Biomedical subjects

H W Mitchell

Publications and source records attributed to H W Mitchell.

At least 19 recordsLinked to original sources

PubMed2006

Delayed and persistent suppression of bronchoconstriction by trypsin in the airway lumen.

Mucosal trypsin, a protease-activated receptor (PAR) stimulant, may have an endogenous bronchoprotective role on airway smooth muscle. To test this possibility the effects of lumenal trypsin on airway tone in segments of pig bronchus were tested. Bronchial segments from pigs were mounted in an organ chamber containing Kreb's solution. Contractions were assessed from isovolumetric lumen pressure induced by acetylcholine (ACh) or carbachol added to the adventitia. Trypsin, added to the airway lumen (300 microg x mL(-1)), had no immediate effect on smooth muscle tone but suppressed ACh-induced contractions after 60 min, for at least 3 h. Synthetic activating peptides (AP) for PAR1, PAR2 or PAR3 were without effect, but PAR4 AP caused rapid, weak suppression of contractions. Lumenal thrombin was without effect and did not prevent the effects of trypsin. Effects of trypsin were reduced by N(omega)-nitro-L-arginine methyl ester but not indomethacin. Trypsin, thrombin and PAR4 AP released prostaglandin E2. Adventitially, trypsin, thrombin and PAR4 AP (but not PAR2 AP) relaxed carbachol-toned airways after <3 min. The findings of this study show that trypsin causes delayed and persistent bronchoprotection by interacting with airway cells accessible from the lumen. The signalling mechanism may involve nitric oxide synthase but not prostanoids or protease-activated receptors.

Analysis of Variance↗

PubMed2005

Elastic properties of the bronchial mucosa: epithelial unfolding and stretch in response to airway inflation.

The bronchial mucosa contributes to elastic properties of the airway wall and may influence the degree of airway expansion during lung inflation. In the deflated lung, folds in the epithelium and associated basement membrane progressively unfold on inflation. Whether the epithelium and basement membrane also distend on lung inflation at physiological pressures is uncertain. We assessed mucosal distensibility from strain-stress curves in mucosal strips and related this to epithelial length and folding. Mucosal strips were prepared from pig bronchi and cycled stepwise from a strain of 0 (their in situ length at 0 transmural pressure) to a strain of 0.5 (50% increase in length). Mucosal stress and epithelial length in situ were calculated from morphometric data in bronchial segments fixed at 5 and 25 cmH(2)O luminal pressure. Mucosal strips showed nonlinear strain-stress properties, but regions at high and low stress were close to linear. Stresses calculated in bronchial segments at 5 and 25 cmH(2)O fell in the low-stress region of the strain-stress curve. The epithelium of mucosal strips was deeply folded at low strains (0-0.15), which in bronchial segments equated to < or =10 cmH(2)O transmural pressure. Morphometric measurements in mucosal strips at greater strains (0.3-0.4) indicated that epithelial length increased by approximately 10%. Measurements in bronchial segments indicated that epithelial length increased approximately 25% between 5 and 25 cmH(2)O. Our findings suggest that, at airway pressures <10 cmH(2)O, airway expansion is due primarily to epithelial unfolding but at higher pressures the epithelium also distends.

Animals↗

PubMed2005

Airway narrowing in porcine bronchi with and without lung parenchyma.

During bronchoconstriction elastic after-loads arise due to distortion of lung parenchyma by the narrowing airway. In the present study, the functional effect of parenchymal elastic after-load on airway narrowing was determined. Airway narrowing was measured in vivo over a range of transpulmonary pressures and compared with in vitro narrowing measured at corresponding transmural pressures. Bronchi were generation 10 with internal diameters of approximately 4 mm. In vivo luminal narrowing was measured by videobronchoscopy in anaesthetised and ventilated pigs. In vitro luminal narrowing was measured by videoendoscopy in isolated bronchial segments. Airways were activated by maximum vagal nerve stimulation and maximum electrical field stimulation in vivo and in vitro, respectively. At 5 cmH2O, stimulation produced a 35.9+/-3.2% (n = 6) and a 36.5+/-2.4% (n = 11) decrease in lumen diameter in vivo and in vitro, respectively. At 30 cmH2O, luminal narrowing fell to 23.7+/-2.0% in vivo and 23.4+/-2.5% in vitro. There was no difference between luminal narrowing in vivo and in vitro at any pressure. In conclusion, these findings suggest that in mid-sized, cartilaginous bronchi, parenchymal elastic after-loads do not restrict airway narrowing.

