Eicosanoid and muscarinic receptor blockade abolishes hyperventilation-induced bronchoconstriction.

This study was designed to test the hypothesis that hyperventilation-induced bronchoconstriction (HIB) results from the combined effects of prostanoid and leukotriene metabolism. A bronchoscope was used in anesthetized dogs to record peripheral airway resistance and HIB before and after combined treatment with inhibitors of cyclooxygenase (indomethacin) and 5-lipoxygenase (MK-0591). Bronchoalveolar lavage fluid (BALF) cells and mediators from hyperventilated and control airways were also measured. Pretreatment with MK-0591 and indomethacin significantly attenuated, but did not abolish, HIB. However, addition of atropine nearly eliminated the residual response. Blockade of eicosanoid metabolism markedly reduced the concentrations of eicosanoids recovered in BALF after hyperventilation. Positive correlations between posthyperventilation BALF prostanoid and epithelial cell concentrations are suggestive of mucosal injury-induced mediator production and release. We conclude that HIB is prevented in the presence of eicosanoid and muscarinic-receptor blockade and that both classes of eicosanoids contribute similarly to the development of HIB.

Mucosal injury and eicosanoid kinetics during hyperventilation-induced bronchoconstriction.

Bronchoalveolar lavage (BAL) of canine peripheral airways was performed at various times after hyperventilation, and BAL fluid (BALF) cell and mediator data were used to evaluate two hypotheses: 1) hyperventilation-induced mucosal injury stimulates mediator production, and 2) mucosal damage is correlated with the magnitude of hyperventilation-induced bronchoconstriction. We found that epithelial cells increased in BALF immediately after a 2- and a 5-min dry air challenge (DAC). Prostaglandins D(2) and F(2alpha) and thromboxane B(2) were unchanged immediately after a 2-min DAC but were significantly increased after a 5-min DAC. Leukotriene C(4), D(4), and E(4) did not increase until 5 min after DAC. Hyperventilation with warm moist air did not alter BALF cells or mediators and caused less airway obstruction that occurred earlier than DAC. BALF epithelial cells were correlated with mediator release, and mediator release and epithelial cells were correlated with hyperventilation-induced bronchoconstriction. These observations are consistent with the hypothesis that hyperventilation-induced mucosal damage initiates peripheral airway constriction via the release of biochemical mediators.

Repetitive hyperpnoea causes peripheral airway obstruction and eosinophilia.

Hyperpnoea of canine peripheral airways with dry air results in airway obstruction, mucosal damage, and inflammation. The purpose of this study was to evaluate the effect of repeated dry air challenge (DAC) on airway obstruction, reactivity and the development of airway inflammation in dogs. Canine peripheral airways received DAC (delivered under general anaesthesia through a bronchoscope) every 48 h for two weeks. Peripheral airway resistance and reactivity were measured prior to each DAC. After the final DAC, bronchoalveolar lavage fluid (BALF) cells and soluble mediators from challenged and control airways were measured. Repeated bronchoscopy had no effect on airway mechanics. Repeated DAC produced cumulative increases in peripheral airway resistance and peak obstructive response to DAC. The response to hypocapnia was also increased in airways receiving repeated DAC. However, when the response to agonists was expressed as a change from baseline, consistent significant increases were not observed. Repeated bronchoscopy produced insignificant changes in BALF cells and eicosanoid mediators. Repeated DAC produced marked eosinophilic inflammation and increased prostaglandins D2, E2, and F2alpha, as well as leukotrienes C4-E4. In conclusion, repeated dry air challenge in dogs in vivo causes persistent airway obstruction and inflammation not unlike that found in human asthma.

Thoracotomy increases peripheral airway tone and reactivity.

Our goal was to investigate the extent to which thoracotomy for chronic vascular instrumentation alters peripheral airway tone and reactivity. Using the wedged bronchoscope technique to measure peripheral airway resistance (RP), pentobarbital-fentanyl anesthetized, ventilated dogs were studied before and (16 +/- 2 d) after a left thoracotomy for chronic implantation of instrumentation to measure the left pulmonary vascular pressure-flow relationship. A map of the airways was constructed as bronchoscopes were advanced and wedged in the middle lobes of both the left and right lung. This allowed us to measure RP in the same sublobar region of the left and right lung both pre- and postoperatively. At the time of postoperative experimentation, all dogs appeared fully recovered from the surgical procedure. Compared with preoperative values, baseline RP (cm H2O.ml-1.s-1) was selectively increased (p < 0.03) postoperatively in the left (0.41 +/- 0.07 versus 1.27 +/- 0.36) but not in the right (0.29 +/- 0.06 versus 0.35 +/- 0.07) lung. Peripheral airway responses to acetylcholine, histamine, hypocapnia, and dry air challenges were all increased (p < 0.05) in both magnitude and duration in the left but not the right lung postoperatively. Total lung volume (helium dilution technique) was decreased (p < 0.01) by 10 +/- 3% postoperatively. However, similar reductions in lung volume were observed in the left and right lung. These results indicate that left thoracotomy for chronic instrumentation selectively increases left lung peripheral airway tone and reactivity, but has no effect on the right lung.

