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Biomedical subjects

D Knighton

Publications and source records attributed to D Knighton.

13 recordsLinked to original sources
PubMed2000

Wound healing: captopril, an angiogenesis inhibitor, and Staphylococcus aureus peptidoglycan.

BACKGROUND: Captopril, an angiotensin-converting enzyme inhibitor, used for treating hypertension and heart failure, inhibits angiogenesis in the corneas of rats in response to basic fibroblast growth factor, slows the growth of experimental tumors in rats, and leads to the regression of Kaposi's sarcoma. Because angiogenesis is key to wound healing, we hypothesized that captopril would impair wound healing. We hypothesized also that because local application at operation of Staphylococcus aureus peptidoglycan (SaPG) increases angiogenesis and accelerates wound healing in rats, SaPG would prevent or ameliorate the postulated captopril-impaired wound healing. MATERIALS AND METHODS: In each experiment, rats were divided randomly into two groups: one drinking tap water, and the other, tap water containing 0.5 mg captopril/ml. All ate chow and drank ad libitum, pre-operatively (4-12 days) and postoperatively (7 days). In experiments 1 and 2, bilateral paravertebral 5.5-cm skin incisions were made aseptically (intraperitoneal sodium pentobarbital), and closed with interrupted No. 35 stainless-steel sutures. On one side, the wound was immediately inoculated with 157 microliter pyrogen-free isotonic saline and on the other side the wound was inoculated with 157 microliter saline containing 4.7 mg SaPG (860 microgram SaPG/cm incision). In the third experiment, polyvinyl alcohol (PVA) sponges (16-17 mg dry wt each) containing either 50 microliter saline or 0.5 mg SaPG in 50 microliter saline were implanted subcutaneously, two on each side, via 1-cm incisions closed with a single suture. In the fourth experiment, 5.5-cm bilateral skin incisions and subcutaneous implantation of PVA sponges were done as described but all sites were instilled with saline only. All rats were euthanized (CO(2) asphyxia) 7 days postoperatively. RESULTS: Wound breaking strength (WBS) of the saline-treated incisions was significantly higher (P < 0.001) in captopril-treated rats than in controls (172 +/- 13 g vs 105 +/- 6 g) in experiment 1 and higher, but not significantly in captopril-treated rats in experiment 2 (153 +/- 8 g vs 114 +/- 6 g) (PNS). SaPG inoculation of the incisions increased WBS significantly in both control and captopril-treated rats: 187 +/- 11 g vs 105 +/- 6 g (P < 0.001) and 283 +/- 16 g vs 172 +/- 13 g (P < 0.001), respectively, in experiment 1, and 217 +/- 13 g vs 114 +/- 6 g (P < 0.0001) (controls) and 266 +/- 17 g vs 153 +/- 8 g (captopril-treated rats) (P < 0.0001) in experiment 2. In experiment 3, subcutaneous PVA saline-inoculated sponge reparative tissue hydroxyproline (OHP) content was similar in control and captopril-treated rats, and SaPG inoculation increased reparative tissue OHP significantly in both groups: 2458 +/- 218 microgram/100 mg dry sponge vs 3869 +/- 230 microgram/100 mg (P < 0.001) (controls) and 2489 +/- 166 microgram/100 mg vs 4176 +/- 418 microgram/100 mg (P < 0.001) (captopril-treated rats). Histologically, angiogenesis and reparative tissue collagen were similar in control and captopril-treated rats, in both saline-inoculated and SaPG-inoculated sponges. In experiment 4 (all incisions and subcutaneous PVA sponges were saline-inoculated), there was no significant difference in WBS between control and captopril-treated rats (107 +/- 6 g vs 96 +/- 5 g, NS). PVA sponge reparative tissue OHP was significantly higher in captopril-treated rats: 3698 +/- 170 microgram/100 mg dry sponge vs 2534 +/- 100 microgram/100 mg (P < 0.0001). CONCLUSION: Unexpectedly, in four experiments, captopril did not inhibit WBS or PVA sponge reparative tissue angiogenesis or collagen accumulation; in fact, WBS was increased significantly in one of three experiments, and PVA sponge reparative tissue OHP was increased significantly in one of two experiments. Also, captopril did not interfere with the wound healing-accelerating effect of SaPG.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

The effect of the platelet derived wound healing formula and the nerve growth factor on the experimentally injured spinal cord.

