Biomedical subjects

J M Davidson

Publications and source records attributed to J M Davidson.

At least 91 records · Page 5Linked to original sources

PubMed1991

Transforming growth factor-beta stimulates wound healing and modulates extracellular matrix gene expression in pig skin: incisional wound model.

Enhanced wound healing is elicited by exogenous administration of transforming growth factor- beta 1 (TGF- beta 1) in split-thickness, excisional wounds in the pig (Quaglino, Lab Invest 63:307-319, 1990). A study was designed to investigate if the selective and localized effects of TGF-beta 1 found in the previous model were dependent upon the type of wound or could be considered a more general effect of the cytokine. Transdermal, sutured incisions in the pig were evaluated by conventional histology and by in situ hybridization to reveal locally affected gene expression of collagen, elastin, fibronectin, stromelysin, TGF- beta 1, and basic fibroblast growth factor. Granulation tissue formation was markedly enhanced at 6 d by a single injection of recombinant human TGF beta 1 at the time of wound closure. Although granulation tissue was confined within the margins of the incisional wound, prominent differences in hybridization signals were observed between control and treated wounds. The stimulatory effect of TGF- beta 1 on granulation tissue formation was accompanied by a distinct enhancement in cells expressing mRNA for several different extracellular matrix proteins including collagens type I and III and elastin, whereas a single injection of human recombinant TGF beta 1 (4 micrograms) at the wound site diminished the expression of the neutral metalloprotease, stromelysin, and enhanced the frequency and intensity of cells expressing TGF- beta 1. The data reinforce the concept that TGF- beta 1 can act as a potent, auto-inductive modulator of connective tissue remodeling during the repair process.

Animals↗

PubMed1990

Fibroblasts from wounds of different stages of repair vary in their ability to contract a collagen gel in response to growth factors.

Wound contraction is one function of granulation tissue which is critical to repair. This study compares the ability of fibroblast-like cells derived from granulation tissue of various ages to contract a tissue equivalent, or a collagen gel, and examines the influence of growth factors implicated in wound repair on collagen gel contraction by these different cell populations. Cells from older granulation tissue (21 and 28 days) have an enhanced ability to contract a tissue equivalent when compared to cells from younger granulation tissue (7 and 14 days) or normal rat skin fibroblasts. Transforming growth factor-beta 1 (TGF-beta 1) enhanced contractility most in those cells which had a greater basal contractile ability. While basic fibroblast growth factor (bFGF) alone had moderately stimulatory effects at low doses (0.1-1.0 ng/ml), higher doses (greater than or equal to 10 ng/ml) inhibited basal contraction. Pretreatment with bFGF followed by exposure to TGF-beta 1, with or without the continued presence of bFGF, delayed gel contraction by cells from skin and early granulation tissue, but bFGF enhanced TGF-beta 1 activity in highly contractile cells. Transforming growth factor-alpha moderately enhanced contraction by cells from older granulation tissue. While both TGF-beta 1 and bFGF enhanced wound repair, their differential effects on the fibroblast-like cell derived from granulation tissue of different ages suggest that phenotypic differences exist between these cell populations. In addition, our results predict significant interactions between polypeptide cytokines at the site of repair.

Animals↗

PubMed1990

Yohimbine attenuates aging-induced sexual deficiencies in male rats.

Since yohimbine strongly stimulates sexual motivation/arousal in rats, it was of interest to determine whether the arousal deficit in aging male rats could be reversed by yohimbine. Three groups from each of two ages (approximately 3 and 15 months) received vehicle, 1 or 4 mg/kg yohimbine. In the mounting test (for arousal/motivation), 1 mg/kg yohimbine significantly increased mount frequency in middle-aged rats, though not to the level of the young animals. In the mating test, the percentage of aging rats intromitting and displaying ejaculatory behavior was less than in the young group, but after 1 mg/kg yohimbine, these behaviors were significantly increased. Vehicle-treated middle-aged rats which had mated showed significantly elevated intercopulatory intervals and ejaculatory behavior latencies. These measures were reduced by 1 mg/kg yohimbine. While behavioral facilitation following yohimbine in aging rats did not reach that of young yohimbine-treated rats, they reached levels at or close to those of nontreated young animals. We conclude that yohimbine treatment can improve age-related deficits seen to occur in aging male rat sexual behavior.

