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Biomedical subjects

J Solway

Publications and source records attributed to J Solway.

At least 55 records · Page 3Linked to original sources
PubMed1995

Persistent airway hyperresponsiveness and histologic alterations after chronic antigen challenge in cats.

We studied the effect of chronic immune sensitization on the airway reactivity and associated cytologic and histologic alterations in initially nonatopic cats, a species that spontaneously develops idiopathic asthma. Seven cats were sensitized by intramuscular injection of Ascaris suum antigen (AA) for 4 wk, and four other cats served as sham controls. Airway sensitization was demonstrated by an increased response to nebulized AA in sensitized animals (RL = 45.9 +/- 6.1 cm H2O/L/s, versus a baseline response of 24.7 +/- 1.5 cm H2O/L/s, p < 0.01), and hyperresponsiveness was demonstrated by an increased response to acetylcholine (ACh)-challenge 24 h after AA (approximately 1.0 log decrease in PD200, p < 0.01). The number of eosinophils in the sensitized animals' bronchoalveolar lavage (BAL) fluid increased 12-fold (p < 0.01 versus control) in response to AA challenge; 32 +/- 5% of the BAL eosinophils had a specific density < 1.050, versus 8 +/- 2% prior to AA challenge (p < 0.05). There was no change in airway reactivity, eosinophil recovery, or density in the control group 24 h after sham challenge with saline. The same seven sensitized cats further received nebulized AA three times weekly for 4 to 6 wk, after which BAL samples were again obtained and ACh dose-response curves generated 72 h after the final administration of nebulized AA. Airway hyperresponsiveness increased (approximately 1.5 log decrease in PD200, p < 0.001) and the number of eosinophils recovered in BAL fluid was increased 11-fold (p < 0.05). Necropsy specimens demonstrated bronchoconstriction in AA-challenged animals but not controls; luminal narrowing was accompanied by: (1) a 29.0 +/- 0.34% increase in smooth-muscle thickness (p < 0.05); (2) goblet-cell and submucosal-gland hypertrophy and hyperplasia; and (3) epithelial erosion and eosinophilic infiltration. We demonstrate in nonhuman species persistent airway hyperreactivity associated with a complete constellation of histologic changes in epithelium, smooth muscle, and mucus glands, and cytologic changes in BAL fluid, all induced by immune sensitization. Our data suggest that chronic immune sensitization per se could be a salient factor in causing many of the changes associated with chronic bronchial asthma.

Acetylcholine↗
PubMed1995

In vivo hyperoxic exposure increases cultured lung fibroblast proliferation and c-Ha-ras expression.

Exposure to hyperoxia has been demonstrated to alter the cell number of lung fibroblasts in vivo. The precise mechanism of lung fibroblast proliferation after hyperoxic exposure has not been elucidated, however. We examined the growth characteristics of lung fibroblasts isolated from 21-day-old rats exposed to air or 100% O2 for 8 days. Cell proliferation was assessed by hemocytometry, [3H]thymidine incorporation, and fractional labeling with the thymidine analog bromodeoxyuridine. Under all conditions tested, fibroblasts isolated from O2-exposed rats grew more rapidly than those from air-exposed rats. Conditioned medium from fibroblasts isolated from hyperoxia-exposed rats failed to increase the [3H]thymidine incorporation of control cells to that observed in cells isolated from hyperoxia-exposed animals, suggesting that an autocrine growth factor was not responsible for the excess proliferation. Sensitivity to exogenous growth factors was assessed by measuring the response to increasing concentrations of insulin-like growth factor-1 (IGF-1). Relative to 1% fetal bovine serum (FBS), concentrations of IGF-1 between 3 and 30 ng/ml significantly increased the [3H]thymidine incorporation of fibroblasts derived from hyperoxic animals, whereas control cells were unresponsive to IGF-1 stimulation. The apparent sensitivity to IGF-1 led us to assess the effect of in vivo hyperoxic exposure on the expression of c-Ha-ras, which encodes a membrane-bound, GTP-binding/hydrolyzing protein essential for progression through G1 in the cell cycle. ras mRNA levels in quiescent, control cells were minimal but increased following serum stimulation. The c-Ha-ras expression of lung fibroblasts from hyperoxia-exposed animals, on the other hand, was substantial in quiescent cells and remained high after serum exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Bronchoalveolar lavage fluid from immature rats with hyperoxia-induced airway remodeling is mitogenic for airway smooth muscle.

