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Biomedical subjects

J S Kerr

Publications and source records attributed to J S Kerr.

At least 55 records · Page 3Linked to original sources
PubMed1990

Effects of nicotine gum on psychomotor performance in smokers and non-smokers.

Two experiments were conducted to investigate the effects of nicotine on human performance. In the first study six smokers, who had been allowed to smoke normally prior to testing, completed a battery of psychometric tests (choice reaction time, memory scanning, tracking and flicker fusion threshold) at set points over 4 h after chewing 0, 2, or 4 mg nicotine polacrilex gum. A second study followed a similar design, but used five non-smoker volunteers who were required to chew only the 0 or 2 mg nicotine gum. Blood nicotine levels following the gum were measured in all subjects. The results indicate that additional nicotine improved both the speed and accuracy of motor activity among the smokers, but did not enhance central cognitive processes. No drug effects were found in the non-smoker study.

Chewing Gum↗
PubMed1990

Strain specific respiratory air space enlargement in aged rats.

We studied lung structure and function in Fischer-344 and Sprague Dawley rats to compare the pathophysiologic features of the aged lung in animal strains. Both strains were maintained under identical conditions of minimal exposure to injurious environmental agents. We measured the number, size, and surface area of alveoli, pressure-volume characteristics and connective tissue content of lungs at midlife (12 or 14 months of age) and old age (24 months of age). Results showed differences in the older versus younger group of the Sprague Dawley strain as indicated by enlarged air spaces [154 +/- 21 (SEM) versus 118 +/- 13 micromicroliter] (p less than 0.05), increased collagen (hydroxyproline content 4.1 +/- 0.1 versus 3.0 +/- 0.1 mg/lung) (p less than 0.05), and a leftward shifted pressure-volume curve. There was no change in surface area or alveolar number. The structural lesions are consistent with air space enlargement with fibrosis and not emphysema. In contrast, no major changes were found in the lungs with age in Fischer-344 rats. We hypothesize that in the Sprague Dawley strain the aging process impairs the ability of the lung to maintain normal structure and function. Two strains of rats which differ pathologically in old age may be useful in the study of the effects of aging on the lung.

Aging↗
PubMed1990

Extracellular collagenase, proteoglycanase and products of their activity, released in organ culture by intact dermal inflammatory lesions produced by sulfur mustard.

Peak (1 and 2 d) and healing (3, 6, and 10 d) inflammatory lesions were produced in rabbits by the topical application of the military vesicant, bis(2-chloroethyl)sulfide, commonly called sulfur mustard (SM). SM produces an acute sterile dermal inflammatory reaction with little or no necrosis, except in the epidermis, which dies during the first day. After an animal was killed, its lesions were excised intact, as full-thickness 1.0-cm2 explants. They were then organ-cultured for 3 d in order to maintain the viability of both local and infiltrating cells. The extracellular fluid in each lesion equilibrated with the culture fluid, which was collected daily and analyzed for collagenase and proteoglycanase activities. These metalloproteinase activities were measured after we had i) destroyed the alpha-macroglobulin inhibitors with KSCN, ii) destroyed the tissue inhibitor of metalloproteinases (TIMP) by reduction and alkylation, and iii) activated the latent proteinase activity with aminophenylmercuric acetate (APMA). Hydroxyproline-containing peptides and glycosaminoglycans (GAG) released into the culture fluids were also measured as indicators of local collagenase and proteoglycanase activity within the inflammatory lesions. In general, the levels of both the metalloproteinases and the products of their activity were higher in second- and third-day culture fluids than in first-day culture fluids, and higher in fluids from SM lesions than in those from normal skin. The activated fibroblast was apparently the major cell type producing the collagenase and proteoglycanase. The hydrolysis of collagen and ground substance occurs pericellularly. An excess of inhibitors exists outside the pericellular region. The daily change in culture fluids apparently decreased such inhibitors, so that by the second and third day of culture we could detect the changes in pericellular enzyme activity that were not detectable on the first day of culture. As the inflammatory lesions healed, the extracellular enzyme products (hydroxyproline and GAG) increased more than the enzymes that produced these products. With healing, a decrease occurs in the extravasation of all serum components, especially the large ones such as the alpha-macroglobulin inhibitors. We propose that during healing, the decrease in these inhibitors allows the metalloproteinases to begin the remodeling process, and that during the peak phase of inflammation, these same inhibitors protect extracellular matrix against hydrolysis by such proteinases.

Animals↗
PubMed1990

Anti-inflammatory and safety profile of DuP 697, a novel orally effective prostaglandin synthesis inhibitor.

