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Biomedical subjects

N Berend

Publications and source records attributed to N Berend.

At least 37 records · Page 2Linked to original sources
PubMed1993

The effect of steroids on radiation-induced lung disease in the rat.

We have used a model of bilateral radiation-induced lung disease in the rat to study the effects of corticosteroids. This model is characterized by interstitial edema at 2 weeks after radiotherapy followed by florid alveolitis with an alveolar protein leak which peaks at 4 weeks. Mast cell density peaks at 7 weeks, and there is a progressive increase in lung collagen (fibrosis) from 5 to 20 weeks. Intraperitoneal corticosteroids or saline were given at the time of irradiation or sham irradiation (protocol 1), every second day during weeks 3 and 4 (protocol 2), or three times weekly during weeks 3 to 8 (protocol 3). In protocol 1, steroids protected the lung from interstitial edema at 2 weeks, delayed the alveolitis without reducing its intensity, and significantly reduced the alveolar protein leak. However, radiation fibrosis was not reduced at 20 weeks. Longer steroid administration (protocol 2) suppressed the alveolar protein leak and delayed and significantly reduced the severity of the inflammatory cell response. Although the tissue mast cell and fibrotic responses were suppressed during and for at least 3 weeks after steroids, the ultimate fibrotic reaction was the same in both irradiated groups. In protocol 3, steroids suppressed the alveolitis and delayed the rise in tissue mast cell density, but did not affect the fibrotic response at 20 weeks. These studies suggest that steroids can suppress the alveolitis provided they are used throughout the period of alveolitis. Although they also delay the tissue mast cell response to radiation, the ultimate fibrosis is not altered. This provides further evidence for the dissociation of alveolitis and fibrosis after lung irradiation and has potential implications for management of radiation-induced lung disease in humans.

Animals↗
PubMed1992

Effects of inhalation of N-formyl-methionyl-leucyl-phenylalanine in the well elderly and in patients with chronic bronchitis.

BACKGROUND: Inhalation of the bacterial peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) produces bronchoconstriction in normal subjects. FMLP thus has a putative role as a mediator of bronchoconstriction associated with bacterial bronchial infection. METHODS: The effects of FMLP inhalation were examined in ten subjects with a history of chronic bronchitis and ten age matched control subjects. Each subject inhaled FMLP doses from 0.025 to 0.8 mumol to determine the provocative dose of FMLP causing a 20% fall in FEV1(PD20FMLP). FEV1 was recorded every five minutes after the final FMLP inhalation until it had returned to 95% of baseline FEV1 or 60 minutes had elapsed. The time to return to 95% baseline FEV1 was recorded or extrapolated from the recovery curve as an index of rapidity of recovery. Total and differential white cell counts were performed on each subject at baseline and five and 15 minutes after the final FMLP inhalation. RESULTS: The geometric mean PD20 FMLP in the patients with chronic bronchitis was 0.06 mumol (95% confidence interval 0.015-0.26), which was significantly lower than that in the control subjects (0.21 mumol (0.02-1.9)). PD20 FMLP in the patients with chronic bronchitis but not age matched controls (p = 0.35) was lower than that found previously in young normal subjects (0.35 mumol (0.07-1.8). The return to 95% baseline FEV1 occurred after 86(10) minutes in subjects with chronic bronchitis and in 81(23) minutes in their age matched controls, in both cases being much slower than that seen in young subjects (29(9) minutes). CONCLUSION: Patients with chronic bronchitis may be especially susceptible to formyl peptides elaborated by bacteria during bacterial bronchial infection.

Administration, Inhalation↗
PubMed1992

Haematological effects of inhalation of N-formyl-methionyl-leucyl-phenylalanine in man.

