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Biomedical subjects

J L Wright

Publications and source records attributed to J L Wright.

At least 19 recordsLinked to original sources
PubMed2006

Cigarette smoke upregulates pulmonary vascular matrix metalloproteinases via TNF-alpha signaling.

Cigarette smoke exposure causes vascular remodeling and pulmonary hypertension by poorly understood mechanisms. To ascertain whether cigarette smoke exposure affects production of matrix metalloproteinases (MMPs) in the pulmonary vessels, we exposed C57Bl/6 (C57) mice or mice lacking TNF-alpha receptors (TNFRKO) to smoke daily for 2 wk or 6 mo. Using laser capture microdissection and RT-PCR analysis, we examined gene expression of MMP-2, MMP-9, MMP-12, MMP-13, and tissue inhibitor of metalloproteinase (TIMP-1) and examined protein production by immunohistochemistry for MMP-2, MMP-9, and MMP-12 in small intrapulmonary arteries. At 2 wk, mRNA levels of TIMP-1 and all MMPs were increased in the C57, but not TNFRKO, mice, and immunoreactive protein for MMP-2, MMP-9, and MMP-12 was also increased in the C57 mice. Increased gelatinase activity was identified by in situ and bulk tissue zymography. At 6 mo, only MMP-12 mRNA levels remained increased in the C57 mice, but at a much lower level; however, MMP-2 mRNA levels increased in the TNFRKO mice. We conclude that smoke exposure increases MMP production in the small intrapulmonary arteries but that, with the exception of MMP-12, increased MMP production is transient. MMPs probably play a role in smoke-induced vascular remodeling, as they do in other forms of pulmonary hypertension, implying that MMP inhibitors might be beneficial. MMP production is largely TNF-alpha dependent, further supporting the importance of TNF-alpha in the pathogenesis of cigarette smoke-induced lung disease.

Animals↗
PubMed2006

Individual, sexual, seasonal, and temporal variation in the amount of sagebrush lizard scent marks.

Although many animals deposit scent marks, previous studies have focused almost entirely on rodents or on the chemical structure of the signal. Here, we study the quantity and temporal pattern of chemical deposition by the territorial sagebrush lizard Sceloporus graciosus, measuring both femoral pore and fecal deposits. Specifically, we tested whether variation in deposition is a good cue of individual and sexual identity and/or whether it is more closely associated with body size and reproductive state, indicators of physiological condition. The results support the latter hypothesis. We found that although the amount of fluid deposited on a single perch (rarely quantified in mammals) carries little information on individual or sexual identity, it reflects the physiological condition and reproductive state of individual lizards and is replenished on a roughly weekly cycle, potentially providing additional information on the producer's activity level. The amount of deposition may thus provide important information to chemical receivers making mate choice and territorial defense decisions. The results further suggest that seasonal increases in gland production allow lizards to mark more sites rather than to influence the quality of the signal on a single perch.

Animals↗
PubMed2006

Advances in the pathology of COPD.

Chronic obstructive pulmonary disease encompasses alterations in the parenchyma, airways and vascular compartments. This review is designed to help surgical pathologists evaluate the lungs of subjects who have clinical manifestations of airflow obstruction so that appropriate clinical-pathological correlations can be performed.

Airway Resistance↗
PubMed2006

The spectrum of intoxication and poisonings among adolescents: surveillance in an urban population.

AIM: Among adolescents, poisoning is a leading cause of injury mortality in the United States. This study describes the epidemiology of poisonings, intoxication, and maladaptive effects of drugs among adolescents age 10-19 years in a large city. METHODS: An injury surveillance system used records at seven hospitals, medical examiner records, and vital records over a two year period. RESULTS: Of 633 cases (618 injuries/100 000/year), 6% were unintentional, 36% self-inflicted, 41% alcohol intoxication, and 15% maladaptive effects of drugs. Alcohol was involved in 45% of cases, 23% illegal drugs, 23% non-prescription drugs, 19% prescription drugs; 19% involved more than one substance. Hospitalization was required in 20%; 8% transferred to another hospital; one died from intoxication. The authors found high rates of self-inflicted poisoning, intoxication, and maladaptive effects of drugs among this urban population. CONCLUSION: The study highlights the need to broadly define poisonings among adolescents and the challenge of assessing intent in some cases.

Adolescent↗
PubMed2006

Risk factors for reduced locomotion in dairy cattle on nineteen farms in The Netherlands.