DuP 697 (5-bromo-2[4-fluorophenyl]-3-[4-methylsulfonylphenyl]-thiophene) is a potent inhibitor of paw swelling in nonestablished and established adjuvant arthritis in rats (ED50 = 0.03 and 0.18 mg/kg/day, respectively). DuP 697 had no effect on phenylquinone writhing in rats (ED50 greater than 100 mg/kg), but was analgetic against inflammation-related pain in the Randall-Selitto assay (ED30 = 3.5 mg/kg) and was a very potent antipyretic agent (ED50 = 0.05 mg/kg). The drug was not ulcerogenic in rats at single doses up to 400 mg/kg. DuP 697 (5 mg/kg i.v.) did not alter renal blood flow or the renal vascular response to angiotensin II in furosemide-pretreated, volume-depleted rats. In contrast, indomethacin (5 mg/kg i.v.) decreased renal blood flow and potentiated the renal vascular response to angiotensin II in these animals. DuP 697 was a moderate inhibitor of bull seminal vesicle prostaglandin (PG) synthesis (IC50 = 2.4 X 10(-5) M) and a potent inhibitor of rat brain PG synthesis (IC50 = 4.5 X 10(-6) M) but was ineffective against rat kidney PG synthesis (IC50 7.5 X 10(-5) M). These differential effects of DuP 697 on PG synthesis by various tissues may account for its high potency as an anti-inflammatory and antipyretic agent and its minimal toxicity profile.

Administration, Oral↗
PubMed1989

Effects of recombinant interleukin-1 beta on phospholipase A2 activity, phospholipase A2 mRNA levels, and eicosanoid formation in rabbit chondrocytes.

We have investigated the effects of recombinant interleukin-1 beta (rIL-1 beta) on phospholipase A2 activity (PLA2), PLA2 messenger RNA levels, and eicosanoid production in rabbit chondrocytes. Phospholipase A2 activity increased 5 fold with exposure to 1.6 x 10(-11) M rIL-1 beta for 20 hours. An mRNA specific for an extracellular PLA2 was detected by RNA blot hybridization after treatment of the cells with rIL-1 beta. Hydroxylated derivatives of arachidonic acid, including prostaglandins, leukotriene B4, 5-hydroxyeicosa 6E, 8Z, 11Z, 14Z-tetraenoic acid, 12-hydroxyeicosa 5Z, 8Z, 10E, 14Z-tetraenoic acid and 15-hydroxyeicosa 5Z, 8Z, 11Z, 13E-tetraenoic acid increased in cells after rIL-1 beta treatment.

Animals↗
PubMed1989

Extracellular phospholipase A2 activity in cell free peritoneal lavage fluid from mice with zymosan peritonitis.

The kinetics and appearance of extracellular phospholipase A2 (PLA2) activity and its relationship to the appearance of arachidonic acid (AA) metabolites in the peritoneal cavity of mice injected with zymosan is described. AA metabolites levels including leukotriene C4 (LTC4) were maximum 15-30 min after zymosan. Peak PLA2 activity was also found 15-30 min after zymosan and was significantly increased above levels found in saline control exudates (3.83 +/- 0.89 and 0.35 +/- 0.11, respectively, p less than or equal to 0.05). Results show that an extracellular PLA2 is present in zymosan peritonitis.

Animals↗
PubMed1989

The effect of immunomodulating drugs on adjuvant-induced arthritis in Lewis rats.

The purpose of this study was to investigate the effects of cyclosporine A (CSA) and methotrexate (MTX) as potential immunomodulators in a nonestablished adjuvant arthritis (AA) model. Non-injected hind paw volumes were reduced when AA rats were treated for 18 days with CSA (100% at 10 mg/kg) or MTX (100% at 0.1 mg/kg). Body weights of drug treated AA rats were increased above untreated AA rats and were similar to non-arthritic controls. AA rats show elevated T helper (W3/25+)/T suppressor (OX 8+) cell ratios (2.0 vs. 3.1, p less than 0.01). The immunomodulators tested all returned these elevated ratios to control non-arthritic levels. Similarly, these drugs returned the reduced mitogen responses and elevated blood granulocyte numbers toward normal non-arthritic control values.

Animals↗
PubMed1989

Phospholipase A2 (PLA2) activity in rabbit chondrocytes.

