Biomedical subjects

N Berend

Publications and source records attributed to N Berend.

At least 55 records · Page 3Linked to original sources

PubMed1987

Failure of systemic N-acetyl cysteine to protect the rat lung against bleomycin toxicity.

In order to see whether systemically administered N-acetyl cysteine (NAC) could protect the lung from bleomycin lung injury, 24 rats were given a constant subcutaneous infusion of NAC (mean 195 mg.kg-1.day-1) for 7 days while 23 rats were given a similar volume of saline. Two days after the start of infusion, half of each group received an endotracheal injection of bleomycin and the other half received a similar volume of saline. All animals were killed 7 days after intratracheal injection and their lungs were prepared for wet-weight to dry-weight ratio (W:D) and morphometric assessment of histological changes. In animals given intratracheal saline, NAC infusion had no effect on weight gain, W:D or morphometry compared to those animals given saline infusions. However, all bleomycin-treated animals had obvious evidence of lung damage. Compared to either group of animals treated with intratracheal saline, the bleomycin-treated groups gained less weight (p less than 0.001), had a higher W:D (p less than 0.001) and an increase in the volume densities of alveolar and duct walls (p less than 0.001), intra-alveolar cells (p less than 0.05) and consolidation (p less than 0.001). There were no significant differences between the two bleomycin-treated groups in any parameter measured. It is concluded that administration of NAC by a constant subcutaneous infusion was not protective against bleomycin lung injury.

Acetylcysteine↗

PubMed1986

Indomethacin inhibits the increased airway responsiveness to histamine following inhalation of C5a des Arg in rabbits.

It has been shown that inhalation of C5a des Arg increases rabbit airway responsiveness to histamine and that this is associated with an influx of neutrophils into the airway walls. This study was undertaken to see if the augmented response to histamine can be blocked by the cyclo-oxygenase inhibitor indomethacin. Spontaneously breathing, anesthetised rabbits were studied in a volume displacement plethysmograph and pulmonary resistance (R1) was measured using the electrical subtraction technique. Histamine does response curves (HDR) were generated by measuring R1 after serial nubulisation of saline and histamine (1, 3, 10, 30 and 100 mg/ml). Aerosols of either saline or C5a des Arg (1.5 ug/ml) were then inhaled by the animals over a time period of 2 min. An HDR was then repeated 4 hours later. In 9 rabbits the inhalation of C5a des Arg resulted in an upward shift of the repeat HDR: the area under the HDR was significantly greater than under the first HDR (p less than 0.05). In 6 rabbits the repeat HDR 4 hours after saline was shifted downwards (N.S.) indicating some degree of tachyphylaxis. When rabbits were pretreated with indomethacin (5 mg/kg i.v.) the repeat HDR following either C5a des Arg (n = 7) or saline (n = 6) were also shifted downwards i.e., the increased airway responsiveness noted after C5a des Arg was abolished. There was no significant difference in baseline saline R1 during the first or second HDR in any group. These results suggest that the increased airway responsiveness following nebulisation of C5a des Arg may be due to release from neutrophils of products of the cyclo-oxygenase pathway.

Administration, Inhalation↗

PubMed1986

Formyl-methionyl-leucyl-phenylalanine causes bronchoconstriction in rabbits.

Formyl-methionyl-leucyl-phenylalanine (FMLP) is a synthetic acylated oligopeptide related to chemotactic peptides released by bacteria. In order to determine whether FMLP causes bronchoconstriction in vivo, we studied the effects of nebulized FMLP on lung resistance (RL) in the rabbit. In fourteen rabbits baseline RL was measured and than dimethylsulfoxide (DMSO) alone and 0.3, 1, 3 and 10 mg/ml FMLP in DMSO was nebulized and inhaled by the rabbits over periods of 2 min each. After each concentration the RL was re-measured and the results expressed as a % of the RL following DMSO alone. In 6 rabbits the response to serial nebulization of DMSO alone was 5.5 +/- 10.4% (mean +/- 2 SD). In 8 rabbits receiving FMLP there was a dose dependent increase in RL of 20% or greater whereas 6 rabbits failed to respond. Since there are known receptors for FMLP on neutrophils, 10 further rabbits were rendered neutropenic using nitrogen mustard and then studied as above. Eight of these rabbits failed to respond significantly to FMLP whereas 2 had a 20% or greater increase in RL. In each bronchial specimen from 6 additional rabbits FMLP failed to induce airway contraction in vitro. We conclude that FMLP causes a variable degree of bronchoconstriction in rabbits, that this response may, in part, be mediated via the neutrophil and is unlikely to be due to direct smooth muscle contraction.

