Biomedical subjects

A Harf

Publications and source records attributed to A Harf.

At least 91 records · Page 5Linked to original sources

PubMed1997

Respiratory resistive impedance in obstructive patients: linear regression analysis vs viscoelastic modelling.

The aim of this study was to test the ability of a simple two segment model to describe the frequency dependence of resistive impedance in obstructive patients, and to investigate the significance of parameters derived from this model. The study was performed in 38 patients, in the basal state and after inhalation of 200 micrograms salbutamol. Impedance data measured over 4-32 Hz were fitted by a general four parameter viscoelastic model describing gas redistribution, and completed by an inertial component. This model yielded Newtonian resistance (Rmin) and maximal resistance (Rmax = Rmin plus delayed resistance due to gas redistribution). Resistive impedance data were also submitted to linear regression analysis over the 4-16 and 17-32 Hz frequency ranges, which respectively, yielded resistive impedance extrapolated at 0 Hz (R0) and resistive impedance estimated at 32 Hz (R32). R0 and R32 were compared to Rmax and Rmin, respectively. The airway response to salbutamol inhalation was assessed by the percentage changes in these parameters (R0%, R32%, Rmax%, and Rmin%, respectively). Significant linear correlations (p < 0.0001) were found between R0 and Rmax, R32 and Rmin, and R0% and Rmax%. Furthermore, the linear regression lines of R0 vs Rmax, and R0% vs Rmax%, were not significantly different from the identity line. These results demonstrate that resistive impedance extrapolated at zero frequency is equivalent to maximal resistive impedance, and can be proposed as an index, not only of the level of airway obstruction, but also of its reversibility.

Administration, Inhalation↗

PubMed1997

Effect of zopiclone on sleep, night-time ventilation, and daytime vigilance in upper airway resistance syndrome.

We have assessed the effects of zopiclone (7.5 mg), a new cyclopyrrolone hypnotic drug, on ventilation, sleep parameters, and daytime vigilance in snorers with upper airway resistance syndrome (UARS). Using a randomized double-blind design, eight male patients with UARS took either oral zopiclone or a placebo each evening for seven consecutive days and then crossed over to the other drug after a 7 day placebo period. Polysomnography followed by a multiple sleep latency test (MSLT) was performed during the last night of each treatment period. Zopiclone produced significant improvements in the sleep efficiency index (total sleep time/time in bed) (placebo 84+/-15% versus zopiclone 91+/-7%) and average MSLT (placebo 10.3+/-3.7 min versus zopiclone 14.9+/-2.8 min), as well as nonsignificant improvements in sleep onset latency and total sleep time. It had no effect on sleep architecture or on the arousal index (placebo 17+/-8 arousals x h(-1) versus zopiclone 17+/-4 arousals x h[-1]). Furthermore, none of the respiratory parameters were significantly affected by zopiclone. In conclusion, zopiclone has no adverse effects on sleep architecture, respiratory parameters during sleep, and daytime sleepiness in patients with UARS.

Airway Resistance↗

PubMed1996

Expression of matrix metalloproteinase gelatinases A and B by cultured epithelial cells from human bronchial explants.

To investigate the role of human bronchial epithelial cells (HBECs) in the maintenance and remodeling of the extracellular matrix, we evaluated the expression by HBECs of 72- and 92-kDa gelatinases under basal conditions and after exposure to bacterial lipopolysaccharides (LPS). Confluent HBECs from explants were cultured in plastic dishes coated with type I and III collagens. Gelatin zymography of HBEC-conditioned media showed constitutive major 92-kDa and minor 72-kDa gelatinases recognized by specific human antibodies and totally inhibited by the metalloproteinase inhibitor EDTA. The identification of the two matrix metalloproteinases was confirmed by quantitative reverse transcription-polymerase chain reaction. Identical patterns of gelatinase expression were observed with repetitive primary cultures issued from the same explants. Zymography showed that exposure of HBECs to LPS induced 2- and 20-fold increases in 92-kDa gelatinase production and activation, respectively, as well as a smaller increase in activated 68-kDa gelatinase. With [3H]gelatin substrate, elevated metallogelatinolytic activity (138 microgram of hydrolyzed gelatin/48 h/10(6) cells) was also observed, whereas no activity was detected in the absence of LPS. A human epithelial cell line (16HBE14o-) exhibited the same basal profile of gelatinase activity, but this profile remained unchanged after exposure to LPS. Quantitative reverse transcription-polymerase chain reaction demonstrated only minimal changes in 92-kDa mRNA levels in response to LPS, but the half-life of 92-kDa gelatinase mRNA was increased with exposure to LPS. In contrast, concomitant slight increases in 72-kDa gelatinase protein and mRNA were found, suggesting that the control mechanisms regulating the expression of 92- and 72-kDa gelatinases by HBECs in response to LPS are divergent. All these data allowed us to propose that HBECs may be actively involved in the physiological and physiopathological remodeling of the airway basement membrane.