The effects of recombinant interleukin-1 beta (rIL-1 beta), recombinant tumor necrosis factor (rTNF alpha) and two growth factors, basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) on PLA2 activity and prostaglandin E2 (PGE2) release were investigated using rabbit chondrocytes. Cellular PLA2 activity increased 2-10 x above controls in the presence of 8 x 10(-12) M (5 U) rIL-1 beta or 5 x 10(-9) M rTNF alpha after 20 hr incubation. PLA2 activity remained constant with 1-50 ng/ml of either growth factor. PGE2 release significantly increased (p less than 0.05) when the chondrocytes were incubated with rIL-1 beta, bFGF and EGF alone, but not with rTNF alpha above. These data suggest PLA2 activity and PGE2 release are not coordinately regulated in rabbit chondrocytes.

Animals↗
PubMed1989

Phospholipase A2 (PLA2) activity in undifferentiated U937 cells.

PLA2 activity has been described in U937 cells. The present study characterized PLA2 activity in these undifferentiated cells. Cells were grown in suspension culture, harvested by centrifugation, and washed and homogenized in a neutral buffer containing standard proteinase inhibitors. A low speed supernatant was fractionated either by acid extraction or by sucrose density gradient centrifugation. PLA2 activity was measured using either L-alpha-1-palmitoyl-2-arachidonoyl[1-14C]-phosphatidylcholine or heat-inactivated [3H]oleic acid-labeled E. coli as substrates. Substrate-specific PLA2 activity was found in the acid-extracted and in the 25% sucrose fractions. Standard inhibitors were investigated with these PLA2 activities. Our results suggest undifferentiated U937 cells contain three distinct PLA2 activities. This is the first indication that more than one PLA2 activity is present in undifferentiated U937 cells.

Escherichia coli↗
PubMed1989

Pretreatment with EDU decreases rat lung cellular responses to ozone.

The phenylurea compound EDU (N-[2-(2-oxo-1-imidazolindinyl)ethyl]-N'-phenylurea) has been shown to protect plants from the damaging effects of ozone exposure. Models of rat lung injury, based on acute exposure to 2 ppm ozone for 3 hr and on exposure to 0.85 ppm ozone for 2 days, were used to determine whether EDU pretreatment of rats protected lungs from oxidant injury. Rats were pretreated with 100 mg/kg body wt EDU by ip administration for 2 days prior to and on the days of ozone exposure. No adverse toxicological effects of EDU pretreatment were observed. Lung superoxide dismutase (SOD) and catalase (CAT) activities were significantly enhanced from 636 to 882 U/lung and from 599 to 856 U/lung, respectively. One day following acute exposure (2 ppm for 3 hr), an ozone-induced increase of polymorphonuclear leukocytes (PMNs) from 0.01 to 1.18 million cells/lung was decreased to 0.68 million by EDU pretreatment. No alteration occurred in the degree of lung permeability indicated by increased lavage fluid albumin. EDU pretreatment also significantly decreased ozone-induced increases in PMN recovery after 2 days exposure to 0.85 ppm ozone from 5.54 to 2.12 million cells/lung. However, in this second case, EDU pretreatment reduced the observed ozone damage, indicated by a decrease in lavage fluid albumin and by a decrease in the macrophage and lymphocyte infiltration associated with this length of ozone exposure. The observation that EDU-treated cultured pulmonary arterial endothelial cells increased SOD and CAT activities identified a potential lung site of EDU interaction. These data demonstrated that although EDU pretreatment appears not to prevent initial ozone damage, it does reduce the infiltration of PMNs and might therefore prevent amplification of the injury associated with this cell type.

Animals↗
PubMed1988

Treatment of experimental silicosis with antifibrotic agents.

We tested the efficacy of 2 antifibrotic agents, the proline analogue cis-4-hydroxy-L-proline (cHyp) and the lathyrogen beta-aminopropionitrile (BAPN), on experimental silicosis in hamsters. Silica (75 mg) was instilled intratracheally, and 3 months later lung hydroxyproline content, the volume density of silicotic nodules in lung parenchyma, fluid-filled lung pressure-volume curves, body weight and survival were measured. Animals were injected with cHyp, 200 mg/kg body weight, or BAPN, 150 mg/kg body weight, twice daily for 3 months. Hydroxyproline contents (mg/lung) at 3 months were: control, 0.8 +/- 0.1; silica, 1.4 +/- 0.1 (P less than 0.05 compared to control); silica-cHyp, 1.2 +/- 0.2; silica-BAPN, 1.4 +/- 0.1 (both NS compared to silica). The volume density of granuloma (% of surface area) was: silica, 0.7 +/- 0.1; silica-cHyp, 5.9 +/- 1.0; silica-BAPN, 9.7 +/- 1.5 (both P less than 0.5 compared to silica). There was no difference among the groups as assessed by lung pressure-volume curves. No toxic effects were produced on the skeletal system as assessed by bone hydroxyproline content and skeletal roentgenograms. Final body weights (g) were: silica, 114 +/- 5; silica-BAPN, 108 +/- 6; silica-cHyp, 88 +/- 7 (the latter P less than 0.05 compared to silica). Survival (%) was: silica, 62%; silica-BAPN, 34%, silica-cHyp, 28% (both P less than 0.05 compared to silica). These data show that cHyp and BAPN treatment did not prevent silica-induced pulmonary fibrosis, led to more extensive silicotic nodules, and were toxic. Both cHyp and BAPN have some efficacy in other models of fibrosis, and the observations in the present study could be specific to silicosis in the hamster.