Animals↗

PubMed1986

Formyl peptide-induced contraction of human airways in vitro.

Formylmethionylleucylphenylalanine (FMLP) is a synthetic analogue of bacterial chemotactic factors. We studied the contraction of human airway tissue in vitro by FMLP. FMLP induced a concentration-dependent contraction of all bronchial spiral strips studied (n = 45). The maximum tension generated in response to FMLP was 86.6 +/- 7.0% (SE) of the maximum response to histamine. The contraction was not reduced by the histamine H1-receptor antagonist pyrilamine, the cyclooxygenase and lipoxygenase inhibitors indomethacin and BW755C, the muscarinic antagonist atropine, or capsaicin which depletes stores of substance P. The concentration-response curve was shifted to the right by the polypeptide antagonist N-t-BOC-phenylalanylleucylphenylalanylleucylphenylalanine and the leukotriene antagonist FPL 55712. When 2 successive FMLP concentration-response curves were performed the maximum response was significantly reduced from 114.8 +/- 9.1% of the histamine maximum to 39.3 +/- 6.1%. The contraction of human airways in vitro by an agent that is structurally and functionally similar to chemotactic peptides released from bacteria may have important implications in airway disease.

Bronchi↗

PubMed1986

Airways hyperreactivity and inflammation produced by aerosolization of human C5A des arg.

The premise of this study was that complement fragments would lead to granulocyte infiltration and to associated changes in airways reactivity. Inflammation was induced in large airways (greater than 1.0 mm) by aerosolization of the complement chemotactic factor, C5a des arg, which was isolated from activated human serum. Pulmonary function (resistance, compliance, and lung volume) and histamine reactivity were assessed at 4 and at 48 h after C5a des arg or a saline sham aerosol. Four hours after exposure to C5a des arg, the animals exhibited evidence of significant bronchoconstriction and hyperinflation. In addition, an increased responsiveness to histamine was demonstrated, which was not correlated with the degree of bronchospasm. By 48 h, these alterations were partially or completely resolved. Histologic examination and quantitation demonstrated significant accumulation of neutrophils, which was limited to airways 0.5 mm in or larger. Saline-treated animals also demonstrated a neutrophil infiltration, but significantly less than those treated with C5a des arg. However, these animals did not demonstrate hyperreactivity to histamine, and there was little change in baseline mechanical function. The mild inflammation associated in the saline control animals was demonstrated to be a result of intubation of the airways. Granulocyte dependence of the effects of C5a des arg was partially established by abrogation of these effects when the animals were rendered granulocytopenic with nitrogen mustard. We conclude that the physiologic responses of the airways to C5a des arg were largely granulocyte dependent. However, since granulocyte accumulation could occur without airways dysfunction, it is suggested that cell activation is an important step in producing neutrophil-associated airways hyperresponsiveness.

Aerosols↗

PubMed1985

Increased responsiveness to methacholine and histamine after challenge with ultrasonically nebulised water in asthmatic subjects.

Responsiveness to inhaled methacholine was compared before and 40-60 minutes after a challenge with ultrasonically nebulised water (UNH2O) in 16 asthmatic patients. The sensitivity to methacholine increased after UNH2O challenge (p less than 0.001). The mean dose of methacholine producing a 20% fall in forced expiratory volume in one second was 0.4 (95% confidence limits 0.2, 0.8) mumol, compared with 0.9 (95% confidence limits 0.5, 1.6) mumol in the first methacholine challenge. When the study was repeated in six asthmatic patients with histamine substituted for methacholine, five of the patients were significantly more sensitive to histamine after UNH2O challenge. It is concluded that challenge with UNH2O produces an increase in airway responsiveness.

Adult↗

PubMed1985

Structure-function correlation of early stages of lung injury induced by intratracheal bleomycin in the rabbit.