Bronchi↗

PubMed1996

Inspiratory work of breathing in ventilated preterm infants.

In ventilated newborns, part of the inspiratory work of breathing (WOB) may be due to the inspiratory efforts preceding inspiratory ventilator flow. This study was designed to quantify the contribution of these efforts to WOB. WOB was evaluated in six intubated preterm infants ventilated by the Dräger Babylog 8000. The ventilatory modes studied were intermittent mandatory ventilation (IMV), continuous positive airway pressure (CPAP), and assist-control ventilation at 10 (ACV10) and 15 (ACV15) cmH2O peak pressure. Mouth flow (V) and esophageal pressure (Pe) were recorded, and WOB was estimate from the area delineated by the esophageal pressure-volume curve, where volume is the time integral of V. Calculation of WOB started either at the onset of the infant's inspiratory flow (WOBi), or at the beginning of the infant's inspiratory muscle efforts, detected on Pe and confirmed on the V tracing (WOBm). WOBm was found to be significantly higher than WOBi under all ventilatory conditions studied. The difference in work of breathing (delta W) between WOBm and WOBi did not depend on the type of ventilatory mode. When delta W was related to WOBm, it amounted to about 30% of WOBm in IMV and CPAP, and 60% in ACV (P < 0.05, ACV15 vs. IMV). These results suggest that, in preterm infants connected to a ventilator, inspiratory efforts preceding flow inspiration might account for a large fraction of the inspiratory work of breathing.

Female↗

PubMed1996

Effect of gas density variations on respiratory input impedance in humans.

The forced oscillation technique is a widely-used non-invasive method of characterizing the dynamic behaviour of the respiratory system. We used the forced oscillation technique to investigate respiratory mechanics in healthy subjects during simulated dives in dry hyperbaric chambers. We observed frequency dependence of input impedance, which was mainly density-dependent. To explain this result, we propose a model of the respiratory system, based on flow redistribution in a two-pathway circuit. This model, using the electrical analogue, is composed of two Resistance-Self Inductance-Capacitance (R-I-C) pathways set up in parallel. It allowed us to explain the dynamic behaviour of respiratory impedance under hyperbaric conditions in healthy subjects. Changes in respiratory impedance according to frequency vary with the relative importance of the inequalities of the two time constants RC and I/R between the two pathways. With low values of density, RC inequality predominates, whereas I/R inequality tends to predominate with high values of density.

Air Pressure↗

PubMed1996

Noninvasive estimate of work of breathing due to the endotracheal tube.

BACKGROUND: Although evidence suggests that secretions lining the inner wall of the endotracheal tube (ETT) often reduce its cross-sectional area, no data are available on the work of breathing as affected by the ETT. A noninvasive method is proposed for estimating the additional work of breathing necessitated by the ETT in patients whose lungs are mechanically ventilated. This method (the acoustic-Blasius method) involves (1) determining the inner geometry of the ETT using the acoustic reflection method and (2) using these geometric data to solve the Blasius equation that characterizes the ETT pressure drop-flow relation. METHODS: To evaluate the acoustic-Blasius method in vivo, the authors computed the work of breathing due to the ETT in four healthy persons breathing through an ETT connected to a pressure-support device and in five tracheally intubated patients receiving mechanical assistance in the pressure-support mode. For the tracheally intubated patients, the reference value was the work calculated from the ETT pressure drop measured between the two ends of the ETT using a pressure catheter. RESULTS: In the healthy participants and the tracheally intubated patients, there was close agreement between inspiratory work per cycle values estimated by directly measuring the ETT pressure drop and calculated using the acoustic-Blasius method: The difference was consistently less than 0.08 joules (< 10% of the reference value). CONCLUSIONS: The data show that the acoustic-Blasius method allows noninvasive quantification of the ETT-related work of breathing in situ.