Aminopropionitrile↗
PubMed1988

A reversible model of acute lung injury based on ozone exposure.

In this study inflammatory responses were determined in rat lungs 0, 1, 3, and 8 days following single 2- and 4-hr exposures to 1.8 ppm ozone. Analysis of lavage fluid immediately following exposure demonstrated enhanced lactate dehydrogenase activity and decreased numbers of lavageable macrophages but no alterations in albumin content. Similar analyses at one day postexposure demonstrated 282% and 456% increases in albumin content and enhanced numbers of lavageable neutrophils from a control value of 0.01 +/- 0.01 to 0.27 +/- 0.10 and 0.78 +/- 0.11 million cells per lung for 2-hr and 4-hr exposures, respectively. The observed increased levels of albumin were also present at 3 days, at which time the number of lavageable neutrophils was not significantly different than control. At both one and 3 days postexposure, lavageable lymphocytes were significantly increased 10-fold from a control value of 0.03 +/- 0.01 million cells per lung. However, the number of lavageable macrophages was unaltered on day 1, but enhanced on day 3, giving values of 0.67 +/- 0.05 (control), 2.25 +/- 0.46 (2 hr), and 2.70 +/- 1.05 (4 hr) million cells per lung. By 8 days both inflammatory cell numbers and albumin levels had returned to control values. Since these data demonstrated different time courses for each inflammatory cell type, this reversible model of acute lung injury should be useful for establishing possible involvement of these cells in processes of lung injury.

Animals↗
PubMed1988

Induction of antioxidant enzyme activities by a phenylurea derivative, EDU.

Oxygen free radicals have the potential to mediate cell injury. Defenses against such radicals include the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX). The purposes of this study were (1) to develop an in vitro model using human cells in which to investigate a potential pharmacologic agent as an inducer of these antioxidant enzymes; (2) to investigate the phenylurea derivative N-[2-(2-oxo-1-imidazolindinyl)ethyl]-N-phenylurea (EDU) in this model with paraquat (PQ) serving as the positive control; and (3) to determine if induction of the antioxidant enzymes by EDU occurs in vivo. Human gingival fibroblasts (Gin-1) were used as the target cell in vitro; PQ and EDU, an inducer of SOD and CAT activities in plants, were evaluated as antioxidant enzyme inducers. Total SOD activity in Gin-1 cells increased 2-fold (p less than 0.05) in the presence of 1.0 mM PQ for 18-48 hr compared with untreated controls. Gin-1 cells incubated with 0.25-2.0 mM PQ for 24 hr had significantly increased total SOD (1.5 to 2.0-fold; p less than 0.05). CAT activity increased with 1.0 and 2.0 mM PQ (p less than 0.05). In the presence of PQ, GSH-PX activity decreased (p less than 0.05) in a concentration-dependent manner, indicating inactivation of this enzyme. No toxicity, indicated by lactate dehydrogenase released into the incubation medium, was noted at PQ concentrations below 5.0 mM. In the presence of 0.125-2.0 mM EDU, total SOD activity in Gin-1 cells significantly increased (1.5 to 2.0-fold; p less than 0.05). CAT activity significantly increased in a dose-dependent manner (p less than 0.05), while GSH-PX activity remained constant following exposure to 0.125-2.0 mM EDU. Intraperitoneal administration of EDU to rats twice a day for 2 days at 100 mg/kg induced SOD activity in heart, liver, and lung compared to controls (p less than 0.05). CAT activity increased in the liver 56% and in the lung 36% (p less than 0.05). GSH-PX activity remained constant. Our findings indicate that Gin-1 cells are a useful model in which to study inducers of antioxidant enzymes in vitro and that the phenylurea compound EDU induces SOD and CAT activities both in vitro and in vivo.

