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Biomedical subjects

J G Martin

Publications and source records attributed to J G Martin.

At least 91 records · Page 5Linked to original sources
PubMed1995

Increased maximal pulmonary response to methacholine and airway smooth muscle in immature compared with mature rabbits.

We compared the effect of maturation upon the maximal pulmonary response to inhaled methacholine in rabbits and also assessed whether there was an age-related difference in the quantity of airway smooth muscle. In sedated, paralyzed, and mechanically ventilated rabbits, pulmonary resistance was measured following increasing doses of aerosolized methacholine (0.5 to 256 mg/ml). The six mature rabbits (6 mo) demonstrated a plateau in their dose-response curves whereas only three of six immature animals (1 mo) had a plateau. The immature compared with the mature animals had a greater maximal increase in pulmonary resistance (950% versus 380%). The lungs were examined by light microscopy to determine morphometrically the area of smooth muscle (ASM) in the airway walls. ASM was normalized for airway size by dividing by the ideal airway area. The normalized ASM was different for the two age groups and the immature animals' airways had more smooth muscle. The relationship between airway size and ASM was similar for the two age groups with smaller airways having proportionately more smooth muscle. The differences with age in ASM area were primarily due to the immature animals having a greater number of airways of small size. There was not a significant relationship between the maximal percent increase in pulmonary resistance and the normalized ASM. We conclude that inhaled methacholine produces a greater maximal increase in the pulmonary resistance of immature than mature rabbits and that this difference is unlikely to be caused by a proportionately greater quantity of ASM in the immature than the mature rabbit airways.

Aging↗
PubMed1995

Adoptive transfer of allergic airway responses with sensitized lymphocytes in BN rats.

To evaluate the role of lymphocytes in the pathogenesis of allergic bronchoconstriction, we investigated whether allergic airway responses are adoptively transferred by antigen-primed lymphocytes in Brown Norway (BN) rats. Animals were actively sensitized to ovalbumin (OA) or sham sensitized, and 14 d later mononuclear cells (MNCs) were isolated from intrathoracic lymph nodes, passed through a nylon wool column, and transferred to naive syngeneic rats. Recipients were challenged with aerosolized OA or bovine serum albumin (BSA) (5% wt/vol) and analyzed for changes in lung resistance (RL), airway responsiveness to inhaled methacholine (MCh), and bronchoalveolar lavage (BAL) cells. Recipients of MNCs from sensitized rats responded to OA inhalation and exhibited sustained increases in RL throughout the 8-h observation period, but without usual early airway responses. Recipients of sham-sensitized MNCs or BSA-challenged recipients failed to respond to antigen challenge. At 32 h after OA exposure, airway responsiveness to MCh was increased in four of seven rats that had received sensitized MNCs (p = 0.035). BAL eosinophils increased at 32 h in the recipients of both sensitized and sham-sensitized MNCs. However, eosinophil numbers in BAL were inversely correlated with airway responsiveness in the recipients of sensitized MNCs (r = -0.788, p = 0.036). OA-specific immunoglobulin E (IgE) was undetectable by enzyme-linked immunosorbent assay (ELISA) or passive cutaneous anaphylaxis (PCA) in recipient rats following adoptive transfer. In conclusion, allergic late airway responses (LAR) and cholinergic airway hyperresponsiveness, but not antigen-specific IgE and early responses, were adoptively transferred by antigen-primed lymphocytes in BN rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

In vitro airway and tissue response to antigen in sensitized rats. Role of serotonin and leukotriene D4.