Humans↗

PubMed1996

Gradual reduction of endotracheal tube diameter during mechanical ventilation via different humidification devices.

BACKGROUND: Limited data suggest that increased resistance to flow within endotracheal tubes (ETT) may occur in patients whose lungs are mechanically ventilated for more than 48 h, especially when airway humidification is inadequate. This could lead to sudden ETT obstruction or induce excessive loading during spontaneous breathing. METHODS: Twenty-three such patients were randomly assigned to three types of airway humidifier based on three different working principles: a Fisher Paykell hot water system (n = 7), a Pall BB2215 heat and moisture exchanger (HME) hydrophobic filter (n = 8), and a Dar Hygrobac 35254111 HME hygroscopic filter (n = 8). The decrease in internal pressure along the ETT and the flow rate were measured in each patient every 2 days. An "effective inner diameter" was derived from these measurements and allowed the inner ETT configuration to be monitored. RESULTS: On the first day of intubation, the mean diameter was similar in the three groups, and was slightly smaller than the in vitro diameter (mean +/- SD: 7.6 +/- 0.6 mm for Fisher-Paykell, 7.7 +/- 0.4 for Pall, and 7.5 +/- 0.4 for Dar). The mean diameter tended to decrease from day to day. At the end of the study, the overall reduction in mean diameter was significantly greater with the hydrophobic HME (Pall) than with the two other systems (Pall: -6.5 +/- 4% vs. 2.5 +/- 2.5% for Dar and 1.5 +/- 3% for Fisher-Paykell; P < 0.01 with analysis of variance). The same was true of the mean reduction in effective inner ETT diameter expressed per day of ventilation (-1.6 +/- 1.5% per day for Pall vs. -0.5 +/- 0.4% for Dar and -0.2 +/- 0.4% for Fisher-Paykell; P < 0.01). In four patients, the ETT became obstructed and emergency repeated tracheal intubation was required. The Pall HME and the Fisher-Paykell system were being used in three and one patient, respectively. Before obstruction, the reduction in ETT diameter was significantly greater for these four patients than for the remaining 23 patients (7.8 +/- 1.4% vs. 3.1 +/- 4.1%; P < 0.01). CONCLUSIONS: During prolonged mechanical ventilation, significant alterations in inner ETT configuration occur frequently and are influenced by the type of humidification device used. In vivo monitoring of ETT mechanical properties might be clinically useful.

Aged↗

PubMed1996

Aerosolized tachykinin antagonists inhibit pentamidine-induce bronchoconstriction in guinea pigs.

To investigate the role of tachykinins in pentamidine-induced bronchoconstriction and airway microvascular leakage in the guinea pig, we examined the effects on bronchoconstriction and microvascular leakage of the nonpeptide antagonists of NK1 and NK2 tachykinin-receptors, respectively, CP-96,345 and SR 48968. Respiratory system resistance was measured by the occlusion method in anaesthetized, tracheotomized and mechanically ventilated guinea pigs. Airway microvascular permeability was evaluated by measuring the quantity of Evans blue dye in the trachea and main bronchi. Aerosolized CP-96,345 or SR 48968 partially abolished pentamidine-induced bronchoconstriction (at 5 to 30 mg/mL pentamidine; 60 breaths) whereas the combination of the two prevented it. In contrast, CP-96,345 and SR 48968 did not prevent the increase in airway microvascular permeability induced by pentamidine (50 mg/mL; 90 breaths) whether they were administered separately or together, by aerosol or intravenously. These results demonstrate that in the guinea pig, pentamidine-induced bronchoconstriction is mediated through both NK1 and NK2 tachykinin-receptor activation and that when directly administered into the airways, tachykinin antagonists effectively prevent pentamidine-induced bronchoconstriction.