Airway Resistance↗

PubMed2004

Cyclical elongation regulates contractile responses of isolated airways.

Bronchoconstrictor responses are quantitatively different when they are evoked under static conditions and during or after periods of deep inspiration. In vivo, deep inspirations produce bronchodilation and protect the lung from subsequent bronchoconstriction (termed bronchoprotection). These effects may be due in part to dynamic stretch on airways produced by cyclical expansion of airway diameter. However, airways also lengthen cyclically during breathing. The effects of cyclical airway elongation on evoked bronchoconstriction have not been examined. This study recorded evoked contractions of pig bronchial segments 1) at different airway lengths, 2) after a period of cyclical lengthening in relaxed airways, and 3) during cyclical lengthening in pretoned airways. Airway segments were mounted in organ baths and bathed in Krebs solution luminally and on the adventitia. Airways were cyclically lengthened by 5-30% of their deflated length at 0.5-2 Hz for 5 min. Contractions were evoked by electrical field stimulation or carbachol and were recorded under isovolumic conditions. Under static conditions, there was a blunt relationship between length and response to electrical field stimulation. After a period of airway length cycling, electrical field stimulation-induced contractions were increased. In airways pretoned with carbachol, cyclical lengthening produced a transient bronchodilation and a sustained increase in contraction. Contractile responses were not blocked by indomethacin. The results show that isolated airways respond actively to dynamic changes in length. Our results indicate that cyclical lengthening of airways could contribute to lung function in vivo but does not appear to account for the phenomenon of bronchoprotection.

Animals↗

PubMed2004

Cholinergic responsiveness of the individual airway after allergen instillation in sensitised pigs.

Allergen exposure of sensitised lungs produces bronchial hyperresponsiveness in vivo associated with airway inflammation and remodelling. It is unclear if hyperresponsiveness is also present in airways in vitro under similar conditions of drug provocation as carried out in vivo, and at different times after allergen-challenge. This study records responsiveness of individual airway segments to acetylcholine (ACh) in sensitised bronchi after instillation of allergen (ovalbumin, OA). Airway histology and sensitivity and maximum effects to ACh were recorded 1, 24 and 72 h and 1 week after OA. OA-instilled airways exhibited eosinophilia and epithelial proliferation. Physiological recordings showed no change in maximum contractions of airway segments to acetylcholine placed in the airway lumen except at 24 h where they were reduced. In contrast maximum contractions to ACh to the airway adventitia were reduced at all times except 1 week, with the greatest change occurring at 24 h. There were no changes in airway sensitivity to either route of ACh in OA-instilled airways but the difference in sensitivity to adventitial and lumenal ACh was reduced. Results show that allergen does not produce hyperresponsiveness at the airway wall but it may alter an interaction between airway smooth muscle and other structural components of the airway.

Acetylcholine↗

PubMed2003

Intraluminal pressure oscillation enhances subsequent airway contraction in isolated bronchial segments.

A period of deep inspiration in humans has been shown to attenuate subsequent bronchoconstriction, a phenomenon termed bronchoprotection. The bronchoprotective effect of deep inspiration may be caused though a depression in the force production of airway smooth muscle (ASM). We determined the response of whole airway segments and isolated ASM to a period of cyclic stretches. Isovolumetric contraction to electrical field stimulation (EFS) was assessed in porcine bronchial segments before and after intraluminal pressure oscillation from 5 to 25 cmH(2)O for 10 min at 0.5 Hz. Morphometry showed that this pressure oscillation stretched ASM length by 21%. After pressure oscillation, the response to EFS was not reduced but instead was modestly enhanced (P < 0.01). Airway responses to EFS returned to preoscillation levels 10 min after the end of oscillation. The increase in EFS response after pressure oscillation was not altered by the addition of indomethacin. In a separate experiment, we assessed isometric force in isolated ASM strips before and after length oscillation. The amplitude, frequency, and duration of length oscillation were similar to those induced in bronchial segments. In contrast to bronchial segments, length oscillation of ASM produced a significant depression in isometric force induced by EFS (P < 0.01). These results suggest that the response of ASM to length oscillation is modified by the airway wall. They also suggest that the phenomenon of bronchoprotection reported in some in vivo studies may not be an intrinsic property of the airway.