A 3-point locomotion scoring system was used that incorporated the position of the back of cows while standing and when walking to investigate risk factors for elevated locomotion scores of 1,450 dairy cows on 19 farms in The Netherlands. Each of the farms was visited twice in an 18-mo period from February 2003 to July 2004. At each visit, all milking and dry cows were scored for locomotion by a single observer. Two multivariable regression models were constructed to identify factors associated with elevated mean locomotion score (increased abnormality) and the percentage of cows with the highest score (score 3). Risk factors for increased locomotion score were having a hoof-trimming stall with foot-lifting apparatus compared with not having such apparatus (increase in locomotion score = 0.15), presence of a footbath at the parlor exit or other site compared with not having a footbath on the farm (increase in locomotion score = 0.17 and 0.19, respectively), not providing supplemental vitamins and minerals to lactating cows compared with supplementing animals (increase in locomotion score = 0.17) and feeding corn silage to heifers compared with not doing so (increase in locomotion score = 0.10). The results provide a framework for hypotheses for future investigations of risk factors for high locomotion scores.

Analysis of Variance↗
PubMed2005

Pulmonary hypertension in chronic obstructive pulmonary disease: current theories of pathogenesis and their implications for treatment.

The development of pulmonary hypertension is a poor prognostic sign in patients with chronic obstructive pulmonary disease (COPD), affecting both mortality and quality of life. Although pulmonary hypertension in COPD is traditionally viewed as a result of emphysematous destruction of the vascular bed and/or hypoxia, recent studies indicate that neither of these factors correlates very well with pulmonary artery pressures. New human and animal experimental data are beginning to show that pulmonary hypertension in this setting is probably a result of the direct effect of tobacco smoke on the intrapulmonary vessels with abnormal production of mediators that control vasoconstriction, vasodilatation, and vascular cell proliferation, ultimately leading to aberrant vascular remodelling and aberrant vascular physiology. These changes are in many ways similar to those seen in other forms of pulmonary hypertension and suggest that the treatments used for primary pulmonary hypertension may be beneficial in patients with COPD.

Animals↗
PubMed2004

Urban youths' perspectives on violence and the necessity of fighting.

OBJECTIVES: To assess youth perceptions of the causes and consequences of violence generally, the causes and consequences of fighting specifically, and to determine how best to approach fighting in the context of violence prevention activities. METHODS: Thirteen structured focus group interviews with youths from three high violence urban settings: a large, urban high school, a training center for disadvantaged youths, and a school for adjudicated youths. Participants were 120 urban, predominately African-American youths and young adults ages 14-22 years (mean: 17.2 years). Seven focus groups were conducted with females, and six with males. RESULTS: Adolescents identified the causes of violence on multiple levels including: individual, family, interpersonal, and community level factors. Most youths (89%) had been in a physical fight. Participants felt that fighting was not "right", but identified situations in which it was necessary. Specifically, fighting was used as a problem solving tool, and could prevent escalation of violence. Youths felt that the adults in their lives, including physicians, were generally ill equipped to give advice about violence, as adults' experiences were so removed from their own. Participants looked to experienced role models to offer problem solving and harm reduction strategies. Youths were open to receiving anticipatory guidance about violence and fighting from primary care physicians they felt comfortable with, and who showed respect for their experiences. CONCLUSIONS: Interventions that include blanket admonitions against fighting should be reassessed in light of youth perceptions that fighting plays a complex role in both inciting and preventing more serious violence.

Adolescent↗
PubMed2003

Transfection of partially purified plasmid DNA for high level transient protein expression in HEK293-EBNA cells.

One of the major constraints to performing large-scale transfections of cultured mammalian cells for the transient expression of recombinant proteins is the production of large quantities of purified plasmid DNA. In this report partially purified plasmid DNA was prepared by a method that combines alkaline lysis of E. coli with standard precipitation techniques. The efficiency of calcium phosphate-DNA co-precipitate formation with crude DNA was similar to that observed for pure DNA, but precipitate formed with crude DNA also contained RNA. The transfection of adherent and suspension-adapted HEK293-EBNA cells with partially purified pEGFPN1 resulted in levels of transient GFP expression equivalent to those achieved with pure DNA. In addition, the co-transfection of 1-200 ml cultures of suspension-adapted HEK293-EBNA cells with two different plasmids encoding the heavy and light chain genes of anti-human RhD IgG1, respectively, yielded similar IgG titers with pure and partially purified plasmid DNA. Finally, it was observed that suspension-adapted cells were more tolerant to the presence of RNA in the plasmid preparations than were adherent cells. These findings are relevant to the field of DNA transfection, including applications ranging from high-throughput screening to large-scale transient protein expression.