We have recently demonstrated that tissue resistance increases during the early response (ER) to antigen challenge in sensitized Brown-Norway rats. The purpose of the present study was to investigate the in vitro airway and tissue responses to antigen and the involvement of the potential mediators serotonin (5-HT) and leukotriene D4 (LTD4). We sensitized Brown-Norway rats with ovalbumin (OA) and subsequently challenged bronchial rings and subpleural parenchymal strips with OA in the organ bath. In selected experiments tissues were incubated with methysergide (a 5-HT receptor antagonist), ketanserin (a 5-HT2 receptor antagonist), MK-571 (a LTD4 receptor antagonist), or MK-886 (5-lipoxygenase inhibitor) prior to challenge. Both bronchial rings and parenchymal strips constricted in response to OA. Methysergide and ketanserin completely inhibited OA-induced constriction of bronchial rings. The effect of MK-571 was not significant, whereas MK-886 partially blocked OA-induced bronchial constriction, suggesting a potential role for LTC4 in antigen-induced airway constriction. In parenchymal strips, methysergide, ketanserin, MK-571, and MK-886 all partially inhibited the OA response, whereas the combinations of methysergide and MK-571 or ketanserin and MK-886 completely ablated the response. These data suggest that both bronchial rings and parenchymal strips constrict after OA challenge but that the relative contributions of 5-HT and LTD4 to the allergic response in central airways and parenchymal tissues differ.

Airway Resistance↗
PubMed1995

Effects of dexamethasone on leukotriene synthesis and airway responses to antigen and leukotriene D4 in rats.

Cysteinyl-leukotrienes (cysteinyl-LTs) are important mediators of both early and late allergen-induced airway responses in atopic asthmatics. We have investigated the effects of glucocorticoids on the in vivo synthesis of cysteinyl-LTs and airway responses to these mediators. Ovalbumin (OA)-sensitized Brown Norway rats, which exhibit early responses and, in most cases, also late responses to late antigen challenge, were treated with either one dose (1 h before antigen challenge) or two doses (2 and 14 h before challenge) of dexamethasone (dex; 300 micrograms/kg). A third group of sensitized rats which did not receive dex served as control animals. All rats were subjected to bile duct cannulation and tracheal intubation 2 h before intratracheal instillation of OA. All of the OA-treated control rats had pronounced early responses (5.5 +/- 1.0 times baseline pulmonary resistance [RL]), whereas 5 of 7 rats had late responses. Biliary levels of N-acetyl-LTE4 increased in all control rats following antigen challenge with a maximum occurring between 1 to 2 h, followed by a decline. There appeared to be a second maximum between 6 to 7 h after challenge, although this could not be demonstrated statistically because of the variability in the response among animals. Treatment with two doses of dex reduced the early response by 57%, completely eliminated the late response, and reduced the levels of N-acetyl-LTE4 in bile by about 80% at all time points.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1995

Cellular infiltration and eicosanoid synthesis in brown Norway rat lungs after allergen challenge.

Allergen challenge of sensitized Brown-Norway (BN) rats results in increased excretion of cysteinyl-leukotrienes (cLTs) in bile. It is unclear whether this reflects an increased capacity of lung cells to synthesize 5-lipoxygenase products, and, if so, which cells are of primary importance. We have examined the effects of allergen challenge on the capacity of a mixture of isolated lung cells from ovalbumin (OA)-sensitized BN rats to synthesize LTs and other eicosanoids. Cells were isolated by enzymatic digestion of lung tissue before and either 6 or 24 h after challenge of sensitized rats with either OA or saline. A23187-induced synthesis of eicosanoids by these cells was measured using high-pressure liquid chromatography. OA challenge resulted in a significant influx of neutrophils into the lungs and a significant increase in the synthesis of 5-lipoxygenase products, in particular LTB4, by lung cells after 6 h. There was a positive correlation between the percentage of neutrophils in unfractionated lung cells and the amounts of LTB4 produced by these cells. OA challenge had little or no effect on the production of cLTs and the cyclooxygenase product 12-hydroxy-5,8,10-heptadecatrienoic acid. There was a significant increase in the infiltration of eosinophils into the lungs 24 h after OA challenge but no increase in the production of cLTs by lung cells at this time, suggesting that eosinophils from BN rats are unlikely to be the major site for the production of these substances. This was confirmed in experiments with partially purified eosinophils obtained from Sephadex-treated rats. In contrast, cLTs were major products of arachidonic acid metabolism by alveolar macrophages from BN rats. We conclude that allergen challenge results in an increased capacity of lung cells to synthesize 5-lipoxygenase products, in particular LTB4. Macrophages, rather than eosinophils, may be an important site for the synthesis of cLTs in BN rat lungs.

