Index Of Bronchoconstriction Research Articles

Role of prostaglandin E2 in bronchoconstriction-triggered cough response in guinea pigs

A feature of cough variant asthma is a heightened cough response to bronchoconstriction. The mediators of this response are unknown. This study was designed to elucidate the role of lipid mediators in bronchoconstriction-triggered cough response in an experimental animal model.We examined the influence of bronchoconstriction on cell components and mediators including prostaglandin E2 (PGE2) in bronchoalveolar lavage fluid (BALF). We studied the cough response to bronchoconstriction (CRB) by measuring the correlation between the increase in enhanced pause (Penh), an index of bronchoconstriction, and cough counts induced by methacholine (Mch) inhalation in conscious guinea pigs. We then examined the effects of intraperitoneal pretreatment with 16, 16-dimethyl-prostaglandin E2 (dm-PGE2) on CRB and cough counts.The total number of cells and cell components in the BALF were not influenced by bronchoconstriction. While levels of PGE2, prostaglandin I2, and cysteinyl leukotrienes were significantly increased, levels of prostaglandin D2, thromboxane B2, and substance P in the BALF were not. Dm-PGE2 significantly decreased the Mch-induced increase in Penh. Following bronchoconstriction by additional Mch inhalation, dm-PGE2 produced an increase in CRB and cough counts in a dose-dependent manner. Additionally, the heightened CRB following dm-PGE2 treatment was suppressed by pretreatment with PGE2 receptor (E-prostanoid EP) -1 and EP-3 antagonists in a dose-dependent manner, but not by EP-2 and EP-4 antagonists. The EP-1 antagonist also decreased cough counts.These results suggest that PGE2 acts as an exacerbating factor for bronchoconstriction-triggered cough. EP1 and EP3 may provide new therapeutic targets for cough variant asthma.

BRONCHOCONSTRICTION-TRIGGERED COUGH IN CONSCIOUS GUINEA PIGS

The aim of the present study was to investigate the relation between bronchoconstriction and cough induced by methacholine (Mch) inhalation and to elucidate the role of C-fibers and rapidly adapting irritant receptors (RARs) in these reactions in conscious guinea pigs. The authors measured enhanced pause (Penh) as an index of bronchoconstriction and also measured the number of coughs induced by Mch inhalation in conscious guinea pigs. The authors also examined the effects of pretreatment with procaterol, capsaicin desensitization and moguisteine on these responses. There was a significant positive correlation between the increase in Penh and the number of coughs induced by Mch inhalation. Procaterol (0.1 mg/kg, intraperitoneal [i.p.]) completely abolished both the Mch-induced increase in Penh and cough. Capsaicin desensitization had no effect on Penh or the number of coughs. Moguisteine (0.02, 0.2, or 2 mg/kg, i.p.) dose-dependently inhibited the number of coughs but not the increase in Penh induced by Mch inhalation. Bronchoconstriction causes cough via RARs, but not C-fibers. Neither RARs nor C-fibers are involved in Mch-induced bronchoconstriction itself.

Effects of inhaled monoethanolamine on bronchoconstriction

We previously reported a 65-year-old man who aspirated an alkaline detergent containing 3.3% w/v (weight of solute per volume of solution) monoethanolamine (MEA) into his lungs, causing asthma-like symptoms. We presently describe the mechanism of MEA-induced bronchoconstriction according to findings in guinea pigs. In anesthetized, artificially ventilated animals, changes in airway opening pressure (P(ao)) were measured as an index of bronchoconstriction. An aerosol of 3.3% MEA solution (0.1 ml kg(-1)) inhaled through a tracheal cannula induced significantly stronger bronchoconstriction than an aerosol of potassium hydroxide (KOH) solution (0.1 ml kg(-1)) at the same pH. MEA-induced bronchoconstriction was significantly suppressed by premedication with intravenously injected atropine sulfate (3 mg kg(-1)), a muscarinic receptor antagonist, or diphenhydramine hydrochloride (10 mg kg(-1)), a histamine-H(1) receptor antagonist. MEA-induced bronchoconstriction was not enhanced by premedication with an intravenous injection of neostigmine (0.1 mg kg(-1)), an acetylcholinesterase inhibitor. When bronchoconstriction was induced by MEA, histamine concentrations in bronchoalveolar lavage fluid (BALF) were not significantly greater than in BALF after KOH-induced bronchoconstriction or in BALF after inhalation of physiologic saline. In vitro, contraction of trachea denuded of epithelium during superfusion with MEA (10 mm) was suppressed by premedication with pyrilamine maleate, a histamine-H(1) receptor antagonist, at 10 and 100 microm. Contraction of trachea denuded of epithelium during superfusion with MEA (10 mm) was suppressed by premedication with atropine sulfate at 10 and 100 microm. These results suggest that asthma-like symptoms may result partly from agonistic MEA effects at histamine-H(1) receptors and muscarinic receptors.