BACKGROUND: N-Formyl-methionyl-leucyl-phenylalanine (FMLP) is a bacterial oligopeptide which stimulates neutrophil chemotaxis, degranulation and superoxide generation. Inhalation of FMLP produces bronchoconstriction in man; in the rabbit this is in part neutrophil dependent. The effects of inhalation of FMLP on peripheral blood leucocytes in normal subjects has been studied. METHODS: This was an open study in non-asthmatic subjects. Change in total peripheral white cell count were studied for 15 minutes after inhalation of 0.4 mumol FMLP in six subjects. Change in total and differential white cell count and spontaneous neutrophil chemiluminescence were then studied five and 30 minutes after inhalation of 0.4 mumol FMLP (n = 7) or diluent (n = 4). Finally, leucocytes from three subjects were labelled ex vivo with technetium-99m labelled sulphur colloid and reinfused. The effect of inhalation of FMLP or diluent on pulmonary neutrophil flux was studied by continuous gamma scanning of a pulmonary window. RESULTS: Leucopenia occurs rapidly after inhalation of FMLP, the nadir of the white cell count (53% of baseline) occurring at four minutes. This was followed by a rebound increase in white cell count evident at 15 minutes (154% of baseline). Five minutes after inhalation of 0.4 mumol FMLP, neutropenia (17% of baseline) and monocytopenia (40% of baseline) were seen followed again by a neutrophilia (213% of baseline at 30 minutes). The eosinophil count was significantly reduced at 30 minutes (24% of baseline). Neutrophil chemiluminescence was elevated (186% of baseline) at the time of the neutropenia. There was no influx of labelled cells to the lung during the period of neutropenia. CONCLUSION: FMLP inhalation activates circulating leucocytes. In vivo production of FMLP in the airway could contribute to bronchial inflammation during bacterial infection.

Administration, Inhalation↗
PubMed1992

Effect of the chest wall and blood volume on pulmonary distensibility.

To determine the reason for increased pulmonary distensibility in excised lungs, we performed deflation pressure-volume (PV) studies in 24 dogs. Exponential analysis of PV data gave K, an index of distensibility. Lung volume was measured by dilution of neon. Compared with measurements obtained in the supine position, with the chest closed, and with esophageal pressure (Pes) to obtain transpulmonary pressure, K was not changed significantly with the chest strapped, with pleural pressure to obtain transpulmonary pressure, or with the chest open. From displacement of PV curves obtained in the supine position and with the chest closed or open, we estimated that Pes was 0.18 kPa greater than average lung surface pressure. An increase in K in the prone and head-up positions was attributed to a traction artifact decreasing Pes. Exsanguination increased K and produced a relative increase in gas volume. These results show that overall pulmonary distensibility is unaffected by an intact chest wall. An increase in K and gas volume after exsanguination probably reflects a decreased pulmonary blood volume, with collapse of capillaries increasing the alveolar volume-to-surface ratio.

Animals↗
PubMed1991

Structure of a human pulmonary acinus.

The structure of the human pulmonary acinus has been described infrequently. The aim of the study was to determine the branching pattern of respiratory bronchioles and alveolar ducts in a human acinus from the peripheral part of the lung, where space constraints may have affected airway branching patterns. The lungs were obtained from an 18 year old victim of a motor vehicle accident and fixed in inflation under a pressure of 25 cm H2O. A block was cut from the lower edge of the right lower lobe and embedded in plastic. Serial sections were cut and the branching pattern of airways subtended by a terminal bronchiole were followed. The acinus was bounded on two sides by pleura and on the remaining sides by connective tissue septa. The terminal bronchiole divided into two respiratory bronchioles, each of which gave rise to four systems of alveolar ducts. Between successive systems of alveolar ducts the respiratory bronchioles continued as single airways, becoming progressively more alveolated towards the periphery but not subtending further branches of respiratory bronchioles. The duct systems became less complex towards the periphery, near to the edge of the lung. The total volume of the acinus was similar to that found in previous studies. This branching pattern has not been described previously in a human acinus.

Adolescent↗
PubMed1991

Effect of neutral endopeptidase inhibition of f-Met-Leu-Phe-induced bronchoconstriction in the rabbit.