Lemakalim attenuates hypocapnia- and dry air-induced bronchoconstriction in canine peripheral airways.

To determine the effect of changes in potassium (K+) flux on airway constriction, we studied effects of lemakalim, a K+ channel opener, and glibenclamide, an ATP-sensitive K+ channel blocker. A wedged bronchoscope technique was used to measure peripheral airway resistance (Rp) in anesthetized dogs. Rp was measured before and after constriction of the airways by hypocapnic challenge, acetylcholine aerosol, or dry air hyperpnea. Lemakalim (5 micrograms/kg i.v.) was administered, and the challenge was repeated. Lemakalim attenuated responses to hypocapnia by 72 +/- 7% (n = 6, P = 0.0007) and to dry air challenge by 37 +/- 8% (n = 6, P = 0.005) but not to acetylcholine. On separate days, sublobar segments were pretreated with aerosolized glibenclamide (2 mg/ml), and responses to hypocapnic challenge were measured before and after lemakalim (5 micrograms/kg i.v.), nifedipine (20 micrograms/kg i.v.), or albuterol (1 microgram/kg i.v.). In the presence of glibenclamide, lemakalim had no significant effect on responses to hypocapnia; however, both nifedipine (n = 6, P = 0.0003) and albuterol (n = 6, P = 0.0001) attenuated responses to hypocapnic challenge. These findings suggest that lemakalim attenuated hypocapnic bronchoconstriction by promoting K+ efflux through ATP-sensitive K+ channels.

The autonomic nervous system modulates dry air-induced constriction in the canine lung periphery.

To determine the modulatory role of the autonomic nervous system on dry air-induced bronchoconstriction (AIB) in the canine lung periphery, we examined the effect of cholinergic, alpha- and beta-adrenergic, and total autonomic ganglionic blockade on AIB. Pretreatment with atropine significantly attenuated AIB by approximately 30%, indicating that AIB is partially mediated via a vagal reflex. Pretreatment with either phentolamine or propranolol did not affect AIB, indicating that alpha- and beta-adrenoceptors, respectively, were not activated in response to dry air challenge. In contrast, pretreatment with hexamethonium significantly potentiated AIB. In addition, exogenous vasoactive intestinal peptide (VIP), a potential neurotransmitter for the nonadrenergic-noncholinergic (NANC) inhibitory system, significantly inhibited AIB. We conclude that (1) neither alpha- or beta-adrenergic efferents are activated during dry air challenge, (2) total autonomic blockade potentiates the response to dry air, and (3) VIP attenuates AIB. Based on these observations, we speculate that NANC inhibitory activity may be stimulated during dry air challenge and antagonizes AIB.

No influence of airway heat flux on airflow-induced bronchospasm.

We used a canine model of airway reactivity to examine the role of airway heat flux in the response to dry air challenge. Airflow-induced bronchospasm (AIB) was assessed by measuring collateral system resistance (Rcs) with a wedged bronchoscope technique in anaesthetized mechanically ventilated dogs. We manipulate post-challenge airway heat flux by exposing peripheral airways to cool dry air (23.9 +/- 0.3 degrees C, 0.8 +/- 0.2 mgH2O.l-1), cool humid air (24.2 +/- 0.2 degrees C, 21.5 +/- 0.3 mgH2O.l-1), or warm humid air (35.3 +/- 0.4 degrees C, 40.6 +/- 0.3 mgH2O.l-1) during the recovery period (n = 14) following a high flow challenge (1,500 ml.min-1 for 2 min) with cool dry air. In a second series of experiments (n = 6), we attempted to further exaggerate airway heat flux during challenge by exposing peripheral airways to warm humid air during both baseline and recovery periods. In comparison to control (i.e. treatment with cool dry air before and after challenge), treatment with warm humid air during recovery period produced a small but significant attenuation (p less than 0.01) in Rcs. Cool humid air during recovery had no affect on Rcs following challenge. Warm humid air during both baseline and recovery tended to attenuate Rcs after challenge (p less than 0.05). We conclude that airway heat flux in itself has no significant physiological affect on AIB in the canine lung periphery.

Dry air-induced late phase responses in the canine lung periphery.