The main purpose of this study is to investigate the effect of platelet derived wound healing formula (PDWHF) and nerve growth factor (NGF) in the treatment of experimental spinal cord injury. PDWHF is a conglomerate of growth factors which include platelet derived growth factor (PDGF), platelet derived angiogenesis factor (PDAF), transforming growth factor-beta (TGF beta) and platelet factor IV (PF4). Complete spinal cord transection was performed at T12 in rats and the treatment of the spinal cord injury was achieved by filling the dead space with type 1 collagen gel impregnated with PDWHF, or with 2.5S-NGF. Controls were treated with only type 1 collagen gel. Animals were sacrificed at 1, 2 or 3 months. Histopathologically, tissue autolysis and cavity formation by phagocytosis expanded 1-3 mm into the cord stumps and the volume of cavitation was less in the two treated groups. In the NGF group, a greater number of surviving nerve cells were observed in this region. Most of the control animals formed only thin, short axonal bundles, however, increased axonal regrowth was noted in animals treated with trophic factors, especially in the NGF group. The NGF group formed thick axonal bundles and abundant neuroma. Increased angiogenesis was observed in the collagen gel matrix and the injured spinal cord parenchyma, in the PDWHF group. Recent studies have shown that mammalian adult CNS possesses the ability for structural and/or functional plasticity following injury under appropriate circumstances. In this in vivo study, exogenous NGF appeared to induce axomal outgrowth and nerve cell survival. PDWHF produced notable angiogenesis which seemed to improve the extracellular microenvironment. This may be important for the delivery of exogenous trophic factors, nutrients and for the changes of extracellular matrices to support nerve cells and axons.

Animals↗
PubMed1993

In vivo angiogenesis by platelet-derived wound-healing formula in injured spinal cord.

In vivo angiogenesis was investigated using platelet-derived wound-healing formula (PDWHF) in the injured cat spinal cord. Twenty-two gauge teflon sheaths, which had been coated with PDWHF-Hydron or only with Hydron, were inserted into the spinal cords of cats and the injured cats were maintained for 3 weeks. Selection of PDWHF-Hydron or Hydron was double blinded. The PDWHF-Hydron group showed notable neovascularization as well as dilation around the injury site, and this was statistically significant when compared to the control group. PDWHF seems to play a role in the healing processes of spinal cord injury and may have important interactions with other growth factors and in particular neurogenic growth factor.

Animals↗
PubMed1992

The effect of growth factor formula (platelet derived wound healing formula) in experimental spinal cord injuries.

The main purpose of this study was to investigate the usefulness of platelet derived wound healing formula (PDWHF) in the treatment of experimentally induced spinal cord injuries in cats. The injury model in ten adult cats consisted of the placement of three 22-gauge Teflon catheter sheaths into the spinal cord at the L2 level. Treatment consisted of coating these sheaths with PDWHF in Hydron. Three animals were used as controls. In the 7 remaining cats, treatment was double blinded. Cats were sacrificed at 3 weeks after injury and injured spinal cord segments were excised for histologic evaluation. Electrophysiologic and clinical motor function were evaluated throughout a period of observation. Evoked potentials in both the treated and control groups indicated incomplete spinal cord lesions due to insertion of the needles. There did not appear to be any significant improvement or difference in the evoked response and clinical function as a result of treatment with PDWHF. The histological findings in the PDWHF-treated group showed significant new vessel formation as well as dilation and around the injury site. This neovascularization, both qualitative and quantitative, was noted in the treatment group. This information, with a limited injury and very simple delivery system for growth factor, would suggest there is definite neovascularization occurring as a result of this treatment and this may be useful in the subsequent wound healing response such as axonal growth and scar tissue formation.

Animals↗
PubMed1992

Complications and mortality of the in-situ saphenous vein bypass for lower extremity ischemia.