Allergens↗
PubMed1995

Transfer of allergic airway responses with antigen-primed CD4+ but not CD8+ T cells in brown Norway rats.

Activated CD4+ helper T cells have been demonstrated in asthmatic airways and postulated to play a central role in eliciting allergic inflammation; direct evidence of their involvement seems to be lacking. We hypothesized that CD4+ T cells have the potential to induce allergic responses to antigen challenge, and tested this hypothesis in a model of allergic bronchoconstriction, the Brown Norway rat, using the approach of adoptive transfer. Animals were actively sensitized to either ovalbumin (OVA) or BSA and were used as donors of T cells. W3/25(CD4)+ or OX8(CD8)+ T cells were isolated from the cervical lymph nodes of sensitized donors and transferred to naive BN rats. 2 d after adoptive transfer recipient rats were challenged by OVA inhalation, and changes in lung resistance (RL), bronchoalveolar lavage (BAL) cells, and serum levels of antigen-specific IgE were studied. After OVA challenge recipients of OVA-primed W3/25+ T cells exhibited sustained increases in RL throughout the entire 8-h observation period and had significant bronchoalveolar lavage eosinophilia, which was detected by immunocytochemistry using an antimajor basic protein mAb. Recipients of BSA-primed W3/25+ T cells or OVA-primed OX8+ T cells failed to respond to inhaled OVA. OVA-specific immunoglobulin E was undetectable by ELISA or skin testing in any of the recipient rats after adoptive transfer. In conclusion, antigen-induced airway bronchoconstriction and eosinophilia were successfully transferred by antigen-specific W3/25+ T cells in Brown Norway rats. These responses were dependent on antigen-primed W3/25+ T cells and appeared to be independent of IgE-mediated mast cell activation. This study provides clear evidence for T cell mediated immune mechanisms in allergic airway responses in this experimental model.

Allergens↗
PubMed1995

A comparison of breathlessness during spontaneous asthma and histamine-induced bronchoconstriction.

The aim of the study was to investigate the possibility that the scoring of breathlessness during histamine bronchial provocation testing might be used to identify asthmatic subjects who sense dyspnea poorly during spontaneous bronchoconstriction. The perception of dyspnea caused by asthma and histamine-induced bronchoconstriction was studied in 17 subjects (10 female and 7 male). All of the subjects had a positive histamine challenge test; the concentration of histamine required to cause a 20% fall in FEV1 (PC20) averaged 3.0 mg/ml. The histamine challenge test was performed with scoring of dyspnea on a modified Borg scale. The subjects subsequently recorded peak expiratory flows (PEF) and dyspnea scores (Borg scale) at home 4 times daily for a 7-d period. We found that the intensity of dyspnea sensed during histamine-induced bronchoconstriction was very variable among subjects. The Borg score for a 20% fall in FEV1 ranged from 0 to 9. However, there was a correlation between the minimum FEV1 and the corresponding Borg score (r = -0.63; p < 0.01). For most subjects, there was no correlation between the magnitude of breathlessness during spontaneously occurring bronchoconstriction and the accompanying decline in PEF. Among subjects there was no relationship between the ability to sense breathlessness during induced and spontaneous bronchoconstriction. Therefore, the sensation of breathlessness during histamine-induced bronchoconstriction cannot be used to identify the asthmatics who perceive dyspnea poorly.

Adolescent↗
PubMed1994

Comparative estimates of neonatal gestational maturity by electrographic and fetal ultrasonographic criteria.

We previously reported a high correlation between electrographic and postmortem neuroanatomic (i.e., sulcal-gyral) estimates of maturity in sick preterm neonates who were clinically abnormal because of neonatal medical illnesses. Electroencephalographic studies have not yet been compared with ultrasonographic measurements in healthy fetuses who subsequently had normal neurodevelopmental outcome. Twenty-five EEG recordings on healthy neonates (28-43 weeks postconceptional age) had EEG estimates of gestational maturity without knowledge of obstetric, neonatal, or ultrasonographic criteria. Thirteen recordings from this cohort were obtained on very premature neonates (i.e., < 32 weeks estimated gestational age). Fetal ultrasonographic determinations of gestational maturity for these 13 subjects were also obtained prior to birth. Ultrasonographic estimates were assigned without knowledge of other clinical data. Gestational age estimates based on electroencephalographic analyses were compared with 5 ultrasonographic estimates of gestational age maturity using multivariate regression (i.e., biparietal diameter, abdominal circumference, femur length, transcerebellar diameter, and head circumference), as well as the mother's last menstrual period. No significant differences were detected between the electrographic and obstetric/ultrasonographic estimates of gestational maturity. An electroencephalographer's assessment of gestational age is as accurate as the fetal ultrasonographic estimates in the asymptomatic preterm neonate whose gestational age is < 32 weeks at birth.