Inhalation of f-Met-Leu-Phe (FMLP) produces dose-dependent increases in pulmonary resistance (RL) in rabbits. We hypothesized that inhibition of neutral endopeptidase (NEP), which has high affinity for FMLP, would augment the response to FMLP inhalation. We found the increase in RL above baseline in response to FMLP to be reduced from 56 +/- 18 to 8 +/- 10% (P less than 0.01) by phosphoramidon (1 mg/kg) and to 15 +/- 6% (P less than 0.02) by thiorphan (3 mg/kg). The geometric mean dose of FMLP producing a 20% rise in RL (PC20RL FMLP) was increased by phosphoramidon from 1.1 to 4.5 mg/ml (P less than 0.05). Enkephalins, which are also NEP substrates, modulate cholinergic neurotransmission in the airway. Inhibition of the FMLP response by phosphoramidon was reversed by coadministration of naloxone (0.1 mg/kg); after atropine (2 mg/kg) the change in RL in response to FMLP was reduced to 7 +/- 4% (P less than 0.01), whereas morphine (0.15 mg/kg) increased PC20RL FMLP to 5.1 mg/ml (P less than 0.05). FMLP-induced bronchoconstriction in the rabbit is vagally mediated, and reduced responses after NEP inhibition may reflect modulation of cholinergic bronchoconstriction by enkephalins. Changes in airway NEP activity may influence the activity of a wide range of its substrates, of which some are bronchoconstrictors and others bronchodilators.

Airway Resistance↗
PubMed1991

Effects of prolonged inhalation of N-formyl-methionyl-leucyl-phenylalanine in rabbits.

On the basis of its potent proinflammatory and spasmogenic effects, N-formyl-methionyl-leucyl-phenylalanine (FMLP), a bacterial oligopeptide, is a putative mediator of bronchoconstriction and airway inflammation during bacterial bronchial infection. However, after an FMLP dose-response curve in rabbits, tachyphylaxis to a second challenge was seen in some rabbits and airway inflammation was absent. This study was designed to reproduce the more prolonged airway exposure to FMLP that may occur during bacterial infection. Two groups of rabbits received FMLP [5 mg/ml in 66% dimethyl sulfoxide- (DMSO) saline] or DMSO diluent alone by nebulization every 15 min for 2 h. Pulmonary resistance (RL) was measured at 1 and 2 h. Recovery from bronchoconstriction was also assessed by measuring RL every 30 min for 2 h after the final FMLP administration. Sections of trachea and large bronchi were prepared and graded by quadrant from 0 to 3 for inflammation, a total score from 0 to 12 being given for each section. There was a progressive increase in RL in FMLP-treated rabbits, reaching 68 +/- 9% above baseline after 120 min, a significantly greater change than after diluent, 8 +/- 12% (P less than 0.01). RL remained elevated above baseline for 90 min after the final FMLP dose. Inflammation scores were greater after FMLP than DMSO: 9.3 +/- 0.5 vs. 4.3 +/- 0.7 (P less than 0.01) in trachea and 5.2 +/- 0.4 vs. 1.7 +/- 0.5 (P less than 0.01) in lobar bronchi. We conclude that prolonged exposure of airways to FMLP produces a sustained increase in RL and airway inflammation, the cardinal features of infective exacerbations of chronic airflow limitation.

Administration, Inhalation↗
PubMed1991

Effects of indomethacin and PEEP on oleic acid induced pulmonary oedema in rabbits.

This study was designed to determine whether indomethacin, a suggested treatment for adult respiratory distress syndrome (ARDS), would inhibit the efficacy of positive end-expiratory pressure (PEEP) in an animal model of ARDS. Functional residual capacity (FRC), alveolar-to-arterial oxygen difference (A-aPo2) and total lung water were measured in rabbits: 30 controls and 30 with oleic acid induced pulmonary oedema. Within each group, four treatments were administered: diluent (n = 12), PEEP (n = 6), indomethacin (n = 6), or PEEP + indomethacin (n = 6). Lung injury was induced at 30 mins and treatment commenced at 45 min. Oleic acid caused a significant increase at 3 h in % increase in A-aPo2 from baseline (105 +/- 12%) attenuated by PEEP (59 +/- 17%) and indomethacin (57 +/- 7%), with the combination of PEEP + indomethacin preventing a significant increase (26 +/- 9%). PEEP increase FRC in both saline and oleic acid animals; this was not reversed by indomethacin. Oleic acid caused an increase in total lung water (5.16 to 6.58 +/- 0.16 g), not influenced by any treatment. These findings suggest that indomethacin did not inhibit the efficacy of PEEP in this model of ARDS.