Aerosols↗

PubMed1996

Respiratory resistance by end-inspiratory occlusion and forced oscillations in intubated patients.

Measurement of respiratory impedance by the forced oscillation technique (FOT) in intubated patients requires corrections for the flow-dependent resistance, inertance, and air compression inside the endotracheal tube (ETT). Recently, we published a method to correct respiratory impedance for the mechanical contribution of the ETT. To validate this correction, we compared the respiratory resistance obtained with this method (Rfo) to the intrinsic (Rmin) and total resistances (RT) measured by the airway-occlusion technique (OCT) in 16 intubated sedated paralyzed ventilated patients. The FOT was applied at functional residual capacity in the 4- to 32-Hz frequency range, whereas the OCT was performed at the end of a normal constant-flow inspiration. Rmin corrected with Rfo measured at 16 and 32 Hz [Rfo(16) = 1.10 x Rmin + 0.10 cmH2O.s.l-1, r = 0.96, P < 0.001; Rfo(32) = 0.93 x Rmin + 0.72 cmH2O.s.l-1, r = 0.97, P < 0.001]. RT corrected with Rfo at 4 Hz [Rfo(4) = 1.11 x RT - 1.48 cmH2O.s.l-1; = 0.92; P < 0.001]. We conclude that the FOT improved by correction for the behavior of the ETT is in good agreement with the OCT in intubated patients.

Adult↗

PubMed1996

Effects of assisted ventilation on the work of breathing: volume-controlled versus pressure-controlled ventilation.

During assisted ventilation, the same tidal volume can be delivered in different ways, with the possibility for the physician to vary the ventilatory target (pressure or volume) and the peak flow setting. We compared the effects on the respiratory work rate of assisted ventilation, delivered either with a square wave flow pattern (assist control ventilation [ACV]) or with a decelerating flow pattern and a constant pressure (assisted pressure-control ventilation [APCV]). In the first part of the study where seven patients were studied, inspiratory time and tidal volume were similar in the two modes of ventilation. High and moderate levels of tidal volume (VT) were studied (12 ml/kg and 8 ml/kg, respectively). To obtain moderate VT, inspiratory time was kept constant and, therefore, mean inspiratory flow was reduced. At high VT, no difference between ACV and APCV was noted for breathing pattern, respiratory drive indexes, respiratory muscle work, or arterial blood gases. All patients exhibited respiratory alkalosis. At moderate VT, normal pH was achieved. In this situation significantly lower levels were observed during APCV than during ACV for the power of breathing (10 +/- 2 versus 19 +/- 5 J/min, p<0.05), transdiaphragmatic pressure swing (7 +/- 1 versus 11 +/- 2 cm H2O, p<0.05), and pressure-time index (252 +/- 43 versus 484 +/- 114 cm H2O.s, p<0.05), even though breathing pattern and gas exchange were similar. In the second part of the study where six additional patients were studied, tidal volume was kept constant at a moderate level (8 ml/kg), and we studied the effect of shortening inspiratory time and increasing mean inspiratory flow. At moderate VT and high inspiratory flow, no significant differences could be found between ACV and APCV, and although pressure-time index tended to be lower during APCV, absolute levels of effort were of small magnitude (56 +/- 55 versus 76 +/- 55 cm H2O.s). We conclude that at moderate VT and low flow rates only, inspiratory assistance delivered at a constant pressure reduces the respiratory work rate more effectively than assist control ventilation.

Aged↗

PubMed1996

Patient-triggered ventilation decreases the work of breathing in neonates.