Functional, inflammatory and morphological characterisation of a cat model of allergic airway inflammation

The aims of this study were to characterise a model of feline allergic airway inflammation and to test through a longitudinal investigation whether five repeated allergen exposures would lead to signs of airway remodelling that would be detectable in vivo. Eight healthy control cats and eight cats sensitised with Ascaris suum allergens were investigated. Barometric whole body plethysmography (BWBP) was used for the assessment of respiratory variables and airway responsiveness (AR). Bronchoalveolar lavage fluid (BALF) was sampled for cytology and determination of F2-isoprostane concentration and matrix metalloproteinase type 9 (MMP-9) activity. Thoracic radiography and bronchoscopy scores were also established. Cats were investigated prior to sensitisation and after inhalation of placebo or allergen challenge 1.BWBP measurements revealed a significant increase of enhanced pause (Penh), an index of bronchoconstriction, and AR in sensitised cats in response to allergen challenge 1. A significant increase in BALF neutrophil and eosinophil %, F2-isoprostane concentration and MMP-9 activity, and increased radiography and bronchoscopy scores were recorded. After a recovery period of 6weeks, all variables except BALF MMP-9 returned to baseline values. Four further allergen challenges induced similar changes to those seen in challenge 1 and no signs of persistent changes suggestive of bronchial remodelling were detectable. The model provides an in vivo approach to functional, inflammatory and morphological changes occurring in response to single and repeated allergen exposure.

Inhaled fluticasone reduces bronchial responsiveness and airway inflammation in cats with mild chronic bronchitis

This study investigated the effect of inhaled fluticasone on lower airway inflammation and bronchial responsiveness (BR) to inhaled carbachol in cats with very mild, chronic bronchitis (n = 5) that were compared with healthy cats serving as controls (n = 6). Chest radiographs, BR tests performed non-invasively by barometric whole body plethysmography (BWBP) and bronchoalveolar lavage (BAL) were performed before and after treatment. BR was quantified by calculating the concentration of carbachol inducing bronchoconstriction (C-Penh300%), defined as a 300% increase of baseline Penh, an index of bronchoconstriction obtained by BWBP. BAL fluid was analyzed cytologically and the oxidant marker 8-iso-PGF2alpha was determined. At test 1, healthy cats and cats with bronchitis were untreated, whereas for test 2 inhalant fluticasone (250 microg once daily) was administrated for 2 consecutive weeks to cats with bronchitis. Control cats remained untreated. Inhaled fluticasone induced a significant increase in C-Penh300% and a significant decrease of BAL fluid total cells, macrophages, neutrophils and 8-iso-PGF2alpha in cats with bronchitis, whilst untreated control cats did not show significant changes over time. This study shows that a 2-week fluticasone treatment significantly reduced lower airway inflammation in very mild bronchitis. BR could be successfully monitored in cats using BWPB and decreased significantly in response to inhaled fluticasone. 8-Iso-PGF2alpha in BAL fluid was responsive to treatment and appeared as a sensitive biomarker of lower airway inflammation in cats.

Evaluation of respiratory function by barometric whole-body plethysmography in healthy dogs