Animals↗

PubMed2002

Relationship of airway narrowing, compliance, and cartilage in isolated bronchial segments.

Structural components of the airway wall may act to load airway smooth muscle and restrict airway narrowing. In this study, the effect of load on airway narrowing was investigated in pig isolated bronchial segments. In some bronchi, pieces of cartilage were removed by careful dissection. Airway narrowing was produced by maximum electrical field stimulation. An endoscope was used to record lumen narrowing. The compliance of the bronchial segments was determined from the cross-sectional area of the lumen and the transmural pressure. Airway narrowing and the velocity of airway narrowing were increased in cartilage-removed airways compared with intact control bronchi. Morphometric assessment of smooth muscle length showed greater muscle shortening to acetylcholine in cartilage-removed airways than in controls. Airway narrowing was positively correlated with airway compliance. Compliance and area of cartilage were negatively correlated. These results show that airway narrowing is increased in compliant airways and that cartilage significantly loads airway smooth muscle in whole bronchi.

Acetylcholine↗

PubMed2001

Relationship of airway responsiveness with airway morphometry in normal and immunized rabbits.

Airway responses to chemical stimuli occur over a wide range of concentrations, with overlap between severe, moderate and mild asthmatic groups and with normal healthy individuals. Mathematical modelling has suggested that relative thickness of the airway wall may account for this range of responsiveness. We have investigated whether in vivo airway responsiveness varies as a function of airway wall thickness in terms of airway smooth muscle area in normal and immunized New Zealand White (NZW) rabbits. Airway responsiveness to inhaled methacholine (MCh) was determined in vivo under neuroleptanalgesia. Subsequently, ex vivo responsiveness to MCh (pD(2)=-log EC(50)) of isolated bronchi from the same animal was established. Smooth muscle area per mm basement membrane (SM/mmBM) was also measured morphometrically in the tested bronchi and the findings related to in vivo and ex vivo responsiveness. We found no relationship between airway responsiveness in vivo and pD(2)values in either immunized or control rabbits. In both control and immunized rabbits, no correlation was found between SM/mmBM and in vivo airway responsiveness. Only in immunized animals with a PCA titre >0, was there a significant correlation (=-0.5986, P<0.05) between SM/mmBM and pD(2). We conclude that airway smooth muscle area per se is not the sole contributor of airway responsiveness in vivo in normal rabbits.

Animals↗

PubMed2001

Physiological responses of the airway wall and lung in hyperresponsive pigs.

Airway hyperresponsiveness (AHR) might be driven by mechanisms inherent to the airway wall, and/or by factors arising from outside the airways. A porcine model of allergen-induced AHR was utilized to investigate physiological responses in intact airways in vitro and their contribution to responsiveness in vivo. Responsiveness to acetylcholine (ACh) was measured in eight ovalbumin (OA)-sensitized/challenged pigs (tests) and eight saline-challenged controls. In vivo responsiveness to ACh was determined from pulmonary resistance (RL). In vitro responsiveness to ACh was determined from airway pressure in isovolumic bronchial segments, after exposure via the adventitial or the luminal surface. Test pigs had lung (255+/-26% increase in RL, p<0.0001) and skin responses to OA, and AHR to ACh (p<0.0001). In vitro, test bronchi were less sensitive than controls to ACh applied to the airway adventitia (negative log of the ACh concentration producing half the maximum response (pD2)=4.18 and 4.58 respectively, p<0.01), but not the lumen. Test bronchi had an increased amount of smooth muscle normalized for airway size versus controls (p<0.05). Maximum responses to lumenal ACh in vitro showed a weak positive correlation with maximum changes to ACh in vivo (r=0.599, p=0.05). This study concludes that the effect of antigen challenge on bronchial responsiveness varies with the route of exposure to acetylcholine. In vitro responses to lumenal acetylcholine are increased despite a possible reduction in responsiveness of airway smooth muscle. Responsiveness of the bronchial wall only partially explains responsiveness of the lungs in vivo.

Acetylcholine↗

PubMed1999

Assessment of the dynamic relationship between external diameter and lumen flow in isolated bronchi.