After measurement of lung volume, pressure-volume relationship of the lungs, flow-volume relationship, and single-breath diffusing capacity, the effect of endotracheal injection of bleomycin (10 micrograms/kg) on structural and functional changes was assessed in 21 rabbits and compared with 8 rabbits who received endotracheal injection of saline. Lung function was reassessed in the control rabbits at 1, 3, and 5 wk, and they were then killed. The bleomycin-treated rabbits were divided into 3 groups and retested at 1 (n = 7), 3 (n = 6), and 5 (n = 8) wk. Each group of animals was killed after the functional assessment, and after fixation the lungs were examined morphometrically. The degree of fibrosis in the bleomycin-treated animals was small even at 5 wk. Volume densities of pulmonary structures, alveolar wall thickness, airway diameters, airway inflammation scores, and fibrosis scores were determined and their correlation with the functional measurements was assessed. Lung volume subdivisions, pressure-volume characteristics, and diffusing capacity for carbon monoxide were significantly reduced, and the resistance of the upstream segment of airways was significantly increased after the bleomycin injection. Changes in lung volume correlated significantly with the volume densities of free alveolar cells, nonparenchymal tissue, and alveolar wall thickness. The exponent K, derived by fitting an exponential function to the pressure-volume data, which is indicative of lung elastic behavior, did not correlate with any morphometric index of interstitial disease. The diffusing capacity for CO was significantly correlated with the volume densities of alveolar wall, nonparenchymal tissue, and alveolar wall thickness, but these correlations became nonsignificant when the diffusing capacity was corrected for alveolar volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Inhibition of bleomycin lung toxicity by N-acetyl cysteine in the rat.

N-acetyl cysteine (NAC) has recently been shown to have antioxidant properties, and since bleomycin produces pulmonary damage via free oxygen radical toxicity, the possible protective effect of NAC on bleomycin lung toxicity was investigated. Rats received saline (n = 7), NAC (n = 6), bleomycin (n = 7) or bleomycin and NAC (n = 6) by direct intratracheal injection. Seven days later the animals were killed and the lungs processed for histology or morphometry. All rats treated with bleomycin only had typical changes of bleomycin lung toxicity whereas the animals treated with bleomycin and NAC had minimal pathology. The control animals had normal lungs. These results were confirmed by morphometry which demonstrated significantly higher volume densities (p less than .01) of alveolar wall and free alveolar cells in the bleomycin group compared to the other 3 groups. It is concluded that NAC inhibits bleomycin lung toxicity when administered by direct intratracheal injection.

Acetylcysteine↗

PubMed1985

The relationship between airway size and lung size.

To investigate the association between airway size and lung size, the relationships between upstream conductance (reflecting airway size) and vital capacity (reflecting lung size) was explored in 22 male and 15 female subjects free of respiratory disease. The size-corrected maximal flows and size-corrected upstream conductances were not significantly correlated with vital capacity in males or females suggesting an association between lung and airway size. This was corroborated by other data from the literature analysed in a similar manner. The data further suggested that for a given lung size, the airways of females were on average as large or larger than those of males.

Adult↗

PubMed1984

Comparison of muscular pulmonary arteries in low and high altitude hamsters and rats.

Measurements were made of the ratio of medial area to total arterial area in the muscular pulmonary arteries of a fossorial species, the hamster, and a non-fossorial control, the rat. It was found that the medial area was less in hamsters than in rats. In addition, chronic hypoxic exposure resulted in further medial thickening in rats, while the hamster was unaffected. The hamster has previously been shown to have a blunted hypoxic pulmonary pressor response, and the present data indicate that this relative unresponsiveness is associated with less pulmonary vascular smooth muscle. In addition, the insensitivity to hypoxia of the pulmonary vasculature and a lack of vascular luminal narrowing may tend to minimize increases in pulmonary vascular resistance during chronic hypoxia in the hamster, and thus be beneficial adaptations for a burrowing species.

Altitude↗

PubMed1984

The relationship between bronchial hyperresponsiveness to methacholine and airway smooth muscle structure and reactivity.

The airway responsiveness of a group of 25 patients scheduled for lung resection was studied. 10 of 25 patients had a greater than or equal to 20% fall in FEV1 in response to inhaled methacholine (responders), with PD20 FEV1 values ranging from 0.6 to 7.3 mumol. Methacholine did not induce a 20% fall in FEV1 in 15 patients (non-responders). The sensitivity to carbachol and histamine of the bronchial smooth muscle resected from these patients was similar in tissue from responders and non-responders. There was no correlation between in vivo responsiveness to methacholine and in vitro sensitivity to carbachol or histamine. The volume of smooth muscle in some of these airway preparations was quantitated. There was a significant correlation between the maximum tension change in response to histamine and the volume of smooth muscle in each airway. There was no similar correlation for carbachol. The in vivo responsiveness to methacholine and in vitro sensitivity to histamine or carbachol was not related to the degree of inflammation in the airways studied. It is concluded that in vivo responsiveness cannot be explained in terms of smooth muscle sensitivity and that there may be differences between histamine and carbachol in the mechanism of contraction of airway smooth muscle.