The objective of the present study was to assess the validity of barometric whole-body plethysmography (BWBP), to establish reference values, and to standardise a bronchoprovocative test to investigate airway responsiveness using BWBP in healthy dogs. BWBP measurements were obtained from six healthy beagle dogs using different protocols: (1) during three consecutive periods (3.5 min each) in two morning and two evening sessions; (2) before and after administration of two protocols of sedation; (3) before and after nebulisation of saline and increasing concentrations of carbachol and histamine both in conscious dogs and in dogs under both protocols of sedation. Enhanced pause (PENH) was used as index of bronchoconstriction. Basal BWBP measurements were also obtained in 22 healthy dogs of different breeds, age and weight. No significant influence of either time spent in the chamber or daytime was found for most respiratory variables but a significant dog effect was detected for most variables. A significant body weight effect was found on tidal volume and peak flow values ( P < 0.05). Response to carbachol was not reproducible and always associated with side effects. Nebulisation of histamine induced a significant increase in respiratory rate, peak expiratory flow, peak expiratory flow/peak inspiratory flow ratio and PENH ( P < 0.05). The response was reproduced in each dog at different concentrations of histamine. Sedation with acepromazine + buprenorphine had little influence on basal measurements and did not change the results of histamine challenge. It was concluded that BWBP is a safe, non invasive and reliable technique of investigation of lung function in dogs which provides new opportunities to characterise respiratory status, to evaluate airway hyperresponsiveness and to assess therapeutic interventions.

IMPORTANCE OF THE ANGIOTENSIN TYPE 1 RECEPTOR IN ANGIOTENSIN II–INDUCED BRONCHOCONSTRICTION AND BRONCHIAL HYPERRESPONSIVENESS IN THE GUINEA PIG

Although angiotensin II (Ang II) causes bronchoconstriction and bronchial hyperresponsiveness to methacholine in mildly asthmatic patients, the responsible mechanisms for these reactions are unclear. The authors examined the effect of intravenous infusion of Ang II on airway constriction in guinea pigs. Furthermore, the effects of subthreshold concentrations of Ang II on bronchial responsiveness to methacholine were investigated. Airway opening pressure (Pao), an index of bronchoconstriction, increased dose dependently after intravenous infusion of 3 and 10 nmol/kg Ang II (72.2 and 236.5 increase above the baseline value, respectively). In another set of experiments, animals received a methacholine inhalation challenge under a constant intravenous infusion of a subthreshold dose of Ang II (2 nmol/kg/min). The Ang II infusion elicited bronchial hyperresponsiveness to methacholine. The provocative concentration of methacholine, which produced a 200% increase above the baseline Pao (PC200), decreased from 306.9 to 156.1 μg/mL upon Ang II infusion. Pretreatment with TCV-116, a type 1 Ang II (AT1) receptor antagonist, but not PD123319, a type 2 Ang II (AT2) receptor antagonist, dose dependently prevented both the Ang II–induced bronchoconstriction and bronchial hyperresponsiveness to methacholine. The authors conclude that Ang II caused bronchoconstriction and induced bronchial hyperresponsiveness to methacholine via the AT1 receptors and that this effect did not involve the release of other bronchoactive mediators.

A reevaluation of the validity of unrestrained plethysmography in mice.

Presently, unrestrained plethysmography is widely used to assess bronchial responsiveness in mice. An empirical quantity known as enhanced pause is derived from the plethysmographic box pressure [P(b)(t), where t is time] and assumed to be an index of bronchoconstriction. We show that P(b)(t) is determined largely by gas conditioning when normal mice breathe spontaneously inside a closed chamber in which the air is at ambient conditions. When the air in the chamber is heated and humidified to body conditions, the changes in P(b)(t) are reduced by about two-thirds. The remaining changes are thus due to gas compression and expansion within the lung and are amplified when the animals breathe through increased resistances. We show that the time integral of P(b)(t) over inspiration is accurately predicted by a term containing airway resistance, functional residual capacity, and tidal volume. We conclude that unrestrained plethysmography can be used to accurately characterize changes in airway resistance only if functional residual capacity and tidal volume are measured independently and the chamber gas is preconditioned to body temperature and humidity.

Noninvasive measurement of midexpiratory flow indicates bronchoconstriction in allergic rats

This study was designed to evaluate the value and applicability of tidal breathing pattern analysis to assess bronchoconstriction in conscious rats. Using noninvasive, head-out body plethysmography and the decrease in tidal midexpiratory flow (EF(50)), we measured airway responsiveness (AR) to inhaled acetylcholine and allergen in conscious Brown-Norway rats, followed by invasive determination of pulmonary conductance (GL) and EF(50) in anesthetized rats. Dose-response studies to acetylcholine showed that noninvasively recorded EF(50) closely reflected the dose-dependent decreases observed with the invasive monitoring of simultaneously measured GL and EF(50). After sensitization and intratracheal boost to ovalbumin or saline, rats were assessed for early and late AR to aerosolized ovalbumin. Ovalbumin aerosol challenge resulted in early and late AR in allergen-sensitized rats, whereas controls were unresponsive. The allergen-specific AR, as measured noninvasively by EF(50), was similar in degree compared with invasively recorded EF(50) and GL and was associated with enhanced IgE and airway inflammation. We conclude that EF(50) is a noninvasive and physiologically valid index of bronchoconstriction in a rat model of asthma.