Histologic studies of large airways suggest that outer airway wall area increases during bronchoconstriction, which could influence the relationship between external diameter and lumen flow. Using isolated bronchi from pigs we simultaneously recorded external diameter using sonomicrometry, and lumen flow of liquid using an electromagnetic flowmeter to determine the relationship between the two. External diameter fell from 4.13+/-0.19 to 3.65+/-0.19 mm (11+/-3%, n = 5) during maximal electrical field stimulation (EFS), and flow decreased by 67+/-9%. External diameter plotted against lumen flow showed hysteresis between contraction and relaxation. External narrowing ceased towards the end of a stimulation period, but flow continued to decrease. This differed from predictions based on an assumption that the wall area does not change during contraction. Histologic sections of bronchi fixed after acetylcholine (ACh) challenge showed an increase in total wall area. These results illustrate dynamic wall movement during bronchoconstriction induced by EFS or acetylcholine.

Acetylcholine↗

PubMed1999

Pulmonary inflammation without bronchial hyperresponsiveness in vivo or in vitro after sephadex instillation in pigs.

1. In rodent models, Sephadex produces pulmonary inflammation that may be associated with bronchial hyperresponsiveness. In the present study we examined whether Sephadex-induced inflammation altered airway narrowing in pigs. 2. Twenty millilitres of 10 mg/mL Sephadex suspension was instilled twice intratracheally into anaesthetized pigs (days 1 and 7 of a 9 day study). In vivo bronchial responsiveness was assessed from the effect of acetylcholine (ACh) aerosol on airways resistance and dynamic compliance before Sephadex instillation and on days 3, 5 and 9. Lung histology and in vitro bronchial responsiveness was assessed on day 9. In vitro responsiveness was assessed by measuring the reduction in flow through perfused 2 mm i.d. bronchial segments in response to ACh applied luminally and adventitially. 3. Sephadex produced a focal peribronchial granulomatous reaction characterized by the presence of macrophages, eosinophils, neutrophils and giant cells. Changes in airway resistance and lung compliance in response to ACh did not change over the study period. The response of perfused bronchial segments to luminally or adventitially applied ACh was also unaltered. 4. Sephadex-induced pulmonary inflammation does not alter airway narrowing in vitro nor bronchial hyperresponsiveness in vivo in the pig.

Animals↗

PubMed1999

Compliance and stability of the bronchial wall in a model of allergen-induced lung inflammation.

Airway wall remodeling in response to inflammation might alter load on airway smooth muscle and/or change airway wall stability. We therefore determined airway wall compliance and closing pressures in an animal model. Weanling pigs were sensitized to ovalbumin (OVA; ip and sc, n = 6) and were subsequently challenged three times with OVA aerosol. Control pigs received 0.9% NaCl (n = 4) in place of OVA aerosol. Bronchoconstriction in vivo was assessed from lung resistance and dynamic compliance. Semistatic airway compliance was recorded ex vivo in isolated segments of bronchus, after the final OVA aerosol or 0.9% NaCl challenge. Internally or externally applied pressure needed to close bronchial segments was determined in the absence or presence of carbachol (1 microM). Sensitized pig lungs exhibited immediate bronchoconstriction to OVA aerosol and also peribronchial accumulations of monocytes and granulocytes. Compliance was reduced in sensitized bronchi in vitro (P < 0.01), and closing pressures were increased (P < 0.05). In the presence of carbachol, closing pressures of control and sensitized bronchi were not different. We conclude that sensitization and/or inflammation increases airway load and airway stability.

Air Pressure↗

PubMed1998

Transition of functional innervation in the developing porcine airway from nitrergic to catecholaminergic.