Aging↗

PubMed1990

Effects of intrathecal administration of 8-OH-DPAT on genital reflexes and mating behavior in male rats.

Systemic administration of the 5HT1A receptor agonist, 8-OH-DPAT, consistently decreases the threshold of ejaculatory behavior and enhances some aspects of arousal. Previous findings by others demonstrated the in copula ejaculatory behavior effect using intrathecal (IT) injection at the level of the lumbosacral spinal cord, but the dose used was in the range that produced results systemically. This study aimed at a) a more comprehensive study of the sexual effects of 8-OH-DPAT and b) use of IT doses of 8-OH-DPAT below those effective when administered systemically. The ex copula genital reflex test showed severe inhibition. At doses of 5 micrograms or more, significant inhibition of the percentage of rats displaying ejaculation occurred, and the two highest doses also significantly reduced the percentage of rats displaying erection. In the in copula mating test, 20 and 80 micrograms IT 8-OH-DPAT, significantly reduced ejaculation latency, intromission frequency and intercopulatory interval. Copulatory plugs, collected at the highest dose only, showed a trend towards weight reduction. We conclude that the facilitation of ejaculatory behavior and some measure of arousal by 8-OH-DPAT can be mediated directly via the lumbosacral spinal cord. An hypothesis for explaining the inhibitory effect on ejaculation ex copula is presented, but the inhibitory effect on erectile reflexes is without interpretation.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1990

Effects of four beta-adrenergic receptor antagonists on male rat sexual behavior.

Antihypertensive medication has been reported to cause serious sexual side effects in men. Frequently mentioned as causing sexual dysfunction are beta-adrenergic receptor antagonists. The purpose of this study was to examine in detail the effects of beta blockers on adult male rat sexual behavior. Thirty minutes following a single subcutaneous injection of propranolol, pindolol, atenolol or labetalol, mating tests were conducted. The mixed beta 1- and beta 2-adrenergic antagonists, propranolol and pindolol, profoundly inhibited male sexual behavior. At the 5 and 10 mg/kg doses, propranolol inhibited ejaculatory behavior to the extent that only 9.1 and 8.3% respectively showed the behavior while pindolol reduced this behavior to 36.4% (16 mg/kg). These drugs also adversely affected various parameters of behavior in a dose-dependent manner. The selective beta 1 antagonist, atenolol, had only minor effects and labetalol even less so at the doses tested. It was suggested that the strongly inhibitory effects of propranolol and pindolol on male rat sex behavior may well be due to their 5-HT1A antagonistic binding properties rather than their beta-antagonistic properties.

Adrenergic beta-Antagonists↗

PubMed1990

Effects of intrathecal and systemic administration of buspirone on genital reflexes and mating behavior in male rats.

Buspirone was studied to determine whether the detailed profile of male sexual behavior observed following treatment with the prototypical 5-HT1A ligand, 8-OH-DPAT, can be generalized to other 5-HT1A agonist drugs. Systemic and intrathecal (IT) routes of administration were compared. Like DPAT, significant reduction in intromission frequency followed IT infusion of buspirone (80-160 micrograms) as did intraperitoneal (IP) injection (1-4 mg/kg). IT doses of 80-160 micrograms and all IP doses significantly reduced ejaculation latency. Intercopulatory interval significantly decreased following IP buspirone but not after IT infusion although there were trends in that direction. All IP doses and 80 micrograms IT significantly shortened the postejaculatory interval. Buspirone inhibited erection and/or ejaculation in the ex copula reflex test. A decrease in percentage of rats displaying erections and ejaculation occurred following either route of administration. Ejaculation was significantly inhibited at the low IT dose of 40 micrograms. We conclude that buspirone affects sexual behavior very much like DPAT or other 5-HT1A drugs, to the extent known. Sexual effects of buspirone were generally similar regardless of route of administration, but the effective doses were clearly lower with IT treatment.

Animals↗

PubMed1990

Effect of static stretching on elastin production by porcine aortic smooth muscle cells.