Effect of neutral endopeptidase inhibitor on bradykinin-induced bronchoconstriction

To evaluate whether neutral endopeptidase (NEP) inhibitors have adverse respiratory effects, the influence of a NEP inhibitor on bradykinin (BK)-induced bronchoconstriction was investigated. In anesthetized and artificially ventilated guinea pigs, changes in airway opening pressure (Pao) were measured as an index of bronchoconstriction. An infusion of phosphoramidon (3 mg kg −1 h −1), a NEP inhibitor, significantly enhanced the bronchoconstriction induced by high-dose BK (30 nmol kg −1, i.v.). Capsaicin (0.1 mg kg −1, i.v.) and SR48968 (0.3 mg kg −1, i.v.), an NK2 receptor antagonist, significantly inhibited the phosphoramidon-induced enhancement of BK-induced bronchoconstriction, although FK888 (3 mg kg −1, i.v.), an NK1 receptor antagonist, did not. Both neurokinin A (NKA) (0.1–3 nmol kg −1, i.v.) and substance P (SP) (0.1–3 nmol kg −1, i.v.) induced dose-dependent bronchoconstriction which was enhanced by phosphoramidon infusion, although these enhancements were more prominent in the NKA series. Phosphoramidon partially inhibited BK degradation in lung homogenate, and both NKA and SP degradation in the lung homogenate were significantly suppressed by phosphoramidon. In bronchoalveolar lavage fluid (BALF), levels of NKA and SP were significantly elevated after a bolus of BK with a phosphoramidon infusion. These results suggest that NEP inhibitors may have adverse respiratory effects resulting from inhibition of the degradation of neurokinins, but mainly of NKA, when a large amount of BK is generated.

Links between multiple chemical sensitivity and asthma in a rat model of cholinergic hypersensitivity: a brief review.

Individuals with multiple chemical sensitivity (MCS) also commonly report symptoms of asthma, but, as far as we have been able to determine, no one has yet suggested that an abnormal cholinergic system may provide the link between asthma and MCS. The present brief review provides evidence for such a link by summarizing recent findings in a genetic animal model of cholinergic hyperresponsiveness. The Flinders Sensitive Line (FSL) rats were developed by selective breeding for increased responses to an anticholinesterase agent similar to commonly used organophosphate pesticides. Relative to their control line, the Flinders Resistant Line (FRL) rats, the FSL rats are more sensitive to drugs that stimulate acetylcholine receptors, alcohol, diazepam, and drugs that have a selective effect on dopamine or serotonin receptors. These findings raise the possibility that the FSL rats may resemble individuals with MCS. Hyperresponsiveness of the airways is a hallmark of asthma. The procedure known as whole-body plethysmography, where breathing can be monitored in freely moving animals, was employed to study the FSL and FRL rats. The FSL rats exhibited a greater index of bronchoconstriction than the FRL rats in response to both a cholinergic agonist and an allergen challenge. Thus, the FSL rats are more sensitive both to a variety of drugs unrelated to the cholinergic system and to cholinergic- and allergen-induced bronchoconstriction. An abnormal cholinergic system may therefore contribute to both MCS and asthma.

Genetically Transmitted Cholinergic Hyperresponsiveness Predisposes to Experimental Asthma

The excitatory innervation of the airway smooth muscle is primarily cholinergic in nature. However, the potential neural mechanism(s) underlying airway hyperresponsiveness, one of the hallmarks of asthma, is not fully understood. In this study, cholinergic hyperresponsive Flinders sensitive line (FSL) rats and their control counterparts, Flinders resistant line (FRL) rats, were repeatedly challenged with different doses of nebulized methacholine (0, 4, 16, 64, and 256 mg/ml) for 5 min. Airway responsiveness was assessed in spontaneously breathing, unrestrained animals by means of whole body plethysmography. Increased airway responsiveness of FSL rats was evidenced as a more pronounced increase in Penh value (enhanced pause, an index of bronchoconstriction) across different concentrations of methacholine. In subsequent experiments, FSL and FRL rats were sensitized to ovalbumin and challenged with nebulized antigen. Our results indicate that the genetically transmitted cholinergic hyperresponsiveness of the FSL rat is paralleled by an increased susceptibility to allergen-induced bronchoconstriction and inflammation of the airways. This study provides further evidence that neural factors can play an important role in determining airway responsiveness and thus may be relevant for the expression of asthma. In addition, the FSL rat may be a useful model for studies of airway hyperresponsiveness.