Brain↗
PubMed1994

Antiproliferative effect of prostaglandin E2 in cultured guinea pig tracheal smooth muscle cells.

The respiratory epithelium plays an important role in modulating airway smooth muscle responsiveness to contractile agonists, and damage of the epithelium may be involved in the pathogenesis of bronchial hyperresponsiveness. This study was undertaken to determine whether prostaglandin E2 (PGE2), a relaxant agent synthesized and released by airway epithelial cells, could exert long-term effects on airway smooth muscle by regulating cell proliferation. Incubation of growth-arrested tracheal smooth muscle cells with serum for 24 h stimulated DNA synthesis in a concentration-dependent manner, as determined by [3H]thymidine incorporation. PGE2 and forskolin, a direct activator of adenylate cyclase, inhibited serum-induced cell proliferation, and the effects were dose dependent. PGE2 and forskolin also stimulated adenosine 3',5'-cyclic monophosphate accumulation. An inhibitor of cyclooxygenase, indomethacin, enhanced DNA synthesis induced by serum. These results indicate that exogenous PGE2 exerts an antiproliferative effect on smooth muscle cells in culture by activation of adenylate cyclase and suggest a role for the epithelium in modulating airway smooth muscle growth.

1-Methyl-3-isobutylxanthine↗
PubMed1994

The role of the leukocyte adhesion molecules VLA-4, LFA-1, and Mac-1 in allergic airway responses in the rat.

Chronic airway inflammation is involved in the pathogenesis of asthma. The leukocyte adhesion molecules VLA-4 of the beta 1 integrin family, and LFA-1 and Mac-1 of the beta 2 family have a demonstrated role in leukocyte-endothelial adherence and may play a role in airway inflammation in asthma. We studied the effects of blocking VLA-4 (CD49d/CD29) and both LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) airway responses and inflammation in rats. BN rats were sensitized with ovalbumin (OA) subcutaneously and were challenged 14 d later with aerosolized OA. Twelve rats were treated prior to challenge with anti-rat VLA-4 monoclonal antibody (mAb), 10 rats received both anti-LFA-1 and anti-Mac-1 mAb, and 14 rats received a control mAb. The pulmonary resistance (RL) was measured for 8 h after challenge. The inflammatory response was evaluated by bronchoalveolar lavage (BAL) and by measuring the lung and airway inflammatory cells retrieved by enzymative dispersion. The early response was significantly decreased in both the anti-VLA-4 group (131% baseline RL) and the anti-LFA-1/Mac-1 group (118%; p < 0.05) compared with the control group (202%). The late response was also significantly decreased in both the anti-VLA-4 (3.7) and anti-LFA-1/Mac-1 (2.6) groups compared with the control group (19.7). The significant differences in bronchoalveolar lavage were a decrease in neutrophils in the LFA-1/Mac-1 group and an increase in macrophages in the anti-VLA-4 group.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1994

In vitro allergic bronchoconstriction in the brown Norway rat.