An in vitro model was developed to assay the effects of static stretching on soluble elastin (tropoelastin, TE) synthesis by porcine aorta smooth muscle cells (SMC). Culture dishes containing SMC adherent to the deformable bottoms were placed over hard convex templates. Stress was applied by placing a weight on the dish covers. Measurement of TE was accomplished by a specific ELISA assay. With this model we demonstrated reproducible stimulation of TE synthesis by stretched SMC. Significant results (161.4% of control; p = less than 0.003 by Student's t-test) were obtained by stretching passage 2 SMC for 3 days with a medium change after the first 18-24 hours, use of 5% newborn calf serum in cultures during stretching, and 50-g weight. DNA content in stretched cultures did not increase over control values. Thus, stretching alone did not cause hyperplasia or hyperploidy in these SMC and, in the absence of other vascular cell elements, was sufficient to increase production of this extracellular matrix protein. Transduction of mechanical force into elastin gene expression by SMC may contribute to the development of thickened arterial tunica media characteristic of hypertensive vessels.

Animals↗

PubMed1990

Effects of estrogen, androgen, and progestin on sexual psychophysiology and behavior in postmenopausal women.

To assess the contribution of gonadal steroids to sexual behavior in aging women, we conducted a 10-week, double-blind, hormone replacement study of 40 naturally menopausal women (mean age, 58.3 yr). Prospective measurements of basal and stimulated vaginal vasocongestion and daily self-reports of mood, physical symptoms, sexual behavior, and perceived sexual pleasure were collected. Daily treatments were either conjugated equine estrogen, i.e. Premarin (P; 0.625 mg), Premarin and medroxyprogesterone acetate, i.e. Provera (PP; 0.625 and 5 mg, respectively), Premarin and methyltestosterone (PT; 0.625 and 5 mg, respectively), or placebo (PL). Compared to placebo, hormone treatment had significantly reduced hot flashes in the P and PP groups by week 4 and in the PT group by week 5. Headaches were reduced in the P vs. PL group, only. Hormone treatment did not significantly alter mood ratings, sexual behaviors, or psychophysiologically measured sexual arousal. PT treatment significantly increased reports of pleasure from masturbation compared to the other three groups, underscoring the apparent contribution of androgens to self-stimulatory behavior. However, the data suggest that in these physically and sexually healthy women, gonadal steroids do not influence major components of sexual functioning, including arousal and a wide variety of sexual activity and experience.

Analysis of Variance↗

PubMed1990

Bartonella bacilliformis stimulates endothelial cells in vitro and is angiogenic in vivo.

Bartonellosis, a biphasic disease caused by motile intracellular bacteria, produces in its tissue phase a characteristic dermal eruption (Verruga peruana) resulting from a pronounced endothelial cell proliferation. Bacteria are found in the interstitium and within the cytoplasm of endothelial cells (Rocha-Lima inclusion). The aim of this study was to determine if Bartonella bacilliformis produce a substance(s) that might be responsible for the vascular proliferation seen in the Verruga. This was assessed in an in vitro system using human endothelial cells and measuring proliferation as well as production of tissue type plasminogen activator after exposure to the endothelial cultures to B. bacilliformis extracts. Our results indicate that B. bacilliformis possess an activity that stimulates endothelial cell proliferation up to three times that of control. The factor(s) is specific for endothelial cells, heat sensitive, larger than 12 to 14 kd, not enhanced by heparin, has no affinity for heparin, and is precipitated by 45% ammonium sulfate. In addition, the B. bacilliformis extracts stimulate production of t-PA antigen in a concentration-dependent fashion. This activity is also heat sensitive and not lost after dialysis (12 to 14 kd). B. bacilliformis extracts, however, do not increase the production of plasminogen activator inhibitor. It was also determined that B. bacilliformis extracts stimulate the formation of new blood vessels in an in vivo model for angiogenesis. These results describe a bacterial factor(s) that stimulates two important steps in the development of new blood vessels in vitro, as well as the formation of new blood vessels in vivo. Determining the mechanism of action, combined with a complete characterization of this factor(s), may help in understanding the pathogenesis not only of the Verruga and angiogenesis in general but also the recently described Cat-Scratch-associated epithelioid hemangiomas in patients with AIDS and Kaposi sarcoma.