During conventional intermittent mandatory ventilation (IMV) in neonates, asynchrony between mechanical and spontaneous breaths is frequent. We tested the hypothesis that patient-triggered ventilation (PTV) reduces the work of breathing (WOB) by providing synchronized assistance for each breath. Accordingly, six intubated preterm infants were studied at the median postnatal age of 34 days while they were being weaned from mechanical ventilation (MV). Patients were ventilated using the Draeger Babylog 8000 (software #3) and studied in four successive modes of MV with a constant level of positive end-expiratory pressure. They were randomly assigned to IMV, PTV with peak inspiratory pressure of either 10 cm H2O (PTV10) or 15 cm H2O (PTV15), and spontaneous ventilation with continuous positive airway pressure. PTV was achieved in the assist/control mode. During PTV, infants adapted their pattern of breathing in response to an increase in tidal volume (median 7.5 ml/kg in IMV versus 8.2 in PTV10 and 8.5 in PTV15, p<0.05) by decreasing their respiratory rate, thus maintaining minute ventilation (439 ml/min/kg in IMV versus 422 in PTV10 and 455 in PTV15, NS) and transcutaneous CO2. WOB fell significantly during PTV compared with its level during IMV (0.81 J/L in IMV versus 0.48 and 0.47 during PTV10 and PTV15, respectively, p<0.05). Power of breathing decreased in the same proportions. These results demonstrate that PTV mode allows reduction of the workload imposed on the respiratory muscles.

Adaptation, Physiological↗

PubMed1996

Evaluation of a knowledge-based system providing ventilatory management and decision for extubation.

We evaluated whether a knowledge-based system (KBS) connected to a ventilator in pressure support mode could correctly predict the ability of patients to tolerate total withdrawal from ventilatory support. The KBS was designed to continuously adapt ventilatory assistance to the needs of the patient, to manage a strategy of gradually decreasing ventilatory assistance, and to indicate when the patient was able to breathe without assistance. Thirty-eight patients for whom weaning was being considered were evaluated using a conventional battery of parameters, including weaning criteria, tolerance of a T-piece trial, and outcome 48h after permanent withdrawal of ventilation. The results of this evaluation were compared with the suggestions made by the KBS at the end of a period of KBS-driven mechanical ventilation inserted in the conventional weaning procedure. The positive predictive value of the KBS was 89%, versus 77% for the conventional procedure and 81% for the rapid shallow breathing index alone. The KBS correctly predicted the course of five patients who tolerated a T-piece trial but required ventilation within 48 h. We conclude that our KBS ensured appropriate patient management during the weaning period and improved our ability to predict responses to weaning.

Adult↗

PubMed1996

Home versus intensive care pressure support devices. Experimental and clinical comparison.

A bench study using an artificial lung model and a clinical study in patients were performed to evaluate six commercially available home pressure support devices. Six devices were tested in the in vitro study, including five designed for home use and one designed for use in intensive care units. Minimal positive end-expiratory pressure (PEEP) varied across home devices, from 0.5 cm H2O to 4.3 cm H2O. Work imposed during exhalation varied up to six-fold across devices. A substantial rebreathing volume has present for the three home devices with a common inspiratory and expiratory line. This rebreathing volume decreased with increasing PEEP level, as expected, but remained substantial at the widely used PEEP level of 5 cm H2O. Use of a non-rebreathing valve increased both the work imposed by the circuit during the exhalation phase and the time required to attain the relaxation equilibrium. Except for two home devices and a bilevel positive airway pressure (BiPAP) device equipped with a non-rebreathing valve, differences in inspiratory trigger sensitivities were small between home and intensive care devices. During pressure support, the total work performed by the machines did not differ by more than 15% between devices, whereas differences of more than 300% were observed in flow acceleration. Only one home device gave a flow acceleration similar to or better than that obtained with the intensive care device. In a randomized, crossover clinical study, we compared a home device to a device specially designed for intensive care use in seven intubated patients during weaning from mechanical ventilation. The main differences between the two devices were trigger sensitivity and initial flow acceleration. For the same level of pressure support, there were no significant differences in arterial PCO2, tidal volume, respiratory rate, or minute ventilation between these two devices. However, the esophageal pressure-time product was 30% higher with the home device (165 +/- 93 versus 119 +/- 80 cm H2O/min, p < 0.05). In conclusion, differences exist between devices in terms of occurrence of rebreathing, speed of attainment of stable pressure support level, and expiratory resistance. These differences characterizing the delivery of pressure support may have clinical impact on the inspiratory effort of patients.