135. Experimental asthma in a genetic animal model of depression

Several empirical studies have reported high prevalence of atopic disordersin Woplewithdepression.In, addition,hyperrqxmsivenessto choiinergicagonists has been found both in people diagnosedwith allergicasthmaand in peoplediagnosedwithdepression.In this study, cholinergic hyperresponsiveFlinders Sensitive Line (FSL) rata (an animal model of depression),and their control counterpartsFlinders Resistant Line (FRL) rats were comparedfor their susceptibilityto experimentalasthma.Airwayresponsivenesswas assessedin spontaneouslybreathing,unrestrainedanimalsby meansof wholebodyplethysmography.Increasedairwayresponsivenessof FSLrats was evidenced as a morepronouncedincreasein Perdrvalue(enhancedpause,an index of bronchoconstriction) acrossdifferentconcentrationsof methacholine (F.,ll, = 10.27;p< O.001). In subsequentexperirnen%FSLandFRLrats weresensitizedto ovalbuminandchallengedwithnebulizedantigen.The data indicate that geneticallytransmittedcholinergichyperresponsiveness of the FSL rat is paralleled by its increased susceptibilityto allergen-inducedbronchoconstriction(Fl,3.r= 54.86; p<O.~1) and inflammationof the airways (FI,34= 15.65;p< O.001).‘flus study provides further evidence for a common cholinergicmechanismin susceptibilityto bothasthmaand depression.

Videomicroscopy of methacholine-induced contraction of individual airways in precision-cut lung slices.

Contraction of airways of different size can be studied in viable lung slices by videomicroscopy. However, at present, application of this technique is limited by the heterogeneous responses obtained. We investigated the use of precision-cut lung slices to examine contraction of individual airways. Lung slices of 250 +/- 20 microns were prepared from Wistar rats and cultured in a roller incubator in serum-free minimum essential medium (MEM). Under these conditions, the slices were viable for at least 70 h, as indicated by leakage of lactate dehydrogenase into the supernatant, thymidine incorporation and ciliary beating. The slices were placed in a newly developed incubation chamber and mounted by a nylon thread that was fixed to a platinum wire. The whole chamber was positioned on a microscope stage, and contraction of single airways was followed under a microscope that was coupled to a CCD-camera. Reduction in airway area was taken as an index of bronchoconstriction and was determined by a computer program. Addition of methacholine resulted in a concentration-dependent (concentration producing half the maximal effect (EC50) = 0.64 +/- 0.08 (mean +/- SD) microM; n = 64) contraction of single airways. In the presence of hydrocortisone, the EC50 was about six times greater, i.e. 3.7 +/- 0.9 microM (n = 7), and the effect of the steroid was largely abolished by propanolol (EC50 = 1.1 +/- 0.1 microM; n = 7). Airways with an area smaller than 35,000 microns2 were nearly nine times more sensitive to methacholine (EC50 = 0.1 +/- 0.03 microM; n = 20) than larger ones (EC50 = 87 +/- 0.27 microM; n = 22). We conclude that cultured precision-cut lung slices are a useful model for routine study of contraction of individual airways of various sizes. The measurements were precise and reproducible and showed that smaller airways are more sensitive to methacholine than larger ones.