Animals↗

PubMed1990

Biochemistry and turnover of lung interstitium.

The lung contains a host of extracellular matrix components that comprise the supporting and adhesive elements of conducting airways, alveoli and the vascular tree. While none of these components is unique to the lung, their peculiar distribution determines the architecture and function of this gas exchange organ. Cells and tissues of the lung interact with the matrix through a variety of surface receptors, especially the integrins and adhesive molecules, some of which may play important roles in lung injury and repair. Collagen type I is the predominant determinant of tensile strength, but as many as 11 other genetic types of collagen with specialized adhesive and connecting functions can be found in various lung structures, including cartilage and basement membranes. Excessive matrix accumulation in the lung is the result of a complex set of influences on gene regulation, part of which may be due to the presence of inflammatory cytokines that directly stimulate matrix synthesis. However, degradation and turnover of the matrix are also critical processes influenced by many of the same mediators. Collagenase and gelatinase (type IV collagenase) are tightly-regulated metalloenzymes that, together with a set of specific inhibitors of metalloproteinases, determine the net abundance and distribution of collagen. Elastases of several biochemical types are also under tight regulation by proteinase inhibitors. Elastin is essential to lung function at the level of alveolar wall resiliency and patency, and loss of elastin in emphysema appears to be due to uncontrolled degradation of the embryologically-established pattern of elastic fibres accompanied by nonfunctional replacement as a response to injury. Injury to the vascular endothelium of the lung, as well as other physiological insults that elevate pulmonary blood pressure, can lead to the excessive accumulation of collagen and elastin in the conductance and resistance arteries of the pulmonary circulation. Mechanical stress and endothelial injury may mediate the medial hypertrophy of these vessels. Extracellular matrix components are critically involved in every stage of lung biology: development, normal function and acute and chronic disease states. To date, only glucocorticoids, cross-linking inhibitors, and protease inhibitors have been used in a general attempt to suppress either excessive matrix accumulation or loss. More detailed understanding of the regulation and specific interactions of matrix components is central to the analysis of disease states and the development of appropriate therapeutic strategies.

Cell Adhesion Molecules↗

PubMed1990

Transforming growth factor-beta stimulates wound healing and modulates extracellular matrix gene expression in pig skin. I. Excisional wound model.

The effect of transforming growth factor-beta 1 (TGF-beta 1) on matrix gene expression has been investigated during the process of wound repair, where the formation of new connective tissue represents a critical step in restoring tissue integrity. Split-thickness excisional wounds in the pig were studied by in situ hybridization in order to obtain subjective findings on the activity and location of cells involved in matrix gene expression after the administration of recombinant TGF-beta 1. Data focus on the stimulatory role of this growth factor in granulation tissue formation, on the enhanced mRNA content of collagen types I and III, fibronectin, TGF-beta 1 itself, and on the reduction in stromelysin mRNA, suggesting that increased matrix formation measured after treatment with TGF-beta 1 is due to fibroplasia regulated by the abundance of mRNAs for several different structural, matrix proteins as well as inhibition of proteolytic phenomena elicited by metalloproteinases. These studies reveal elastin mRNA early in the repair process, and elastin mRNA expression is enhanced by administration of TGF-beta 1. Moreover, we show that TGF-beta 1 was auto-stimulating in wounds, accounting, at least in part, for the persistent effects of single doses of this multipotential cytokine.

Animals↗

PubMed1989

Differential stimulation of collagenase and chemotactic activity in fibroblasts derived from rat wound repair tissue and human skin by growth factors.