Adult↗

PubMed1996

Effect of zolpidem on sleep and ventilatory patterns at simulated altitude of 4,000 meters.

The purpose of this study was to assess the effect of zolpidem 1 0 mg, a new imidazopyridine hypnotic drug, on sleep and respiratory patterns at a simulated altitude of 4,000 meters. Eight male subjects spent three nights in a decompression chamber. The first study night was spent at the ambient pressure corresponding to sea level. The two other nights were spent at a simulated altitude of 4,000 meters with either zolpidem or a placebo in random order according to a double-blind, crossover design. All subjects showed periodic breathing (PB) during sleep at simulated high altitude. Furthermore, altitude was associated with decreases in total sleep time (TST), slow-wave sleep (SWS), and REM sleep, and with significant increases in Stage 1 duration and in the arousal index. Most arousals were synchronous with the hyperpneic phase of PB. The main finding of our study is that zolpidem improved sleep characteristics at high altitude, inducing a decrease in sleep onset latency (placebo, 22 +/- 12 min versus zolpidem, 10 +/- 6 min), an increase in SWS duration (placebo, 46 +/- 28 min versus zolpidem, 69 +/- 28 min), and a reduction in the arousal index during SWS (placebo, 7.4 +/- 4.1 per h versus zolpidem: 2.4 +/- 1.0 per h). Furthermore, none of the respiratory parameters were significantly affected by zolpidem in any sleep stage. In conclusion, zolpidem improved sleep quality at high altitude without adversely affecting respiration.

Adult↗

PubMed1996

Estimation of occlusion pressure during assisted ventilation in patients with intrinsic PEEP.

We conducted a study to assess the validity of the occlusion pressure (P0.1) measured during activation of the trigger mechanism (P0.1(aw)trig) in patients showing variable levels of PEEPi during pressure-support ventilation. We first compared P0.1(aw)trig and P0.1 measured with the conventional method (i.e., the airway pressure drop after the first 100 ms of an occluded inspiration) in 16 patients with chronic obstructive pulmonary disease (COPD). We observed good agreement and a highly significant correlation (r = 0.99; bias = 0.3 +/- 0.5 cm H20) between the two methods. In a second part of the study, we compared, in 17 patients, P0.1(aw)trig with (P0.1(es)), measured as the depression generated on the esophageal pressure tracing in the first 100 ms of the inspiratory negative swing, and with P0.1 measured on the P(es) tracing simultaneously with P(aw)trig (P0.1(es-synchro)). Our results showed a good correlation and good agreement between P(aw)trig and P0.1(es) (r = 0.92; bias = 0.3 +/- 0.5 cm H20); P(aw)trig and P0.1(es-synchro) (r = 0.97; bias = 0.1 +/- 0.2 cm H20); and P0.1(es) and P0.1(es-synchro) (r = 0.95, bias = 0.2 +/- 0.4 cm H20), respectively. This study suggests that reliable measurements of inspiratory drive can be obtained easily, on a breath-by-breath basis, from airway pressure tracings during pressure-support ventilation in patients with variable levels of PEEPi.

Airway Resistance↗

PubMed1996

Efficacy of cardiopulmonary resuscitation using intratracheal insufflation.