We retrospectively reviewed the records of 88 patients who underwent a total of 95 in-situ bypass operations. Seventy-eight percent were diabetics, 56% hypertensives, 23% had a history of a myocardial infarction, 18% a previous stroke or transient ischemic attack, and 19% a renal transplant. Eighty-eight percent had general anesthesia. Eighty-four percent of the operations extended distal to the popliteal trifurcation, with an average operating time of 5.12 +/- 1.25 hours and blood loss of 354 +/- 239 ml. The overall mortality was 4.2%, with two deaths due to wound sepsis and two deaths due to congestive heart failure. The perioperative myocardial infarction rate was 6.3%. The average age of the patients who died was significantly greater than the age of those who survived (78.2 +/- 17.7 years vs. 59.9 +/- 14.8 years, p less than 0.05). The Goldman risk index was not helpful in predicting cardiac complications. The results show that patients undergoing in-situ bypass operations are at high risk for cardiovascular complications. Aggressive perioperative evaluation and management similar to that shown to reduce such complications in abdominal aortic aneurysm surgery should be helpful.

Adult↗
PubMed1991

Identification and partial characterization of angiogenesis bioactivity in the lower respiratory tract after acute lung injury.

Survival after acute lung injury (ALI) depends on prompt alveolar repair, a process frequently subverted by the development of granulation tissue within the alveolar airspace. Immunohistochemical examination of the intraalveolar granulation tissue confirmed that capillaries as well as myofibroblasts were the principal cellular constituents. We therefore hypothesized that angiogenesis factors would be present on the air-lung interface after ALI. To evaluate this hypothesis, bronchoalveolar lavage fluid from patients with ALI (n = 25) and patient controls (n = 8) was examined for angiogenesis bioactivity by its ability of induce endothelial cell migration. While lavage fluid from controls had no bioactivity, lavage fluid from 72% of patients with ALI promoted endothelial cell migration. Heparin affinity, ion exchange, and gel filtration chromatography resolved the bioactivity into at least two moieties. One appeared identical to the well characterized endothelial cell growth factor, basic fibroblast growth factor. The other was a 150-kD non-heparin binding protein that mediated endothelial cell migration and attachment in vitro, and the growth of new vessels in vivo. These data are consistent with the hypothesis that the growth of capillaries into the alveolar airspace results from angiogenesis factors present on the alveolar surface of the lung after ALI.

Acute Disease↗
PubMed1989

Hypoxia and endotoxin induce macrophage-mediated suppression of fibroblast proliferation.

Cellular mechanisms and environmental factors contributing to wound failure following shock and wound contamination are unclear. The activation of macrophages by exposure to hypoxia (pO2 less than 20) and/or lipopolysaccharide (10 micrograms/ml) in vitro was investigated for its effect on macrophage regulation of fibroblast proliferation. The effect on fibroblast proliferation of conditioned medium from activated murine macrophages or co-culture with activated macrophages was tested by measuring 3T3 fibroblast incorporation of 3H-thymidine and culture DNA content. Unstimulated macrophages produced growth factors that increase fibroblast proliferation (proliferation index (PI) = 1.4 +/- 0.15, p less than 0.05 vs. control). Activation by hypoxia alone had little effect on macrophage regulation of fibroplasia (PI = 1.55 +/- 0.28, N.S. vs. unstimulated macrophages). LPS activated macrophages suppressed fibroplasia and the combination of hypoxia with LPS augmented the suppression (PI = 0.5 +/- 0.11, LPS alone, p less than 0.05 and 0.25 +/- 0.05, LPS + hypoxia, p less than 0.01). In addition, hypoxia + LPS treated co-cultures had reduced DNA contents, suggesting reduced cell numbers (12.5 +/- 2.6 micrograms vs. 8.2 +/- 2.0 micrograms). We screened several macrophage cytokines for their direct effect on 3T3 proliferation and found that mr-Tumor Necrosis Factor-alpha (150 units) also suppressed proliferation. Conditioned supernatants from LPS activated macrophages contained 12 +/- 2 units of mrTNF as measured by L929 cytolysis; however, this was significantly less than required to induce suppression of proliferation by direct addition. The regulatory role of the macrophage appears to be dependent on its level of activation. Activation by hypoxia and LPS altered macrophage regulation of fibroblast proliferation from stimulation to suppression.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Lower-extremity venous thrombosis: comparison of venography, impedance plethysmography, and intravenous manometry.