The ovalbumin (OA)-sensitized Brown Norway rat (BN) demonstrates early-response (ER) and late-response (LR) allergic bronchoconstriction. To determine whether these responses could be replicated in vitro, we studied lung explants from 8-wk-old male BN rats (wt: 239 +/- 28 g), of which 19 were sensitized to OA (test) and 16 served as controls. Two weeks after sensitization, the animals' lungs were removed, filled with a 1% (wt/vol) agarose-containing solution at 37 degrees C, and cooled to 4 degrees C. Transverse slices (0.5 to 1.0 mm thick) were cut and cultured overnight. Airways were visualized with an inverted microscope and baseline images were obtained with a video camera. To study the ER, 40 airways from 15 test rats and 29 airways from 10 control rats were challenged with 2 micrograms OA and imaged each minute for 10 min. To study the LR, 40 airways from 12 test rats and 44 airways from 12 control rats were challenged with 2 micrograms OA and imaged each hour for 8 h. The maximal response (MR) for each airway was defined as the percent of airway closure. The ER and LR were both defined as an MR > or = mean + 2 SD of the controls. An ER occurred in 38 of 40 test and 2 of 29 control airways (mean MR: 42 +/- 24% versus 4 +/- 3%, p < 0.001), and was completely blocked by methysergide pretreatment in 13 airways.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1994

Airway and tissue responses to antigen challenge in sensitized brown Norway rats.

It has recently been shown in several species that lung tissue resistance increases after administration of exogenous bronchoconstrictors. This finding suggests the possibility that lung parenchymal tissues could be involved in the pathophysiology of pulmonary allergic responses. To test this hypothesis, we sensitized Brown Norway rats with ovalbumin (OA) and performed experiments in anesthetized, open-chested, mechanically ventilated (respiratory frequency [f] = 1 Hz, tidal volume [VT] = 9 ml/kg, positive end-expiratory pressure [PEEP] = 3 cm H2O) animals. We affixed alveolar capsules to the lungs to measure alveolar pressure and calculated the resistance of lung (RL), tissue (Rti), and airway (Raw) under control conditions and after aerosol administration of saline (S) (n = 10) or OA (n = 14). To assess lung morphometry during the late response, the lungs of six S and six OA animals were frozen with liquid nitrogen (PEEP = 3 cm H2O) and processed via freeze substitution. Airway constriction was assessed by measuring the ratio of the airway lumen (A) to the ideally relaxed airway (Ar). Tissue distortion was assessed by measuring the mean linear intercept between alveolar walls (Lm), an atelectasis index (ATI) derived by calculating the ratio of tissue/airspace, and the standard deviation (SD) of Lm and ATI. In the OA group, all animals demonstrated an early response (ER; RL, Rti, Raw = 183.5 +/- 7.7, 159.7 +/- 9.9, 232.5 +/- 17.2% baseline, respectively) and 11 animals showed a late response (LR; RL, Rti, Raw = 178.9 +/- 5.1, 191.3 +/- 11.5, 176.6 +/- 17.3% baseline, respectively). Neither ER nor LR were observed in the saline group.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1994

[Animal models of bronchial hyperreactivity].

Airway responsiveness is increased in a variety of airway diseases. To understand the mechanism of enhanced airway responsiveness, in particular as it pertains to asthma, animal models have been developed and extensively explored. The guinea pig and Basenji-greyhound dog are the best characterized animals showing airways hyperresponsiveness and appear to bear substantial resemblances to asthmatic human subjects. Challenge with bronchoconstrictive agonist results in bronchoconstriction and transient vascular leak. Both phenomena contribute to the degree of airway narrowing. Adenosine challenge tests not only the responsiveness of the airways, but also that of the airway effector cells such as the mastocyte. Bradykinin and tachykinin cause indirect airway narrowing, probably by liberation of leukotrienes. Responsiveness can be enhanced by immune and non-immune challenges. Ozone, Sephadex, various contractile agonists (leukotriene D-4, bradykinin, platelet-activating factor), as well as certain cytokines (IL-1, IL-2, TNF-alpha) can enhance airway responsiveness. Cyclooxygenase and lipooxygenase products appear to be involved. Allergen-induced hyperresponsiveness is associated with airway inflammation and appears to involve bradykinin and PAF acutely and growth of airway smooth muscle chronically.

Adenosine↗
PubMed1993

Allergen-induced airway responses in rats pretreated with Sephadex.