Epidermal growth factor and cartilage-derived basic fibroblast growth factor (EGF and CD-bFGF) are mitogens shown to increase the rate of wound repair in animal models. In addition to being a mitogen for granulation tissue, CD-bFGF stimulates the recruitment of cells to the wound site. CD-bFGF and a closely-related chondrosarcoma-derived fibroblast growth factor stimulated chemotaxis of granulation tissue cells in vitro, each factor having a maximum activity at a concentration of 55 pM. Epidermal growth factor was also a potent chemoattractant for rat granulation tissue fibroblasts; however, maximum activity was obtained at 1.7 nM. Cells from all stages of wound repair were chemotactically responsive to these factors, but there was some attenuation of the response to bFGF in cells derived from fully-organized day 28 granulation tissue. Collagenase-catalyzed restructuring of collagen, an additional significant feature of wound repair, is probably critical to cell movement in an extracellular matrix. Cells derived from organizing (6-day old) sponge granulation tissue secreted latent collagenase constitutively in vitro. In the presence of serum, the production of collagenase was stimulated three-four fold by 1.8 nM bFGF derived either from cartilage or chondrosarcoma. When serum was present, as at a wound site, collagenase production was not enhanced by the addition of EGF. Cells from fully organized, day 21 sponge granulation tissue did not secrete latent collagenase constitutively and could not be stimulated to do so by the addition of EGF, bFGF, or phorbol ester. Human skin fibroblast collagenase production was also stimulated by bFGF and was refractory to EGF. While both classes of growth factor have the ability to promote wound healing, the varying responses they elicit in cell populations from the wound site emphasize the different pathways of cellular activation.

Cartilage↗

PubMed1989

Penile and finger sensory thresholds in young, aging, and diabetic males.

To investigate the possible role of sensory function in conditions affecting sexual function, sensory thresholds were compared between young healthy men (n = 14, means age = 29.8), aging men (n = 15, means age = 67.3), and men suffering from diabetic impotence (n = 15, means age = 45.0). Using the psychophysical method of forced choice, vibrotactile and electrical stimulation thresholds were deterlmined in two separate sessions at two body sites: the fingertip and the ventral surface of the penis, just proximal to the glans. Vibrotactile penile thresholds (VTP) were lowest for young (Y) subjects and much higher for both aging (A) and diabetic (D) subjects. Electrical stimulation of the penis (ESP) showed the same trends, although the differences only approached significance (p = 0.06). The vibrotactile finger threshold (VTF) was significantly higher for A subjects as compared with Y and D subjects, but there was no difference between the Y and D groups. Diabetic patients had significantly higher thresholds for electrical stimulation of the finger (ESF), in contrast to the VTF finding. Finger thresholds were significantly lower than penile thresholds for all groups, and the change in threshold from finger to penis was greater in both aging and diabetic than in young subjects. Age was positively correlated with thresholds for ESF, ESP, VTF, and marginally for VTP when all three groups were analyzed together. However, in general the results of threshold determinations could not be attributed merely to age. Based on a detailed questionnaire of sexuality, VTP was negatively correlated with sexual activity and both ESP and VTP were negatively correlated with erectile capacity. The data are consistent with a genital sensory role for age-related and diabetic changes in sexual function.

Adult↗

PubMed1989

A component analysis of the effects of DPAT on male rat sexual behavior.

Male rat sexual behavior was examined in a variety of tests following a single acute IP injection of the serotonin1A (5-HT1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT). The objective was to determine the effects of 5-HT1A receptor stimulation on the components of sexual behavior (arousal/motivation, erection and ejaculation) using this prototypical 5-HT1A ligand. In the ex copula genital reflex test, DPAT dramatically inhibited ejaculation and the display of penile erections. When examined in the mating behavior test, DPAT caused a significant reduction in intromission frequency (IF), ejaculation latency (EL), intercopulatory intervals (ICI) and postejaculatory interval (PEI). The decrease in IF and EL indicated a lowering of the behavioral-ejaculatory threshold, while the reduction in ICI and PEI indicated a stimulation of two aspects of sexual arousal. Further tests, however, revealed complexities. Using the mounting test (with genital anesthesia) as an assessment of sexual arousal, no effect of DPAT was found. Collection and examination of the coagulated ejaculates resulting from mating (copulatory plugs) provided evidence of an impairment in ejaculation, as a result of DPAT treatment. The data suggests that 5-HT1A receptor stimulation lowers the behavioral-ejaculatory threshold despite inhibition of ejaculation in and ex copula; as well as stimulating specific aspects of sexual arousal. It remains to be determined whether the effects on arousal were either due to nonselectivity as currently believed or because 5-HT1A receptor stimulation affects alpha 2-adrenoceptor activity by some as yet undefined mechanism; and as a result modulates sexual arousal.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1989

Heterogeneity of elastin expression in cutis laxa fibroblast strains.