We previously demonstrated that hyperoxia-exposed immature rats develop airway smooth muscle layer thickening; this remodeling appears partially attributable to smooth muscle hyperplasia. In this study, we tested the hypothesis that excess mitogenic activity for airway smooth muscle cells is present within the lungs of hyperoxia-exposed immature rats. We assessed the proliferative effect of bronchoalveolar lavage (BAL) fluid from air- and O2-exposed animals on cultured rat tracheal smooth muscle cells. BAL fluids from air- or O2-exposed immature rats increased DNA synthesis ([3H]-thymidine incorporation at 24 h of incubation) and cell number (compared with DMEM-treated control cells, at 2 days of incubation), but BAL fluid from O2-exposed animals had significantly greater mitogenic effects. This excess mitogenic activity was lipid inextractable and was ablated by trypsin digestion, indicating that at least one polypeptide growth factor was responsible; molecular sieve fractionation demonstrated a molecular weight of > 10 kD. Because platelet-derived growth factor (PDGF) has been identified in other models of hyperoxia exposure, we tested the further hypothesis that PDGF contributes to the observed excess mitogenic activity. Addition of neutralizing anti-PDGF antibodies to BAL-stimulated smooth muscle cultures did not reduce BAL fluid-induced mitogenesis. These data indicate that the lungs of O2-exposed rats contain excess mitogenic activity for airway smooth muscle, attributable to non-PDGF polypeptide growth factors. It is conceivable that this abnormal mitogenic activity contributes to O2-induced airway smooth muscle remodeling observed in immature rats in vivo.

Animals↗
PubMed1995

Hypertonicity, but not hypothermia, elicits substance P release from rat C-fiber neurons in primary culture.

Isocapnic dry gas hyperventilation provokes hyperpnea-induced bronchoconstriction in guinea pigs by releasing tachykinins from airway sensory C-fiber neurons. It is unknown whether dry gas hyperpnea directly stimulates C-fibers to release tachykinins, or whether this physical stimulus initiates a mediator cascade that indirectly stimulates C-fiber tachykinin release. We tested the hypotheses that mucosal hypothermia and/or hyperosmolarity--physical consequences of airway heat and water loss imposed by dry gas hyperpnea--can directly stimulate C-fiber tachykinin release. Neurons isolated from neonatal rat dorsal root ganglia were maintained in primary culture for 1 wk. Cells were then exposed for 30 min at 37 degrees C to graded concentrations of NaCl, mannitol, sucrose, or glycerol (0-600 mOsm) added to isotonic medium, or to isotonic medium at 25 degrees C without or with 462 mOsm mannitol added. Fractional release of substance P (SP) was calculated from supernatant and intracellular SP contents following exposure. Hyperosmolar solutions containing excess NaCl, mannitol, or sucrose all increased fractional SP release equivalently, in an osmolarity-dependent fashion. In marked contrast, hypothermia had no effect on fractional SP release under isotonic or hypertonic conditions. Thus, hyperosmolarity, but not hypothermia, can directly stimulate tachykinin release from cultured rat sensory C-fibers. The lack of effect of glycerol, a solute which quickly crosses cell membranes, suggests that neuronal volume change represents the physical stimulus transduced by C-fibers during hyperosmolar exposure.

Animals↗
PubMed1994

Immune sensitization augments epithelium-dependent spontaneous tone in guinea pig trachealis.