Even though the eosinophil is potentially an important contributor to airway narrowing during the late allergic airway response, direct evidence of its participation is lacking. Therefore, we examined the effects of eosinophilia induced by Sephadex on the magnitude of the late airway response of sensitized rats following allergen challenge. Brown Norway rats were actively sensitized to ovalbumin (OA). At the same time and 14 days later, a test group was administered Sephadex G200 (0.5 mg intravenously). The animals were challenged with an aerosol of OA and pulmonary resistance (RL) was measured over 6 h. The early response to OA reached a peak more rapidly and the magnitude of the late response, measured as the area under the curve of RL against time, was significantly greater in the Sephadex-treated group (48.3; geometric mean) compared to the control animals (18.9; p < 0.02). The percentage of eosinophils was increased in the bronchoalveolar lavage of Sephadex-treated animals (4%) compared to the controls (0.9%; p < 0.02) following OA challenge. These results demonstrate that Sephadex induces eosinophilia in Brown Norway rats and is associated with an increase in the late allergic airway response. This is consistent with the hypothesis that the eosinophil is an important determinant of the late response.

Administration, Inhalation↗
PubMed1993

Airway-parenchymal interdependence and bronchial responsiveness in two highly inbred rat strains.

To investigate if airway-parenchymal interdependence may account for differing bronchial responsiveness between inbred rat strains, Fisher and Lewis 12-wk-old male rats were anesthetized, tracheostomized, and placed in a pressure plethysmograph. Functional residual capacity, total lung capacity [lung volume at transpulmonary pressure (PL) of 30 cmH2O], and specific compliance were determined and were found to be similar. Rats were paralyzed and mechanically ventilated. Concentration-response curves were constructed by calculating lung resistance (RL) and lung elastance (EL) after nebulization of saline and then doubling doses of methacholine (0.0625-512 mg/ml). In Fisher (n = 8) and Lewis (n = 7) rats RL and EL were again determined at a lung volume corresponding to 2 cmH2O PL above FRC. The doubling, maximal, and half-maximal effective concentrations were determined for RL and EL. The doubling of effective concentrations of RL and EL were significantly less for Fisher rats. Other groups of Fisher (n = 5) and Lewis (n = 5) rats were similarly exposed to three concentrations of methacholine (64, 128, and 256 mg/ml), and determinations of RL and EL were made at lung volume corresponding to PL of 0, 2, 4, and 8 cmH2O. In both groups, Lewis rats exhibited a significant effect of volume on maximal RL and EL, whereas Fisher rats did not. The absence of volume effect on bronchoconstriction in the hyperresponsive Fisher strain is consistent with the hypothesis that altered airway-parenchymal interdependence contributes to bronchial hyperresponsiveness.

Administration, Inhalation↗
PubMed1993

Responsiveness of and interactions between airways and tissue in guinea pigs during induced constriction.

Mechanical interdependence between airways and tissues can modify the magnitude of induced bronchoconstriction. We questioned whether the guinea pig, an animal with abundant airway smooth muscle, would differ from other species in the relative responsiveness of and interactions between airways and tissues. Therefore we induced constriction with aerosolized methacholine (MCh) and partitioned responses into airway and tissue components. We measured tracheal and alveolar pressures using alveolar capsules in open-chest guinea pigs (n = 9) during mechanical ventilation [frequency = 1 Hz, tidal volume = 6 ml/kg, positive end-expiratory pressure (PEEP) = 5 cmH2O] and calculated the resistance of lung (RL), tissue (Rti), and airway (Raw) before and after administration of aerosols of MCh in progressively doubling concentrations (0.063-16 mg/ml). In separate animals (n = 10), measurements were made at 3-13 cmH2O PEEP. After aerosols of saline and MCh (0.125-32 mg/ml), measurements were repeated at 3, 7, and 11 cmH2O PEEP. At submaximal levels of constriction, the airways and lung tissues demonstrated similar responsiveness. Increasing PEEP increased RL and Rti and decreased Raw under baseline conditions. At low concentrations of MCh, increasing PEEP increased RL but decreased RL at the highest concentration. Increases in PEEP significantly increased Rti at all concentrations of MCh but decreased Raw only at 8 mg/ml of MCh. These observations demonstrate that, in guinea pigs, during submaximal constriction, airways and tissues behave similarly; moreover, airway-parenchymal interdependence is important in determining the level of bronchoconstriction.

Aerosols↗