Cutis laxa is a genetically heterogeneous connective tissue disease that occurs in both inherited and acquired forms. The most apparent defect is loose, redundant, nonresilient skin, but systemic connective tissue abnormalities exist, especially in conjunction with the early onset or autosomal recessive variety. The elastic fiber shows morphologic alterations. We studied dermal skin biopsies and cultured skin fibroblasts from 6 patients with congenital forms of cutis laxa in an effort to correlate alterations in elastin morphology and metabolism. In general, ultrastructural analysis revealed occasional variance in collagen fiber diameter, whereas elastic tissue varied in content, appearance, and the proportion and manner by which elastin and microfibrillar component associated. Fibroblast cell lines comprised of normal donors from a similar age group produced an average of 35 +/- 10 X 10(3) tropoelastin molecular equivalents per cell per hour, as measured by an ELISA. Three of six cutis laxa cell strains were markedly (5-20-fold) reduced in tropoelastin production. Two of these cell strains had specifically reduced levels of tropoelastin production relative to total protein synthesis. Analysis of elastin specific messenger RNA levels indicated this reduced expression of tropoelastin was regulated at a pretranslational level. In other strains, diminished production of elastin did not appear to be the primary defect, underscoring the heterogeneous nature of cutis laxa at both the biochemical and ultrastructural levels.

Blotting, Northern↗

PubMed1989

Accumulation and regulation of elastin in the rat uterus.

The relative levels of elastin-specific mRNA were used as a measure of tropoelastin expression in uteri from pregnant Sprague-Dawley rats. The levels of elastin-specific mRNA were also correlated with values for net tropoelastin production and net deposition of mature, crosslinked elastin. The total content of uterine elastin increased throughout gestation, reaching maximal levels at Day 19 of gestation, which were three times those of nongravid tissue. Following involution, the elastin content decreased rapidly to near baseline values by 5 days postpartum. The content of soluble elastin, estimated using an enzyme-linked immunosorbent assay, paralleled in part the increase in elastin deposition and elastin mRNA levels. Uterine elastin metabolism appears to be unlike that in other elastic tissues, e.g., lung and large blood vessels. In most elastin containing tissues, the protein is synthesized during discrete developmental periods and is not readily degraded. However, uterine elastin is continuously expressed, and appears to be in a continual cycle of degradation and replacement.

Animals↗

PubMed1989

Monospecific antibodies implicate basic fibroblast growth factor in normal wound repair.

Exogenous polypeptide growth factors influence the rate of wound healing and other biological processes, but there is no direct evidence that these peptides have an intrinsic role. To test whether basic fibroblast growth factor is involved in wound repair, rats were implanted with subcutaneous polyvinyl alcohol sponges containing slow-release pellets releasing either a polyclonal neutralizing antiserum directed against basic fibroblast growth factor, preimmune IgG, or nothing. Histological and biochemical evaluation of the granulation tissue that infiltrated the sponges showed anti-basic fibroblast growth factor to cause significant reductions in DNA, protein, and collagen content when compared with either preimmune IgG or placebo at the early stages of wound repair.

Animals↗

PubMed1988

The elastogenic effect of recombinant transforming growth factor-beta on porcine aortic smooth muscle cells.

Transforming growth factor-beta, a peptide growth factor, is known to be a multifunctional regulator of cellular activity. The effect of this growth factor on extracellular matrix formation is well established, but its effects on elastin, a critical component of lung, skin, and blood vessels are unknown. In the present study, by use of an Enzyme-Linked Immunoassay method, we found that transforming growth factor-beta strongly increased elastin production in cultured porcine aortic smooth muscle cells. In a dosage-dependent study, 1.0-10.0 ng/ml transforming growth factor-beta promoted elastin production 2-3 fold. In a time-dependent study, at least an 8 h pre-treatment with 10.0 ng/ml transforming growth factor-beta was required for sustained increases in elastin production. The effects of transforming growth factor-beta on cultured aortic smooth muscle cells suggest that this cytokine may be an important mediator of elastin formation during atherosclerosis and hypertension.

Animals↗