1. We determined the distribution and chemical nature of the inhibitory neurotransmitter(s) to the airway smooth muscle (ASM) before and after birth. 2. Relaxation responses to electrical field stimulation (EFS) were studied in isovolumic bronchial segments from foetal (approximately 100/115 days gestation) and adult (25 kg) pigs, and in isovolumic tracheal segments from the foetus, and tracheal smooth muscle strips from the adult pig. Preparations were conditioned in low doses of atropine (10(-7) M) to reduce the effects of excitatory neurotransmission and then exposed to carbachol to produce submaximal muscle tone. Some studies were also carried out on bronchial segments from 4 week old pigs. 3. EFS (65 V, 2 ms, 5-20 Hz for 5 s) produced a TTX-sensitive relaxation in epithelium-intact and epithelium-denuded preparations. In foetal bronchial and tracheal preparations, EFS-induced relaxation was strongly inhibited by N(G)-nitro-L-arginine (L-NOARG, 10(-6) to 10(-4) M; P<0.01-0.001). However, in the adult, only relaxations of the trachea were inhibited by L-NOARG; bronchi were resistant to L-NOARG and also to N-nitro-L-arginine methyl ester (L-NAME, 10(-4) M). The inhibitory actions of L-NOARG (10(-6) to 10(-4) M) were substantially reversed by 10(-2) M L-arginine. Experiments with bronchial segments from 4 week old pigs showed partial inhibition of relaxations by L-NOARG. 4. The L-NOARG-insensitive relaxations recorded in the adult bronchus were blocked by propranolol (10(-6) M). 5. The onset of relaxation to EFS was more prompt and the rate of relaxation more rapid in foetal bronchi than in adult bronchi (P<0.0005). Maximum relaxation and recovery times were the same. 6. Foetal and adult bronchi were relaxed by sodium nitroprusside (SNP) with similar sensitivity and maximum effect. The rate of relaxation to SNP was not different in the two ages. 7. In the absence of atropine and carbachol, excitatory cholinergic responses to EFS (65 V, 2 ms, 5 Hz for 20 s) were not altered by L-NOARG (10(-4) M) or L-NAME (10(-4) M) in the adult bronchus but were modestly increased by L-NOARG in the foetal bronchus (P<0.01). 8. The tracheobronchial tree appears functionally innervated by nitrergic input to the smooth muscle before birth. However, at or after 4 weeks of age the inhibitory neural input to the bronchi is catecholaminergic, but it remains nitrergic in the trachea. There is also a weak nitrergic pre- or postsynaptic inhibition of the effects of cholinergic neurotransmission in the foetal bronchus but not in the adult.

Animals↗

PubMed1998

Concurrent measurement of smooth muscle shortening, lumen narrowing and flow to acetylcholine in large and small porcine bronchi.

Models of airway function indicate that responsiveness (flow reduction) to bronchoconstrictor provocation depends on airway smooth muscle shortening and airway wall morphology. The contribution of these factors to the responsiveness of central and peripheral bronchi was assessed. Lumen flow was recorded in porcine perfused small (2 min i.d.) and large bronchial segments (6 mm i.d.). Lumen diameter was recorded in the same airways after inserting an endoscope. Smooth muscle shortening, relative wall area (WAr), smooth muscle and cartilage thickness and mucosal folds were measured morphometrically. The effect of acetylcholine (ACh; 10(-6)-10(-1) M) on functional measurements was determined by curve fitting. Maximum muscle shortening was 30% in small and 19% in large bronchi (p<0.01) and lumen narrowing was 49% and 39%, respectively. High doses of ACh stopped flow in small bronchi, but produced a plateau in large bronchi. Small airways were 250-times more sensitive to ACh than large airways, for all measurements. Smooth muscle and cartilage thickness and numbers of mucosal folds were greater in large than in small bronchi (p< or =0.01). Lumen narrowing and flow reduction were greater than predicted on the basis of muscle shortening and WAr (p<0.05). The structure of airways from the two groups was qualitatively similar, but responses were markedly different. Greater narrowing and flow responses of small bronchi were directly associated with smooth muscle responsiveness in situ. The results suggest that in vivo changes in airway wall shape or dimensions, or luminal secretions, exert a significant effect on airway flow, particularly in the small airways.

Acetylcholine↗

PubMed1997

Bronchial compliance and wall structure during development of the immature human and pig lung.

Maturational changes in the specific compliance could potentially contribute to the development or clinical presentation of respiratory diseases in infants and children. Changes in the specific compliance during development and its structural basis have been well characterized, but changes in bronchial compliance and the mechanisms involved have received little attention. Semistatic pressure-volume curves were generated for isolated bronchial segments from late-term foetal, immature and adult pigs. A small number of bronchi from human infants were also studied. The amount of cartilage in the bronchial wall of pigs of different ages was measured histologically, and morphometric changes in the wall of inflated bronchi were investigated. The specific compliance of bronchi approximately halved from 1 to 4 weeks of age. No change in specific compliance was observed either between 4 week old and adult pigs, or between late-term foetal and 1 week old pigs. Changes in the total wall and cartilage areas did not correlate with changes in specific compliance. Inflation to 20 cmH2O transmural pressure reduced the total wall area of bronchi from 1 week old pigs. Significant changes in bronchial distensibility occur during the early postnatal period. These changes in specific compliance are not caused by an increase in the amount of cartilage. The increase in luminal volume during inflation of bronchial segments occurs, partially, by compression of the airway wall against the cartilage layer.