The effects of constant-flow insufflation (CFI) of air in the trachea at the distal end of a modified endotracheal tube as the sole mode of ventilation during cardiopulmonary resuscitation (CPR) were studied in pigs. The ventilatory effect of CFI (15 +/- 2 L/min) generating a positive pressure of about 10 cm H2O with concomitant chest compression was studied first. In nine sedated, paralyzed animals disconnected from the ventilator, CFI alone did not significantly alter the decrease in PaO2 and the rise in PaCO2 observed during apnea. By contrast, the combination of precordial compression and CFI (CFI-CPR) maintained arterial blood gases over a 4-min period at the level obtained during mechanical ventilation. In the second part of the study, ventricular fibrillation was induced and CFI-CPR was compared with standard CPR using conventional mechanical ventilation during two successive 4-min periods, in random order. Ventilatory parameters were identical in the two situations, whereas hemodynamic parameters were similar or better with CFI-CPR than with standard CPR. Significant differences were observed between standard CPR and CFI-CPR for systolic aortic pressure (72 +/- 22 versus 82 +/- 27 mm Hg, respectively; p < 0.02) and for systolic (322 +/- 216 versus 431 +/- 237 ml/s; p < 0.01) and mean (116 +/- 106 versus 143 +/- 108 ml/s; p < 0.01) common carotid blood flows. The ease of use of CFI together with its beneficial hemodynamic effects suggests that CFI deserves to be investigated further as a mode of ventilation during CPR.

Animals↗

PubMed1996

Role of gelatinase B and elastase in human polymorphonuclear neutrophil migration across basement membrane.

Polymorphonuclear neutrophil (PMN) migration across basement membrane is thought to be dependent on the degradation of membrane constituents. PMN gelatinase B, a metalloproteinase able to degrade type IV collagen, may be involved in this phenomenon. PMN gelatinase B is released in the extracellular medium as a latent proform and then activated, mainly by PMN elastase. We investigated the role of gelatinase B in PMN migration across a Matrigel basement membrane matrix coated onto a filter, in a Boyden chamber. The effects of gelatinase and elastase inhibitors on PMN migration in this system were tested. Chemokinesis of PMN was tested in the same Boyden chamber across a filter free of basement membrane. The agarose method was used to test the same inhibitors for effects on PMN chemotaxis. In both systems, FMLP 10(-7)M was used as a chemoattractant. Addition of 10(-8)M TIMP-1 (the preferential gelatinase B inhibitor) inhibited trans-basement membrane PMN migration by 52 +/- 6% (P<0.05), without affecting PMN chemokinesis, chemotaxis, or degranulation. Also, (Ala)(2) Pro Val chloromethyl ketone (AAPVCK) 100 micron, a specific elastase inhibitor, inhibited trans-basement membrane PMN migration by 51 +/- 8% (P<0.05), without affecting PMN chemokinesis, chemotaxis, or degranulation. The AAPVCK-TIMP combination led to a decrease in migration across Matrigel basement membrane (46 +/- 2%, P,0.05)similar to that seen with TIMP alone. AAPVCK was responsible for inhibition of gelatinase B activation, leading to a decrease in activated gelatinase from 14% to 2% of total gelatinase release (P<0.05). All these results strongly suggest that gelatinase B is a major factor of PMN migration across basement membrane and that elastase may contribute to this process by activating pro-gelatinase B.

Amino Acid Chloromethyl Ketones↗

PubMed1996

Airway epithelial damage induced by sulfur mustard in guinea pigs, effects of glucocorticoids.

Sulfur mustard (SM) represents a potential chemical warfare agent. In order to characterize SM-induced airway epithelial damage, we studied the effects of an intratracheal injection of 0.3 mg/kg of SM in guinea pigs, 5 h, 24 h, 14 days and 35 days after exposure. During the acute period, lesions prevailed in tracheal epithelium exhibiting intra-epithelial blisters, inflammatory cell infiltration and columnar cell shedding with exposure of basal cells. Fourteen days after intoxication, tracheal epithelium appeared disorganized and showed a significant decrease in height and cell density. Tracheal epithelium recovery was still not complete even 35 days after SM-intoxication. At day 14, in SM-intoxicated guinea pigs treated with betamethasone from day 7 to day 14, epithelium height, cell density and cell proliferation (evaluated by immunohistochemistry) were significantly increased compared to untreated guinea pigs. In conclusion, the lesions observed in SM-intoxicated guinea pigs seem to be in accordance with clinical human observations and are relevant to the study of airway epithelial damage induced by SM. This animal model could be used to illustrate tracheal epithelium regeneration mainly derived from basal cells and to show glucocorticoid effects on airway epithelial recovery after chemical aggression.

Animals↗