Antiasthmatic Activity of a Novel Thromboxane A&lt;sub&gt;2&lt;/sub&gt; Antagonist, S-1452, in Guinea Pigs

We examined the effect of a potent thromboxane (Tx) A2 receptor antagonist, calcium (1R, 2S, 3S, 4S)-(5Z)-7-(((phenylsulfonyl)amino)bicyclo[2.2.1] hept-2-yl)-5-heptenoate dihydrate (S-1452), on antigen- and various allergic-spasmogen-induced contractions of guinea pig lung parenchymal strips and on the increase in insufflation pressure, an index of bronchoconstriction, in anesthetized guinea pigs. In isolated guinea pig lung parenchymal strips, S-1452 showed competitive antagonism of the contractile activity of U-46619, a TxA2 mimetic, with a pA2 value of 8.9. The compound also inhibited the contraction induced by prostaglandin (PG) D2 and PGF2 alpha, but a TxA2 synthetase inhibitor, OKY-046, did not. In contrast, both drugs inhibited not only leukotriene (LT) D4-induced contraction but also antigen-induced contraction in the presence of a histamine antagonist. In anesthetized guinea pigs, oral administration of S-1452 markedly inhibited the bronchoconstrictions induced by intravenous injection of U-46619, PGD2, PGF2 alpha, LTD4 and platelet-activating factor (PAF) with ED50 values of 0.006, 0.031, 0.112, 0.033 and 0.115 mg/kg, respectively, but OKY-046 inhibited only that by LTD4 and PAF. Additionally, bronchoconstriction following intravenous injection of antigen was almost completely suppressed by S-1452 (0.1 mg/kg) and partially by OKY-046 (300 mg/kg) in passively sensitized guinea pigs which were treated with diphenydramine and propranolol. The inhibitory effect of S-1452 against U-46619-induced broncho-constriction persisted up to 7 h after oral administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of leukocyte depletion in noncholinergic bronchoconstriction of guinea pigs

To test the role of leukocytes in the activation of afferent C-fibers in the lung, 33 guinea pigs, 18 control and 15 experimental or leukocyte depleted, were used. The leukocyte depletion was accomplished with an intraperitoneal injection of cyclophosphamide (100 mg/kg) 96 h prior to the study. On the day of the study, bronchial constriction was produced either by exsanguination ( n = 17) or by capsaicin injection (16 μg/kg, i.v.) ( n = 16) in anesthetized-paralyzed animals. Venous blood samples were collected for leukocyte counts. At 1–30 min following the above treatment, the maximal expiratory flow maneuver was performed and a decrease in the maximal expiratory flow at 50% baseline total lung capacity (żmax 50) was used as an index of bronchoconstriction. The leukocyte count decreased significantly following the pretreatment with cyclophosphamide [an average of 6217 ± 612 (control) vs. 2242 ± 334/mm 3 (experimental)]. Exsanguination caused a gradual decrease in V̇max 50 with time, indicating a temporal increase in bronchoconstriction. Capsaicin injection, on the other hand, caused an immediate (1 min) marked bronchoconstriction, which attenuated gradually with time. At a specific time point, leukocyte depletion did not produce any significant change in V̇max 50 compared to the control group for both types of bronchoconstrictions. Based on these results, we conclude that leukocytes may play an insignificant role in the bronchoconstriction caused by the activation of afferent C-fibers in guinea pig lungs under our experimental conditions.

In vivo exposure to hyperoxia increases airway responsiveness in rats. Demonstration in vivo and in vitro.

Studies regarding O2-induced lung injury have concentrated on damage to alveolar structures and pulmonary vasculature without consideration of alterations that may be occurring in airways. This study was undertaken to determine the effects of in vivo hyperoxic exposure on airway responses to excitatory stimuli in intact, anesthetized rats and in intrapulmonary bronchi isolated from hyperoxia-exposed rats. Using lung conductance (G1) as an index of bronchoconstriction, intravenously administered 5-hydroxytryptamine (5HT) elicited greater bronchoconstrictor responses in anesthetized, mechanically ventilated rats that had been exposed to 85% O2 for 7 days rather than to air. Further, airways of hyperoxia-exposed rats were more sensitive to the effects of intravenously administered 5HT as evidenced by the lower log dose of 5HT required to decrease G1 30%. Cylindrical segments of intrapulmonary bronchi isolated from hyperoxia-exposed rats were more responsive to the contractile effects of 5HT and electrical field stimulation. However, no differences in responsiveness to bethanechol or KCl were observed between the two groups. The log concentration of 5HT and the log frequency of electrical field stimulation that elicited half-maximal responses were smaller in bronchi isolated from hyperoxia-exposed animals, indicating an increase in sensitivity of the airways to these stimuli. These results suggest that prolonged exposure to greater than ambient levels of O2 can alter airway function; however, the mechanism responsible for these changes remains to be determined.