Bioreactors↗
PubMed2003

Generating MHC Class II+/Ii- phenotype after adenoviral delivery of both an expressible gene for MHC Class II inducer and an antisense Ii-RNA construct in tumor cells.

Tumor cells engineered by gene transduction to be MHC Class II+/Ii- are novel APCs capable of presenting endogenous tumor antigen epitopes to activate T helper cells. The MHC Class II+/Ii- tumor cell phenotype is created by transfecting genes for either CIITA or IFN-gamma, and inhibiting induced Ii mRNA by an Ii reverse gene construct (Ii-RGC). Adenoviral vectors are preferred for the delivery of such genes because of high infection efficiency and ubiquity of the adenoviral receptor on many cell types and tumors. Here we show that at 5 MOI (multiplicity of infection), recombinant adenoviruses with CIITA or IFN-gamma genes converted virtually all MC-38 colon adenocarcinoma cells and Renca renal carcinoma cells in culture to MHC Class II+/Ii+ cells. A single recombinant adenovirus with both genes for IFN-gamma and Ii-RGC (rAV/IFN-gamma/Ii-RGC) efficiently induced the MHC Class II+/Ii- phenotype. Injection of tumor nodules with rAV/Ii-RGC and rAV/CIITA/IFN-gamma combined with a suboptimal dose of rAV/IL-2 induced a potent antitumor immune response. The methods are adaptable for producing enhanced genetic vaccines, attenuated virus vaccines (eg, vaccinia), and ex vivo cell-based vaccines (dendritic and tumor cells).

Adenoviridae↗
PubMed2003

A neutrophil elastase inhibitor reduces cigarette smoke-induced remodelling of lung vessels.

Cigarette smoking produces pulmonary hypertension (PHT) through unknown mechanisms. In animal models acute smoke exposure induces cell proliferation in the small arteries adjacent to the alveolar ducts, and chronic exposure results in muscularisation of these vessels, with changes related to the development of PHT. Studies indicate that serine-elastase inhibitors can prevent experimental monocrotaline-induced PHT. This study examined whether they could also prevent cigarette smoke-induced pulmonary vascular disease. Guinea-pigs were exposed to cigarette smoke or air for 6 months. Some animals also received ZD0892, an orally active, synthetic, selective, serine-elastase inhibitor. The percentage of muscularised, small, pulmonary arteries was determined by morphometric analysis of histological sections and vascular cell proliferation by proliferating cell nuclear antigen staining. Vascular cell proliferation was markedly increased in the smoke-exposed animals and the percentage of completely muscularised small vessels was increased four-fold. Cell proliferation indices correlated with muscularisation indices. In the animals treated with ZD0892, the number of completely muscularised vessels was reduced by 50% and cell proliferation was reduced by 61%. These data suggest that smoke-induced cell proliferation leads to pulmonary arterial muscularisation. Serine-elastase inhibitors appear to be able to reduce cell proliferation and vascular remodelling.

Analysis of Variance↗
PubMed2002

Smoking cessation decreases the number of metaplastic secretory cells in the small airways of the Guinea pig.

To ascertain whether cessation of smoke exposure would decrease small-airway secretory-cell metaplasia, guinea pigs were exposed to daily cigarette smoke using a nose-only exposure system for 4 and 8 mo; an additional group was exposed to smoke for 4 mo and then air recovery for 4 mo ("ex-smokers"). Numbers of secretory cells per millimeter of basement membrane were calculated for each bronchiole from measurements of histologic sections stained with Alcian blue/periodic acid Schiff, and cumulative histograms were constructed. Smoke exposure was associated with a significant increase in numbers of secretory cells at 4 mo and 8 mo, although there was no increase in numbers beyond the 4-mo exposure period. In the ex-smoking group, secretory cells were reduced compared to the 4- or 8-mo smoking group, but continued to be greater than controls. We conclude that, in a guinea pig model, smoking produces secretory-cell metaplasia in the airways and that smoking cessation allows partial recovery of normal structure.

Animals↗
PubMed2001

The importance of ultramicroscopic emphysema in cigarette smoke-induced lung disease.