Adult↗

PubMed1984

Protective effect of hypoxia on bleomycin lung toxicity in the rat.

The effect of hypoxia on the development of bleomycin lung toxicity was studied in 26 rats. Thirteen rats received an endotracheal injection of saline, and 13 rats received a similar injection of 1.5 units of bleomycin in saline. Six saline-treated and 6 bleomycin-treated rats were exposed to 10% oxygen for 2 days prior and 2 days subsequent to the injections, and then breathed air for a further 5 days before being killed. The other rats breathed air continuously, and were also killed 7 days after the injections. Although all bleomycin-treated animals had some evidence of lung toxicity, histologic examination of the lungs revealed markedly reduced bleomycin toxicity in the rats exposed to hypoxia. This was confirmed by morphometry, which demonstrated that the volume density of alveolar walls (mean +/- SEM) was significantly lower in the bleomycin-hypoxia group (11.8 +/- 0.8%) than in the bleomycin-air group (18.8 +/- 1.1%) (p less than 0.001). It is concluded that hypoxia offers protection against bleomycin lung toxicity in the rat.

Animals↗

PubMed1984

The effect of bleomycin and oxygen on rat lung.

The interaction of bleomycin and oxygen on rat lung was studied by giving endotracheal injections of bleomycin or saline to rats which subsequently breathed air or oxygen for 24 or 48 h. In the first protocol bleomycin or saline treated rats were exposed to 24 h of air or 100% oxygen and then breathed air for a further 6 d after which they were killed. In the second protocol bleomycin or saline treated rats were exposed to 48 h of air or up to 48 h of 100% oxygen. All animals in this protocol either died or were killed at the 48 h time point. The lungs were fixed in full inflation and 6 histological sections prepared from each. The volume densities of alveolar air, duct air, alveolar walls, intra-alveolar cells and non-parenchyma were quantitated using standard point counting techniques. In addition, the percent of alveoli containing fibrin was determined. The results demonstrated a synergistic effect of oxygen and bleomycin toxicity after both 24 and 48 h oxygen exposure. This was most marked for alveolar fibrin deposition which was significantly greater (p less than 0.001) in the bleomycin and oxygen groups than the saline/air, saline/oxygen or bleomycin/air groups. In the 48 h study the volume density of intra-alveolar cells was also significantly greater in the bleomycin/oxygen group than all other groups (p less than 0.05). It is concluded that bleomycin and oxygen exhibit synergistic toxic effects and that their concurrent administration should be avoided.

Animals↗

PubMed1984

Cholinergic responses in the human lung parenchymal strip: a structure-function correlation.

We have examined the contractile response of the human lung parenchymal strip to carbachol. Responses were highly variable both within and between subjects. In only 50 of the 72 strips studied could a measurable cumulative concentration-response relationship to carbachol be elicited (geometric mean EC50 3.1 x 10(-7) mol/l, 95% confidence limits 2.2, 4.2 x 10(-7) mol/l). In 22 strips, no such response could be elicited. Fifteen lung strips, including some which contracted to carbachol and others which did not, were subjected to morphometric analysis, using a point-counting procedure, to estimate volume proportions of tissue components of the lung strips. There was a significant correlation (r = 0.71, P less than 0.01) between maximal contraction of a strip to carbachol and its volume proportion of airways. These results suggest that the contractile response to carbachol in the human lung parenchymal strip originates from airway smooth muscle.

Aged↗

PubMed1983

Topographical differences in the physiological response of canine airway smooth muscle.