Animals↗
PubMed1990

Bronchodilatation induced by deep breaths in relation to transpulmonary pressure and lung volume.

Induced bronchoconstriction in normal subjects can be transiently reversed by a deep breath (airway hysteresis). The mechanisms of airway hysteresis are not fully understood. The aim of these studies was to determine whether the nature of the deep breath (slow or fast inspiration, five or 10 second breath hold) affects the resultant bronchodilatation. Bronchoconstriction was induced in 10 normal subjects by inhalation of histamine until specific airway conductance (sGaw) was halved (mean (SEM) post-histamine sGaw 0.099* (0.009) s-1 cm H2O-1). A subsequent deep breath to total lung capacity (TLC) increased sGaw by 57% (13%) and neither the rate of inspiration to TLC nor periods of breath holding at TLC produced a significantly different degree of bronchodilation. Reducing the volume of the deep breath produced progressively less bronchodilatation and this was no longer significant after a breath to 68% (2%) TLC. To determine whether the volume of the deep breath or the accompanying increase in transpulmonary pressure (PstL) was responsible for the effect on sGaw, subjects were studied with an oesophageal balloon in place with and without their chest strapped. Subjects took a deep breath to a PstL of 20 cm H2O after bronchoconstriction had been induced by histamine. The degree of bronchodilatation (mean (SEM) %) was not significantly different (strap on 25 (6), strap off 36 (5)) even though significantly larger lung volumes (as % TLC) were reached with the strap off (strap on 57 (2), strap off 78 (3)). These results suggest that PstL rather than lung volume during a deep breath determines airway hysteresis.

Adult↗
PubMed1990

Effects of continuous positive airway pressure breathing on lung volume and distensibility.

In this study the effects on lung elastic behavior of 10 min of breathing at a continuous positive airway pressure (CPAP) of 10 cmH2O were examined in 10 normal subjects. To investigate whether any changes were induced by release of prostaglandins, the subjects were also pretreated with the cyclooxygenase inhibitor indomethacin. CPAP produced a significant (P less than 0.001) upward shift of the pressure-volume (PV) curve [change in total lung capacity (delta TLC) 374 +/- 67 (SE) ml, mean delta volume at a transpulmonary pressure of 15 cmH2O (delta VL15) 279 +/- 31 ml] with no change in K, an index of lung distensibility. After CPAP the PV curves returned to normal base line within 20 min. The same pattern was observed after indomethacin, but the increase in TLC was significantly less (P less than 0.01) (mean delta TLC 206 +/- 42 ml) mainly because of a slight and not statistically significant increase in base-line TLC. In five subjects further PV curves with and without CPAP were obtained greater than or equal to 7 days after indomethacin. The responses were not significantly different from those obtained before indomethacin (mean delta TLC 366 +/- 89, mean delta VL15 296 +/- 42 ml). We conclude that CPAP produces an upward shift of the PV curve without a change in lung distensibility. In addition, there may be a small degree of resting alveolar duct tone that is influenced by indomethacin.

Adult↗
PubMed1989

The effect of histamine challenge on platelet count and platelet activation.

There is conflicting evidence of platelet involvement in asthmatic bronchoconstriction. We sought direct evidence of platelet activation and indirect evidence of platelet sequestration following histamine challenge (HC) in 14 asthmatics and seven non asthmatic control subjects. Peripheral platelet counts and levels of beta thromboglobulin (BTG) were measured immediately before and following HC in the 21 subjects. There were no significant differences in the platelet counts or BTG levels, before or after HC, within or between the two groups. These results do not support platelet activation or accumulation in the lungs occurring immediately following histamine induced bronchoconstriction in asthmatics.

Adolescent↗
PubMed1989

The "destructive index" in nonemphysematous and emphysematous lungs. Morphologic observations and correlation with function.

