the eye that occurs in conditions such as diabetes mellitus. Likewise, the angiogenic peptide SIKVAV, because of its role in endothelial cell block vessel formation, may be useful for treating ischemia. The recent progress that has been made in characterizing basic mechanisms of action of laminin has laid the groundwork for more direct studies of its clinical relevance.

Amino Acid Sequence↗
PubMed1993

Role of laminin in endothelial cell recognition and differentiation.

The vascular endothelium normally is maintained in a quiescent state, but under certain conditions it is induced to undergo marked changes in behavior and form new vascular structures. A complex interaction among various growth and differentiation factors and the extracellular milieu regulates this behavior. One series of signals affecting endothelial behavior is provided by laminin, a major structural protein of basement membrane. These signals have been studied using Matrigel, a reconstituted basement membrane preparation from the murine Englebreth-Holm-Swarm sarcoma, in an in vitro assay of endothelial cell differentiation. Three biologically-active sequences from the laminin molecule have been evaluated. Synthetic peptides that include the sequences -RGD-, -YIGSR-, and -SIKVAV- mediate, respectively, cell binding to Matrigel, alterations in cell morphology, and induction of migration and collagenase activity. Preliminary data indicate that observations made with this system may be relevant to endothelial function in vivo. Endothelial cell differentiation on Matrigel may thus be a useful in vitro model for the study of certain steps in angiogenesis.

Amino Acid Sequence↗
PubMed1992

Angiotensin-converting enzyme inhibitors for systemic hypertension in young and elderly patients.

Whereas many physicians have been reluctant to treat hypertension in the elderly because of perceived limited benefits and the risk of side effects associated with traditional antihypertensive agents such as diuretics and beta blockers, studies and clinical experience have shown that elderly as well as younger patients can benefit from treatment. In recent years, angiotensin-converting enzyme (ACE) inhibitors have been found to be safe and effective in both young and elderly hypertensive patients without many of the adverse effects associated with traditional agents. ACE inhibitors possess characteristics that meet many of the special needs of elderly patients, including reduction of left ventricular mass, lack of metabolic and lipid disturbances, no central nervous system effects, no risk of induction of cardiac failure, and low risk of orthostatic hypotension.

Aging↗
PubMed1992

Early occurrence of end-stage renal disease in a patient with infantile nephropathic cystinosis.

We report the case of a patient with infantile nephropathic cystinosis who required renal transplantation at age 30 months. Exhaustive evaluation did not identify a cause of progressive renal failure other than cystinosis. The patient's genetic lesion was allelic with those of other patients with cystinosis; fusion of this patient's fibroblasts with fibroblasts from another patient with infantile nephropathic cystinosis did not demonstrate complementation of the biochemical defect.

Clone Cells↗
PubMed1992

MIDAS: hypertension and atherosclerosis. A trial of the effects of antihypertensive drug treatment on atherosclerosis. MIDAS Research Group.

Although clinical trials of the efficacy of antihypertensive treatment have demonstrated impressive reductions in the incidence of stroke, the reduction in coronary artery disease mortality has been less impressive. It may be that the antihypertensive drugs used in these trials induced metabolic disturbances, or produced inadequate regression of left ventricular hypertrophy, thus blunting the reduction in risk of coronary artery disease expected with blood pressure-lowering. Isradipine, a dihydropyridine calcium antagonist known to be an effective antihypertensive agent, has also displayed pronounced antiatherogenic effects in animals. Thus, a reasonable hypothesis could be that isradipine not only reduces the level of blood pressure, but also may have a positive effect on the evolution of atherosclerotic plaque in coronary and carotid arteries, thereby leading to prevention of clinical sequelae of atherosclerosis. On this basis, a 3-year clinical trial is being carried out in the United States--the Multicenter Isradipine/Diuretic Atherosclerosis Study (MIDAS)--to establish the efficacy of isradipine in inhibiting atherogenesis and retarding the progression of atherosclerosis in carotid arteries of hypertensive patients. The primary end point of the study is intima-media thickness and the extent of atherosclerotic plaque in the carotid arteries, as measured by B-mode ultrasonography.

Antihypertensive Agents↗
PubMed1991

Steroid-dependent nephrotic syndrome following renal transplantation for congenital nephrotic syndrome.

A boy developed recurrent steroid-responsive nephrotic syndrome following renal transplantation for congenital nephrotic syndrome. The first episode was associated with mild tubulointerstitial rejection on kidney biopsy. Subsequent episodes showed normal histology by light microscopy and epithelial foot process fusion on electron microscopy, consistent with minimal change nephrotic syndrome. Serum analysis for soluble immune response suppressor was negative pre-nephrectomy, positive during each bout of nephrotic syndrome, and negative during each remission. This case represents de novo occurrence of steroid-sensitive minimal change nephrotic syndrome following renal transplantation for congenital nephrotic syndrome. We stress the need for histological examination of the renal allograft to diagnose rejection, recurrent disease, or de novo disease.