This study was undertaken to compare impedance plethysmography with lower-extremity venography and venous manometry in the diagnosis of acute deep venous thrombosis (DVT) of the lower extremity. Ninety-six extremities were studied. In this population, in which the prevalence of acute DVT was 43.8%, plethysmography had a sensitivity of 86.8% and a specificity of 72.0%. The predictive value of abnormal findings at plethysmography was 70.2%, and the predictive value of normal findings at plethysmography was 87.8%. Venous manometry was performed successfully in 89 extremities. A statistically significant difference was shown in the mean intravenous pressure between patients with and without acute DVT. However, there was considerable overlap between the two populations, limiting the predictive value of impedance plethysmography in any given patient.

Adult↗
PubMed1984

Carotid surgery without angiography.

We propose that circumstances exist in which angiography is not necessary or is unwarranted for the diagnosis and treatment of carotid arterial disease. High quality real-time B-mode ultrasonographic imaging, combined with both pulsed gated, and continuous wave Doppler analysis, shows a remarkably close correlation with the pathologic abnormality identified at operation. Scanning in the vascular laboratory not only provides quick, noninvasive, accurate assessment of the atherosclerotic disease, it can also provide plaque and blood flow detail not previously attainable. Carotid surgery can be effectively and safely performed in selected patients with the aid of ultrasonography and Doppler analysis without the need for invasive angiographic imaging.

Aged↗
PubMed1977

Avascular and vascular phases of tumour growth in the chick embryo.

The chick embryo was used to study the relationship between the onset of tumour neovascularization and tumour growth. Walker 256 carcinosarcoma was implanted on the chrioallantoic membrane (CAM) of about 600 embryos aged 5-16 days. Tumour diameter and changes in the CAM vasculature in response to the implants were recorded daily. Representative tumours were examined by light microscopy of Epon-embedded tissue and autoradiography after injection of [3H]-thymidine. Tumours remained avascular for 72 h, after which they were penetrated by new blood vessels and began a phase of rapid growth. The rate of growth during this vascular phase was greatest for implants on 5- and 6-day-old embryos and decreased the later the day of implantation. The time of onset of tumour angiogenesis appears to be independent of the immunological state of the chick embryo, although the rate of growth after vascularization may be modified by the onset of immunity. This study suggests that the avascular and vascular phases of tumour growth are separable, and that the avascular tumour population lives under the growth constraints which limit the size of a tumour spheroid growing in soft agar or aqueous humour.

Animals↗
PubMed1976

Tumor angiogenesis activity in cells grown in tissue culture.

Normal, viral transformed and tumor-derived cells grown in tissue culture and representing different species were tested for their ability to produce an extracellular tumor angiogenesis factor (TAF). TAF was assayed by measuring the host-mediated vascular response of the chorioallantoic membrane to TAF preparations. All of the viral transformed and tumor-derived cells tested, including SVT2, SVW126, Welker 256 rat carcinoma, B-16 mouse melanoma, human glioblastoma, and human meningioma cells, produced TAF. The potency of the TAF preparations, as measured by the number of cells needed to induce a positive vascular response on the chorioallantoic membrane, varied from cell line to cell line. The most potent cells tested were the glioblastoma and maningioma brain tumor cells. Since these brain tumors are found to be the most highly vascularized tumors in vivo, it was concluded that a correlation exists between the vascularity of a tumor in vivo and the potency of TAF in vitro. There was no detectable angiogenesis activity induced by density-inhibited BALB/c primary mouse embryo or early-passage human skin fibroblasts, even when relatively large numbers of cells were used to make a sample. However, density-inhibited BALB/c 3T3 aan W138 human embryonic lung fibroblasts, two cell lines widely regarded as demonstrating "normal" growth behavior in culture, produced TAF. From these and other observations, it was suggested that BALB/c 3T3 and W138 are not fully "normal" cells. Furthermore, it was suggested that the production of TAF is an early event in the cell transformation process that precedes the loss of density inhibition of growth in vitro.

Angiogenesis Inducing Agents↗