Antioxidants↗
PubMed1988

Neutrophil response following intratracheal instillation of collagen peptides into rat lungs.

Inflammatory lung diseases are associated with destruction of interstitial collagen and release of degraded collagen fragments into the lower respiratory tract. To determine whether degraded collagen might be one factor mediating the cellular influx, we measured polymorphonuclear leukocytes (PMN) in bronchoalveolar lavage fluid following intratracheal instillation of collagen peptides. The responses to collagenous peptides derived from collagen digested with bacterial collagenase and to the collagenous-like polytripeptide (proline-proline-glycine) were examined. Both types of collagen peptides were chemotactic for human PMN in vitro. Two days following instillation of 5 mg collagenous peptides, we observed a threefold increase in the percentage of PMN in lavage fluid with a maximum (fivefold) response on day 6. Since other chemoattractants produce a response within hours when instilled intratracheally, we postulated that the late neutrophil influx produced with collagen may be the result of production of a neutrophil chemoattractant by alveolar macrophages. Alveolar macrophages treated with collagenous or collagenous-like peptides released PMN chemotactic factors, and the time course of release of chemotactic activity by alveolar macrophages in vitro correlated with the in vivo finding of a 2-6-day delay in PMN accumulation in the lungs. These observations are consistent with the idea that collagen peptides may stimulate alveolar macrophages to produce chemotactic factors for neutrophils. This mechanism may play a role in the accumulation of phagocytic cells in the lung following injury.

Animals↗
PubMed1987

Acute lung inflammation in rats induced by phorbol myristate acetate (PMA).

Intratracheal administration of PMA produces acute lung injury in part due to the generation of O2-derived free radicals. This study evaluated the role of the antioxidant enzyme superoxide dismutase (SOD) in PMA-induced lung injury in the rat. PMA was instilled into rats intratracheally (20-60 micrograms/kg), and the lungs were lavaged 4 hr later. Total number of cells recovered from lavage after PMA treatment was not different from the total number recovered from controls; lavagable PMNs increased in a dose-dependent manner. Albumin in lavage fluid (an index of lung vascular permeability) was significantly increased at 60 micrograms/kg PMA. SOD (10,000 U) + PMA (60 micrograms/kg) reduced the albumin level but significantly increased both total number of cells and number of PMNs recovered from lavage fluid. To investigate the possibility that SOD decreases the ability of PMNs to adhere, PMN aggregation was measured in vitro. The results indicated that 10,000 U SOD can inhibit PMA-induced aggregation by 50%. In contrast, aggregation to other stimuli (e.g., fMet-Leu-Phe, A23187) was unaffected by SOD. We conclude SOD prevents PMA-induced lung permeability and diminishes PMN adherence.

Animals↗
PubMed1987

Reduction of chronic hypoxic pulmonary hypertension in the rat by an inhibitor of collagen production.

Chronic hypoxic pulmonary hypertension in the rat is associated with increased collagen and elastin in the pulmonary artery. We investigated whether excess vascular collagen contributes to chronic hypoxic pulmonary hypertension by administering the proline analogue cis-4-hydroxy-L-proline (cHyp), an agent relatively specific for inhibiting collagen production, to rats exposed to chronic hypoxia. Sprague-Dawley rats (weighting 200 g) were exposed to air or hypoxia (10% O2-90% N2) for 3 wk. Groups studied were: air-exposed injected with saline, air-exposed injected with cHyp, hypoxic injected with saline, and hypoxic injected with cHyp. At the end of 3 wk, we measured mean right ventricular pressure (RVP) of animals breathing room air and hydroxyproline and desmosine contents of the main pulmonary artery trunk. Hypoxia increased RVP from 13 +/- 1 to 27 +/- 1 mm Hg (p less than 0.05); cHyp partially prevented this increase since RVP was 17 +/- 1 mm Hg (p less than 0.05). There was no effect of cHyp on cardiac output. Hypoxia increased collagen from 0.9 +/- 0.1 to 2.0 +/- 0.3 mg/artery (p less than 0.05); cHyp completely prevented this increase since collagen was 1.0 +/- 0.2 mg/artery (p less than 0.05). Hypoxia increased elastin from 1.1 +/- 0.1 to 2.4 +/- 0.2 mg/artery (p less than 0.05); cHyp had no apparent effect since elastin was 2.1 +/- 0.1 mg/artery. Also, cHyp did not affect RVP or vascular collagen or elastin in air-breathing animals. The cHyp treatment prevented luminal narrowing and thickening of arteriolar walls by hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