We examined the relationship of the newly described "Destructive Index" (DI) to emphysema using nine nonemphysematous and 13 emphysematous lungs obtained at autopsy. The amount of emphysema was assessed by the panel method (emphysema grade, EG) and measurement of the mean linear intercept (Lm). The DI depends on three components--alveolar wall/duct disruption, DId; alveolar fibrosis, DIf; and classic emphysema, DIe. DIf was a minor component in our series. The mean DI was 5.8 +/- 2.5, 10.9 +/- 3.9, and 55.7 +/- 7.0% (+/- 1 SEM) in the nonemphysematous (panel grade EG = 0), mild (0 less than EG less than or equal to 25), and moderate to severe (30 less than or equal to EG less than or equal to 60) emphysematous lungs, respectively. The increase in the DI in mild emphysema did not reach significant levels (p less than 0.2). The mean DId was 5.6 +/- 2.5, 10.0 +/- 4.0, and 12.8 +/- 3.9% in the above categories, and the DId in mild emphysema did not differ significantly from that of the nonemphysematous lungs. Lm showed a similar trend and alveolar disruption did not precede airspace enlargement, rather both changes appeared to advance in parallel. The DI correlated closely with EG (r = 0.83, p less than 0.01), but this was due to the component of DIe. The DIe increased steeply in the lungs with EG greater than or equal to 30.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1989

The effect of anticholinergic and beta-agonist pretreatment on bronchoconstriction induced by N-formyl-methionyl-leucyl-phenylalanine.

N-Formyl-methionyl-leucyl-phenylalanine (FMLP), an acylated tripeptide bacterial neutrophil chemotactic factor, has been shown to be a bronchoconstrictor by inhalation in man in vivo. It thus has a putative role in the generation of bronchoconstriction associated with bacterial bronchial infection. We have investigated the effect of pretreatment with the anticholinergic agent, ipratropium bromide (IB), and the beta 2-agonist, fenoterol (F), on FMLP-induced bronchoconstriction. Ten non-asthmatic subjects aged 21-28 yrs performed dose-response curves to nebulized FMLP on 3 study days after pretreatment with saline, F or IB. Amongst the 8 subjects who bronchoconstricted by 20% to FMLP there was a significant increase in the provocative concentration causing a 20% fall in forced expiratory volume in one second (FEV1) (PC20FMLP) after both IB and F. F was significantly better than IB. When comparison was made using absolute fall in FEV1 and including all 10 subjects the same results were found. Partial inhibition of FMLP-induced bronchoconstriction by IB suggests that part of the effect of FMLP is vagally mediated. We suggest that F is acting via modulation of FMLP-induced rises in intracellular free calcium.

Adult↗
PubMed1988

The effect of L-glutamic acid on airway function and reactivity in the rabbit.

The ingestion of monosodium glutamate in sensitive individuals has been reported to cause severe asthma. We therefore studied the effects of L-glu on airway function and histamine (H) responsiveness in the rabbit. Histamine dose response curves (HDR's) were performed by measuring total lung resistance (RL) after inhalation of saline and increasing concentrations of H (1-30 mg/ml). The concentration of H producing a 20% increase in RL (PC20H) was obtained by interpolation. To assess the effects of L-glu, 8 rabbits were infused with L-glu (0.2 g/kg/hr) or saline in random order (14 days apart) for 4 hours followed by an HDRC. To look at possible late effects, a repeat HDRC was also performed in 6 rabbits 12 hours after completion of the L-glu infusion. In order to see whether rabbits rendered hyperresponsive responded to L-glu, the above protocol was performed in 7 rabbits following the inhalation of 3 micrograms of the activated complement fragment C5a des Arg. The L-glu infusions increased the plasma levels approx. ten-fold (mean +/- SEM 0.119 +/- 0.012 base-line, 1.272 +/- 0.061 mmol/l post infusion). L-glu did not increase the PC20H or baseline RL in either the normal rabbits at 4 or 12 hours or in the C5a des Arg treated rabbits at 4 hours. It is concluded that L-glu does not cause bronchoconstriction or an increase in airway responsiveness to H in the rabbit.

Administration, Inhalation↗
PubMed1988

Effect of inhaled formyl-methionyl-leucyl-phenylalanine on airway function.