Although controversial, late phase responses in asthmatic subjects have been reported several hours after exercise. We previously showed that exposure to dry air increases collateral system resistance (Rcs) in the canine lung periphery, and produces acute airway responses analogous to those that characterize human exercise-induced asthma. We used a dual wedged bronchoscope technique in anaesthetized male mongrel dogs to monitor Rcs in: 1) control segments continuously exposed to 200 ml.min-1 of 5% CO2 in air and 2) dry air challenged segments exposed to 2000 ml.min-1 5% CO2 for 5 min. We examined Rcs at 5 min and approximately 5 h post-challenge in an attempt to document late phase airway obstruction. Five min after dry air challenge Rcs initially increased 114 +/- SE 22%; contralateral control segments remained unchanged (n = 9). Five hour post-challenge, Rcs in dry air exposed segments was elevated 81 +/- 20% above pre-challenge baseline (p less than 0.01); contralateral control segments did not change significantly over the 5 h period. Cell profile analyses of lavage samples at 5 hours revealed that neutrophils and eosinophils were significantly increased (p less than 0.03) in dry air challenged segments when compared to controls. Leukotriene C4/D4 concentration in lavage was correlated (p less than 0.02) with neutrophil infiltration. Thus, we conclude that the canine lung periphery represents a reproducible model of a dry air-induced late phase reaction.

Regional and temporal variation in canine peripheral lung responses to dry air.

Variation in dry airflow-induced broncho-constriction (AIB) in the canine lung periphery was examined using a wedged bronchoscope technique. Collateral system resistance (Rcs) was measured before and after dry-air challenge. Base-line Rcs was similar throughout the lung periphery, between dogs, and over time. Increasing base-line Rcs was correlated with increasing maximum Rcs 5 min postchallenge (Rcs5), increasing change in Rcs (dRcs5), and decreasing percent change in Rcs above base line (%Rcs5). In contrast to repeated challenge in which base-line Rcs was similar, the magnitude of AIB associated with consecutive challenges with unequal base lines depended on the parameter used to evaluate the response (i.e., Rcs5, dRcs5, or %Rcs5). Peripheral lung resistance then increased to a stimulus specific maximum regardless of base-line Rcs, although data expressed as %Rcs5 or dRcs5 may obscure this observation. Although a change in peripheral lung resistance does not necessarily imply airway narrowing, it is consistent with the idea that changes in Rcs are independent of the collateral system's resting tone.

Airflow-induced bronchospasm. Imbalance between airway cooling and airway drying?

We used an animal model of airflow-induced bronchospasm (AIB) to examine the role of airway cooling in responses to dry air challenge. A bronchoscope was wedged in situ into perfused lower lobes of anesthetized dogs. Through the bronchoscope, dry air was delivered, resistance to collateral flow (Rcs) was measured, and airway wall temperature (Taw) was monitored. A dry-air challenge through the bronchoscope produced a fall in Taw and a rise in Rcs, presumably related to evaporative heat loss (EHL) and/or an increase in osmolarity. By changing the temperature of blood perfusing the lobe it was possible to lower Taw without affecting either EHL or osmolarity. Four series of experiments were performed. In the first series, Taw was lowered in 2 ways: by increasing dry air flow and by cooling the pulmonary perfusate. After a 2-min challenge with dry air, Rcs rose. After lowering Taw with cooled blood for 2 min, Rcs did not rise. In the second series of studies, Taw was lowered for 15-min periods by reducing the temperature of blood. Neither cooling per se nor rewarming after the 15 min of cooling initiated increases in lung tone. In the third series of experiments, a 2-min dry air challenge was performed while the lobe was perfused with cool blood. Despite greater reductions in Taw during the dry-air challenge, responses after the challenge were virtually abolished. In a final series of experiments in which pulmonary perfusion was stopped during challenge, airway cooling was enhanced, and responses were again significantly attenuated. Thus, cooling actually depressed increases in Rcs produced by dry-air challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Airflow-induced bronchoconstriction: role of epithelium and eicosanoid mediators.

We examined the role of cyclooxygenase-derived metabolites and epithelial cells in airflow-induced bronchospasm. Male dogs were anesthetized and collateral system resistance (Rcs) was measured with the wedged-bronchoscope technique. A 2-min high flow challenge with dry air in nine animals produced a mean increase in Rcs of 69 +/- 13% (SE). After treatment with indomethacin (5 mg/kg), the response was significantly attenuated; Rcs increased only 40 +/- 8%. Bronchoalveolar lavage performed 5 min after a dry air challenge yielded fluid with greater concentrations of prostaglandin D2 (PGD2) and thromboxane B2 than samples from unchallenged segments. Challenge with humidified air produced a smaller physiological response than did challenge with dry air. Lavage samples obtained after dry challenge had greater concentrations of PGD2 than samples taken after challenge with humidified air. After dry air challenge, epithelial cells in lavage fluid were increased by 454 and 515% when compared with control and humidified air challenge, respectively. Significant correlations were found between epithelial cell number and PGD2 recovered in lavage fluid after dry air challenges. We conclude that both epithelial cells and prostaglandins play an important role in peripheral lung responses to dry air.