Child, Preschool↗
PubMed1991

Dose-response relationship of ramipril in patients with mild-to-moderate hypertension.

The dose-response relationship of ramipril was examined in 216 subjects with mild-to-moderate essential hypertension in a double-blind, placebo-controlled, multicenter study. Ramipril capsules (1.25, 2.5, 5, or 10 mg) or placebo capsules were administered once daily for 12 weeks. Significant reductions in supine and standing diastolic and systolic blood pressures were seen at end point in the ramipril 2.5, 5, and 10 mg treatment groups compared with placebo. The antihypertensive effect was greater at higher doses. The minimum effective dose of ramipril was 2.5 mg once daily.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Control of interleukin 1 (IL-1) activity. I. Inhibition of IL-1 activity by soluble immune response suppressor (SIRS) in vitro.

Soluble immune response suppressor (SIRS), a nonspecific inhibitor of cellular and humoral immune responses and cellular proliferation, reversed IL-1-induced inhibition of autologous rosette formation by thymocytes. In addition, SIRS prevented the IL-1-induced increase in resistance of thymocytes to the lytic action of hydrocortisone. Kinetic experiments showed that the action of SIRS on thymocytes was rapid (less than 15 minutes), although a longer time was required to exert protective effects on thymocytes. SIRS also inhibited the stimulation of thymocyte proliferation induced by Con A and IL-1 a costimulatory assay of IL-1 activity. Moreover, SIRS inhibited the IL-1-stimulated expression of complement receptors on neonatal B cells. The inhibitory effects of SIRS were selectively directed towards IL-1, since SIRS did not interfere with induction of LAK cells by IL-2, and did not reverse inhibition of autologous rosette formation induced by factors other than IL-1, such as IL-4, a proline rich polypeptide and lactoferrin. The results presented in this report demonstrate that SIRS may be a selective inhibitor of IL-1 activity with respect to T and B cells, rendering them unresponsive to IL-1 activation and/or maturation signals.

Animals↗
PubMed1990

Acebutolol effects on lipid profile.

The relation between lipid profile and the incidence of coronary artery disease has been confirmed by the results of epidemiologic and intervention studies. Among antihypertensive agents, beta blockers, particularly those without intrinsic sympathomimetic activity (ISA), are generally reported to have negative effects on lipids, which may increase the risk of coronary artery disease. The ongoing Treatment of Mild Hypertension Study, now in its third year, has evaluated 847 patients to date with regard to lipid profile. Additional end points measured in this multicenter, randomized, controlled, double-blind study include blood pressure reduction and target organ deterioration. During the trial, all patients received nutritional and behavioral counselling to modify their diet, exercise habits and alcohol and sodium consumption to control their hypertension by nonpharmacologic means. In addition, some patients were randomized to receive low doses of 1 of the 5 classes of antihypertensive medication: acebutolol, a beta blocker with ISA (n = 124); amlodipine, a calcium channel blocker (n = 122); chlorthalidone, a diuretic (n = 125); doxazosin, an alpha blocker (n = 128); enalapril, an angiotensin-converting enzyme inhibitor (n = 127) or placebo (n = 221). At 1 year, acebutolol showed a statistically significant (p less than 0.001) decrease in total cholesterol (-12.7 mg/dl) compared with placebo (-5.2 mg/dl) and with chlorthalidone (1.0 mg/dl); a significant (p less than 0.001) decrease in low-density lipoprotein cholesterol (-6.0 mg/dl) compared with placebo (+0.7 mg/dl) and with chlorthalidone (+8.0 mg/dl) and no change in high-density lipoprotein cholesterol (-0.4 mg/dl).

Acebutolol↗
PubMed1990

A regulatory system for soluble immune response suppressor production in steroid-responsive nephrotic syndrome.

Patients with nephrotic syndrome frequently have suppressed immune responses. Previously, it has been determined that subjects with steroid-responsive nephrotic syndrome (SRNS) produce the lymphokine, soluble immune response suppressor (SIRS). In the present group of experiments, a potential pathway of suppressor cell activation was investigated. Sera from patients with SRNS stimulated normal CD8+ lymphocytes to produce SIRS. Serum SIRS-inducing activity was abrogated by treatment with proteinase K or boiling, but was not affected by dialysis, acidification to pH 2, or heating to 56 degrees C. This serum factor could be distinguished functionally and antigenically from SIRS and from interferon (IFN) alpha or IFN gamma. Supernatants of cultured patient lymphocytes enriched for CD4+ cells were also found to activate normal CD8+ lymphocytes to produce SIRS. The lymphocyte-derived activity showed similar characteristics to those of the serum factor. Molecular weight of both factors was estimated to be 13,000 to 18,000 daltons by gel filtration chromatography, and activity of serum and lymphocyte supernatant from the same patients eluted with similar patterns on reversed-phase HPLC. These data suggest that serum SIRS-inducing activity is derived from a suppressor-inducer lymphocyte, and indicate the presence of a regulatory mechanism for SIRS production in steroid-responsive nephrotic patients.

Child↗