A comparison of three measures of the response to inhaled methacholine

In studies of asthma prevalence bronchial responsiveness has usually been measured as the provocative dose of bronchoconstrictor causing a 20% fall in FEV1 (PD20FEV1). This is relatively insensitive and only 10-20% of subjects in a general population sample will show such a response. Attempts to increase sensitivity, such as the use of the provocative dose causing a 10% fall in FEV1 (PD10FEV1), have not demonstrated any overall advantage, due to poorer repeatability. It has been suggested that measurement of bronchial reactivity using flow at low lung volumes measured from a partial flow volume curve is a more sensitive index of bronchoconstriction than PD20FEV1. If equally repeatable, it would have advantages in epidemiological practice. In 20 subjects with asthma, we compared the sensitivity and repeatability of PD10FEV1, PD20FEV1, and the provocative dose causing a 40% fall in flow at 30% of vital capacity (PD40V30P) following methacholine challenge. PD40V30P was more sensitive than both PD20FEV1 and PD10FEV1 by 1.48 and 0.35 doubling doses (DD) of methacholine, respectively. PD20FEV1 and PD40V30P showed equal repeatability, the 95% range for a single estimate of both being 2.02 DD. PD10FEV1 was less repeatable, with a 95% range of 2.35 DD. Values for the intraclass correlation co-efficient, which measures the ability of a test to discriminate between subjects, were 0.63, 0.79 and 0.69 for PD10FEV1, PD20FEV1, and PD40V30P, respectively. The increased sensitivity and comparable repeatability of measurement of bronchial reactivity for PD40V30P suggest that this method may be useful for studies of asthma prevalence.

Substance P-inducing massive postmortem bronchoconstriction in guinea pig lungs

To further examine the role that substance P plays in initiating the observed massive postmortem bronchoconstriction in guinea pig lungs and to explore the role of neural reflex in this airway spasm, six groups of animals were employed: control (n = 6), morphine (n = 6), substance P (n = 5), chronic capsaicin pretreatment + substance P (n = 5), tetrodotoxin (TTX) + acute capsaicin (n = 4), and chlorisondamine + acute capsaicin (n = 5). Pressure-volume curves were performed prior to and following the initiation of artificial pulmonary perfusion with 1% bovine serum albumin and 5% dextran in Tyrode's solution. A decrease in inflation volume (the lung volume between transpulmonary pressure of 0 and 30 cmH2O during inflation) was used as an index of bronchoconstriction. In control animals, inflation volume decreased to 20-30% of the base-line value at 15-30 min of perfusion, indicating massive bronchial constriction during this time period. Morphine (an agent inhibiting substance P release) significantly attenuated the spasm, whereas the presence of substance P in the perfusate markedly enhanced the constriction. Depletion of endogenous substance P by chronic capsaicin pretreatment did not affect exogenous substance P-induced spasm. Acute capsaicin-induced bronchoconstriction was significantly attenuated by TTX but was not affected by the ganglionic blocking agent, chlorisondamine. These data suggest that substance P initiates the massive postmortem bronchoconstriction in guinea pig lungs and that substance P is released by local stimulation of sensory nerve endings via axonal reflex.

Bronchoconstriction and apnea induced by cigarette smoke: nicotine dose dependence.

Recently, evidence was presented to suggest that nicotine absorbed from cigarette smoke was the main cause of smoke-induced bronchoconstriction (Hartiala et al., J Appl Physiol (1985) 59(1): 64–71). However, due to the qualitative nature of the data, it remains unclear whether cigarette-smoke-induced bronchoconstriction is related to the nicotine content of the smoke in a dose-dependent manner. Experiments were performed on intact anesthetized dogs (n = 6). Each animal spontaneously inhaled 300 cc smoke containing low (0.37 mg), medium (1.46 mg), or high (1.80 mg) levels of nicotine. Isometric tension was measured in an isolated tracheal segment not exposed to the smoke as an index of bronchoconstriction. In all dogs there was a nicotine dose-dependent increase in tracheal tension. The time in expiration (Te) in the breath following smoke inhalation was prolonged, the magnitude of prolongation being dependent upon the nicotine content of the smoke. These results suggest that bronchoconstriction and changes in Te induced by cigarette smoke are nicotine-dependent.