The resting membrane potential (Em), electrical and contractile response were studied in three anatomically separate areas of trachealis muscle and also in bronchial muscle (2nd generation) isolated from mongrel dogs. These responses were studied before and after administration of a single dose of histamine, serotonin, carbachol and prostaglandin F2 alpha. A cross-sectional area of airway smooth muscle in each preparation was directly assessed from the histological sections. These values were used to evaluate isometric tension (in g/mm2). It was found that (1) cross-sectional area of airway smooth muscle varies with location; (2) resting membrane potential of airway smooth muscle from upper, middle and lower portions of dog trachea was similar, i.e., -60.4 +/- 0.8, -60.2 +/- 0.4 and -60.8 +/- 0.9 mV, respectively; (3) resting membrane potential of bronchial airway smooth muscle (2nd generation) was -63.4 +/- 0.5 significantly higher (P less than 0.01) than the membrane potential observed in the trachealis muscle; (4) both contractile and electrical changes after single doses of histamine and serotonin administration showed a vertical gradient response. The largest contractile and electrical responses to these two agents were found in preparations from the lower portion of trachea and the smallest response was observed in upper tracheal preparations; (5) contractile responses after a single dose of carbachol and PGF2 alpha, when expressed as isometric tension also showed vertical gradient. In contrast, membrane potential changes after carbachol and prostaglandin F2 alpha were similar in all three types of tracheal segments. Airway smooth muscle of the 2nd generation of bronchi showed large responses after single doses of histamine, carbachol and prostaglandin F2 alpha but the response after serotonin was smaller than that seen in the lower trachea.

Animals↗

PubMed1983

Small airways disease.

Over the last 10 years the non-specific term "small airways disease" has been applied to a number of histologic lesions seen in the peripheral airways of smokers. It is becoming recognized that airway inflammation is the most important of these lesions. This pathology may be the precursor to the subsequent development of emphysema and is an important cause of the functional abnormality in smokers. A current hypothesis is that small airways disease may be detected early in the smoking careers of subjects who later develop chronic respiratory disability. In these individuals particularly, complete cessation of smoking should be the primary therapeutic goal. With the recent development of special tests to assess small airways function, the presence of small airways disease can be detected in asymptomatic smokers who may have normal routine lung function tests. However, most of the tests to assess airway function are also influenced by other physiological factors such as loss of elastic recoil. We await the results of long term epidemiological studies to confirm the above hypothesis that early small airways disease leads to chronic disability. Without such confirmatory evidence, the routine use of these special tests cannot at present be advocated.

Airway Resistance↗

PubMed1983

Breathing He-O2 shifts the lung pressure-volume curve of the dog.

To determine whether breathing a mixture of 80% He-20% O2 affects the lung pressure-volume (PV) curve, eight anesthetized paralyzed dogs were studied in a volume-displacement plethysmograph. Static PV curves on air were compared with PV curves obtained after equilibration with He-O2. The He-O2 PV curves were significantly shifted upward by an average of 5% total lung capacity. There was no change in compliance, indicating that the shift was due to lung expansion rather than a change in elasticity. Pretreatment of the dogs with cyclooxygenase inhibitors abolished the PV shift with He-O2. Four dogs had PV curves recorded on air and a mixture of O2, SF6, and Ne, a gas mixture with the same density as air but with 45% greater viscosity. The PV curve shift was even greater than observed with He-O2 and could again be virtually abolished with a cyclooxygenase inhibitor. These results suggest that breathing a high-viscosity gas mixture results in alveolar duct dilatation due to the release of a prostaglandin bronchodilator. This may need to be taken into account in the analysis of flow augmentation with He-O2.

Animals↗

PubMed1983

Low temperature inhibits bleomycin lung toxicity in the rat.

In order to see if exposure to cold temperature affects the development of bleomycin lung toxicity in mammals, 14 rats received endotracheal injections of bleomycin, while another 14 rats received saline. Half of the saline-treated animals were then exposed to room temperature for 7 days (SRT), and half were exposed to 4 degrees C for 7 days (SC). The bleomycin-treated animals similarly yielded groups kept at room temperature (BRT) and in the cold (BC). After 1 wk the rats were killed and the lungs were sectioned for assessment of histologic changes. All the bleomycin-treated animals had evidence of lung toxicity but this was much less marked in group BC than in group BRT. The lungs in group SC remained normal. These results were confirmed by morphometric methods, which showed significantly increased volume proportions of alveolar walls in groups BRT and BC compared with that in groups SRT and SC (p less than 0.001), with BRT being greater than BC (p less than 0.001). It is concluded that exposure of bleomycin-treated rats to low ambient temperature significantly reduces lung toxicity.

Animals↗