Formyl-methionyl-leucyl-phenylalanine (FMLP), a synthetic, acylated tripeptide analogous to bacterial chemotactic factors, has been shown to cause bronchoconstriction in guinea pig, rabbit, and human airways in vitro. To determine whether FMLP causes bronchoconstriction in man in vivo, a preliminary study was undertaken in which five non-smokers (mean age 35 years, FEV1 94% (SEM 5%) predicted) and five smokers (mean age 34 years, FEV1 93% (6%) predicted) inhaled aerosols of FMLP. None of the subjects showed airway hyperresponsiveness to histamine (the provocative concentrations of histamine causing a fall of greater than or equal to 20% in FEV1 (PC20) were over 8 mg/ml). FMLP dissolved in 50% dimethylsulphoxide and 50% saline in concentrations of 0, 0.06, 0.12, 0.25, 0.5, 1.0, 2.0, and 4.0 mg/ml was administered to the subjects by means of a French-Rosenthal dosimeter, FEV1 being recorded after inhalation of each concentration. Dose dependent falls in FEV1 occurred in five non-smokers (geometric mean 1.76, 95% confidence limits 0.87-3.53 mg/ml) and three smokers (0.23, 0.07-0.78 mg/ml), with two smokers not responding by 20% to the highest concentration of FMLP. On a separate day the FMLP dose-response curves were repeated after nebulisation of 500 micrograms of ipratropium bromide. The PC20 FMLP in the responders more than doubled. In six additional normal subjects a histamine inhalation test was performed before and four and 24 hours after inhalation of FMLP. All subjects remained unresponsive to histamine. These results show that FMLP is a potent bronchoconstrictor in some non-asthmatic individuals in vivo and this may be important in bronchoconstriction related to infection in patients with chronic obstructive lung disease.

Adult↗
PubMed1988

Deferoxamine infusion does not inhibit bleomycin-induced lung damage in the rat.

It has been proposed that the pneumonitis and subsequent lung fibrosis induced by bleomycin occurs when bleomycin is complexed with ferrous iron and oxygen. In order to see whether chelation of free iron reduced tissue damage induced by intratracheal bleomycin, deferoxamine (DFO) was administered by continuous subcutaneous infusion to overcome its rapid renal excretion. Thirty-three rats received DFO and 30 rats received an equivalent volume of saline by 7-day infusion pumps. Three days after commencement of infusion, half of each group received intratracheal bleomycin, the remainder received intratracheal saline. Three weeks after intratracheal injection, the rats were killed and their lungs were removed for histologic and morphometric assessment and collagen estimation. When compared with animals given intratracheal saline, both bleomycin-treated groups had significant evidence of lung toxicity, but DFO was not protective. Similarly, DFO infusion did not reduce the elevation in collagen concentration (bleomycin/saline, 49 +/- 3.6; bleomycin/DFO, 49.8 +/- 4.1; saline/saline, 39.6 +/- 3.9; saline/DFO, 43.4 +/- 3.8 mg.g-1 wet lung weight) or total lung collagen (bleomycin/saline, 29.9 +/- 6.3; bleomycin/DFO, 33.7 +/- 1.8; saline/saline, 15.5 +/- 2.2; saline/DFO, 17.8 +/- 1.9 mg.left lung-1) induced by bleomycin. This lack of effect was not due to iron contamination of the DFO in the pump or to loss of chelation capacity of DFO, at least for as long as 6 days after pump implantation. No DFO was detected in homogenized lung tissue (limits of detection of assay was 8 x 10(-5) M).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Airway responses in vitro following C5a des Arg-induced hyper-responsiveness in vivo in rabbits.

The mechanism of C5a des Arg-induced airway hyper-responsiveness in rabbits was investigated. Airway smooth muscle from rabbits which had been pretreated in vivo, was studied in vitro. Tracheal rings, segmental bronchial rings, subsegmental bronchial spirals and lung parenchymal strips were all prepared from each rabbit lung. Although C5a des Arg produces hyper-responsiveness to histamine in vivo, which is inhibited by indomethacin, the airway smooth muscle responses in vitro from control, C5a des Arg and C5a des Arg plus indomethacin pretreated rabbits did not differ. The neutrophil counts in the tracheal and subsegmental bronchial specimens were increased in the C5a des Arg-treated group. Indomethacin significantly (P less than 0.05) inhibited the neutrophil influx in the subsegmental bronchi. It is concluded that intrinsic smooth muscle function is unaltered following C5a des Arg-induced hyper-responsiveness in vivo.

Airway Resistance↗