Age Factors↗

PubMed1997

Effect of transmural pressure on preloads and collapse of immature bronchi.

Immature airways are highly compliant compared to the adult, suggesting that trachea and bronchi from immature animals may be easily compressed. Although tracheal compression has been extensively studied, the effect of transmural pressure on occlusion of immature bronchi has been neglected. The transmural pressure at which the lumen closed was determined from the transmittance of pressure along the lumen of isolated bronchi from late-term foetal, 1 and 4 week old pigs. Bronchi from eight cases of sudden infant death syndrome (SIDS) were also studied. In several experiments, smooth muscle tone was produced either by electrical field stimulation or carbachol challenge, and the relationship between active muscle tone and resting transmural pressure was studied. Bronchi from foetal, 1 and 4 week old pigs were occluded by intraluminal pressures of -4, -5 and -24 cmH2O. SIDS bronchi closed at -11 cmH2O. Histological and endoscopic investigations showed that closure of the bronchi occurred along a plane and was not uniform along the bronchus. Carbachol precontraction increased the transmural pressure required to close bronchi by approximately 5 cmH2O. The relationship between muscle tone and resting pressure was the same in all age groups, except when transmural pressure was at or below closing pressure. Bronchi from immature animals and human infants are vulnerable to collapse by small changes in transmural pressure. Bronchial closure is partly dependent on smooth muscle tone, particularly in younger animals.

Aging↗

PubMed1996

Uncoupling in the wall of the cartilaginous bronchus of the pig produced by smooth muscle contraction.

Studies in small non-cartilaginous airways suggest that the cross sectional area of the airway wall (comprising the smooth muscle and mucosa) is unaltered during the contraction-relaxation cycle produced by bronchial provocation. In the present study we examined whether the wall area of large cartilaginous bronchi remained constant during bronchoconstriction produced by acetylcholine (ACh, 10(-4)-10(-2)M), and if not the effect of this on the narrowing of the bronchial lumen. Narrowing of the lumen and adventitia of bronchial segments, 3.6 mm id from pigs, was simultaneously recorded using endoscopy and video imaging of the airway lumen. Concurrently, the shortening of the smooth muscle was estimated morphometrically from the same bronchi fixed during muscle contraction. In individual bronchi, ACh produced from 5 to 60% shortening of the smooth muscle, which caused up to 64% narrowing of the bronchial lumen, but only approximately 10% narrowing of the adventitia. Lumen narrowing was greater than predicted. Morphological assessment showed a doubling of the area between the smooth muscle and the cartilage, in response to maximum smooth muscle contraction by ACh. In contrast the area of the smooth muscle and mucosa did not change. Similar changes in bronchial morphology were produced in whole lung slices, incubated in ACh or histamine. We conclude that the inner airway wall uncouples from the outer wall during muscle contraction and that this increases the narrowing of the airway lumen relative to the adventitia.

Acetylcholine↗

PubMed1996

Intramural elastase injection increases responsiveness of isolated bronchial segments.

In cartilaginous bronchi, the smooth muscle is attached to the adventitial cartilage by a fibro-elastic matrix. In pigs, this matrix is stretched during muscle contraction so the inner airway wall reversibly uncouples from the outer wall. We hypothesized that inflammatory cell derived proteases may degrade this fibro-elastic matrix, increasing airway responsiveness. Airway responsiveness was determined from the sensitivity of perfused 2.0-3.5 mm id porcine bronchial segments to acetylcholine (ACh 10(-6)-10(-2)M) and from airway lumen narrowing imaged directly using a fibre-optic endoscope and video camera. Elastase (3 microliters, 1% solution) injected between the cartilage and the smooth muscle doubled sensitivity to ACh (P < 0.001) in perfused segments. Maximal airway narrowing to 10(-2) ACh was also increased from 54% to 60% (P < 0.05). Smooth muscle contraction, recorded isometrically, was not increased by elastase. We conclude that proteases may increase airway wall uncoupling in vitro, possibly by reducing the wall load, and thereby increasing responsiveness.

Acetylcholine↗