To determine the role of the alveolar pores in cigarette smoke-induced lung disease, we examined the alveolar pores of guinea pigs exposed to cigarette smoke for 12 months, and compared these data to those obtained from sham-smoked animals, correlating the data with airspace size and lung function. We found that the smoke-exposed animals had a larger mean number of pores per alveolus (p < 0.001), and the distributions of pore size and shape were significantly shifted to indicate a larger and more irregular pore configuration (p < 0.001, 01 respectively). In the smoke exposed group, there was a significant correlation of pore number with total lung capacity (TLC) (0.68 p < 0.05), RV (0.70, p < 0.05), and FEV(0.1)/FVC(-0.77, p < 0.02). No correlations were identified between pore size or shape and the lung function tests. We conclude that cigarette smoke exposure produces an increase in the number of alveolar pores, a process which we believe represents ultramicroscopic emphysema. These alterations appear to precede any increase in airspace size, and may help to explain abnormal lung function in cigarette smokers without macroscopic emphysema or small airway disease. This is the first study to clearly document an increased number of alveolar pores, with a significant number of either/or large and irregular pores, after chronic smoke exposure, but in the absence of gross emphysema.

Animals↗
PubMed2001

Diseases of the small airways.

The respiratory tree is involved in a wide range of pathological conditions. The consequences of these processes vary from negligible to severe airflow obstruction with resultant hypoxia and respiratory failure. Although almost all of the processes described herein are associated with activation of cytokines, ecosanoids, or peptide hormones, detailed descriptions of these interactions are beyond the scope of this article.

Acute Disease↗
PubMed2001

Characterization of spirolides a, c, and 13-desmethyl c, new marine toxins isolated from toxic plankton and contaminated shellfish.

Three additional marine toxins, spirolides A (1), C (3), and 13-desmethyl-C (7), were isolated from contaminated scallops and phytoplankton collections obtained from a Nova Scotian aquaculture site, as well as from batch cultures of the dinoflagellate Alexandrium ostenfeldii obtained as a single-cell isolate from these phytoplankton assemblages. The structures of these new spirolide derivatives, characterized by mass spectrometry and NMR, indicate a close relationship with spirolides B (2) and D (4) isolated previously from contaminated shellfish in the same area. All of these compounds display "fast-acting" toxicity in the traditional bioassay used for monitoring shellfish, and this is related to the presence of a cyclic imine function in all these compounds. Those spirolides containing a vicinal dimethyl group in the seven-membered ring are resistant to oxalic acid hydrolysis, whereas those that do not are readily hydrolyzed. These observations suggest that the extra methyl group on the seven-membered imine ring of 3, 4, and 7 appears to block the process of imine hydrolysis perhaps by stereochemical interference.

Animals↗
PubMed2001

Alpha-1-antitrypsin and a broad spectrum metalloprotease inhibitor, RS113456, have similar acute anti-inflammatory effects.

There is increasing evidence that antiproteases are able to affect the inflammatory response. To further examine this question, we administered human alpha-1-antitrypsin (alpha1AT) or a synthetic metalloprotease inhibitor (RS113456) to C57 mice followed by a single intratracheal dose of quartz, a dust that evokes a marked, lasting, polymorphonuclear leukocyte (PMN) infiltrate. At 2 hours after dust administration, both antiproteases completely suppressed silica-induced PMN influx into the lung and macrophage inflammatory protein-2 (MIP-2)/monocyte chemotactic protein-1 (MCP-1) (neutrophil/macrophage chemoattractant) gene expression, partially suppressed nuclear transcription factor kappaB (NF-kappaB) translocation, and increased inhibitor of NF-kappaB (IkappaB) levels. By 24 hours, PMN influx and connective tissue breakdown measured as lavage desmosine or hydroxyproline were still at, or close to, control levels after antiprotease treatment, and increases in NF-kappaB translocation and MIP-2/MCP-1 gene expression were variably suppressed. At both time points, neither agent prevented silica-induced increases in amount of whole lung MIP-2 or MCP-1 protein, but both did prevent increases in whole lung intercellular adhesion molecule-1 (ICAM-1) at 24 hours. Inactivating the alpha1AT by oxidation to the point that it no longer possessed antiproteolytic properties did not affect its ability to suppress inflammation. Both antiproteases also prevented the silica-induced acute inflammatory response in mice with knocked out genes for macrophage metalloelastase (MME -/-), mice that develop inflammation, but not connective tissue breakdown, and the pattern of alpha1AT breakdown fragments was identical in control and MME -/- animals. These findings suggest that, in this model of acute PMN mediated inflammation, a serine protease inhibitor and a metalloprotease inhibitor have similar anti-inflammatory properties, that inflammation is not mediated by proteolysis with generation of chemotactic matrix fragments, and that classic antiproteolysis (complexing of protease to antiprotease) probably does not play a role in suppression of inflammation. The antiproteolytic effects of these agents do not seem to be mediated by protection of endogenous alpha1AT.

Animals↗