We examined epithelial modulation of tracheal smooth muscle (TSM) responsiveness in vitro from guinea pigs receiving active immune sensitization in vivo. Initially, guinea pigs were either ovalbumin sensitized (by aerosol) or sham sensitized with normal saline; TSM responsiveness was assessed isometrically as active tension (AT) after equilibration by electrical field stimulation in vitro. For epithelium-intact (Epi+) tissues, sensitization caused an increase in baseline active spontaneous tone (1.89 +/- 0.20 g AT) vs. sham-sensitized tissues (1.18 +/- 0.28 g AT; P = 0.02). Spontaneous tone in sensitized TSM in which the epithelium was removed (Epi-) (1.01 +/- 0.14 g AT) was substantially less than from Epi+ tissues (P = 0.01) and did not differ from sham-sensitized epithelium-denuded tissues (0.82 +/- 0.24 g AT; P > 0.05). Indomethacin caused a reduction in spontaneous tone to comparable magnitude for all treatment paradigms. Immune sensitization caused physiological reduction in the ability to relax in response to isoproterenol; the concentration of isoproterenol eliciting 50% relaxation of spontaneous tone was 7.10 +/- 0.13 (-log M) for TSM from sensitized guinea pigs compared with 8.20 +/- 0.27 (-log M) for sham-sensitized tissues (P = 0.006). However, after precontraction with exogenous acetylcholine, relaxation caused by isoproterenol was not affected by either indomethacin or epithelial removal. Muscarinic responsiveness to acetylcholine was augmented by immune sensitization; however, the increase in response to acetylcholine was attenuated by epithelium removal or cyclooxygenase blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1994

Exposure of immature rats to hyperoxia increases tracheal smooth muscle stress generation in vitro.

Recently, we demonstrated that chronic exposure to hyperoxia causes in vivo airway muscarinic receptor hyperresponsiveness in the developing rat [Am. J. Physiol. 262 (Lung Cell. Mol. Physiol. 6): L263-L269, 1992]. To test whether airway cholinergic hyperresponsiveness might result from intrinsic alterations in smooth muscle contractility, we measured the effect of in vivo hyperoxia on the contractile force elicited by acetylcholine (ACh) of isometrically mounted tracheal rings in vitro. Tracheal rings were obtained from 3-wk-old rats exposed to air or to > 95% O2 for 8 days. Muscarinic responses were determined by measuring the force elicited by exposure to increasing concentrations of ACh. Responses were normalized to the morphometrically determined tracheal smooth muscle cross-sectional area in a plane perpendicular to the axis of force generation. In vivo O2 exposure significantly increased maximal ACh-induced stress generation (response to 10(-3) M ACh: air, 15.92 +/- 1.37 g/mm2; O2, 21.78 +/- 1.52 g/mm2; P = 0.010). The ACh-induced stress generation of cylinders from hyperoxic rats was substantially reduced by both epithelial removal and treatment with the cyclooxygenase inhibitor indomethacin. We conclude that in vivo hyperoxic exposure increases tracheal smooth muscle contractile function in vitro and that epithelium-derived prostaglandin(s) contributes to the observed increase in maximal contractile responsiveness.

Animals↗
PubMed1994

Ontogeny of dry gas hyperpnea-induced bronchoconstriction in guinea pigs.

Adolescent guinea pigs (AGPs) demonstrate dry gas hyperpnea-induced bronchoconstriction (HIB) that shares key features with HIB in humans with asthma. The airways of immature animals exhibit enhanced reactivity to diverse types of stimulation. We tested whether dry gas HIB is also increased in newborn guinea pigs (NGPs). We quantified HIB as the fractional increase of respiratory system resistance (Rrs) over baseline (BL) in five 4- to 7-day-old NGPs after 10 min of hyperpnea, as well as changes in Rrs elicited by intravenous methacholine or capsaicin, and compared these responses with those of AGPs. During hyperpnea, analogous stimuli were delivered by mechanically imposing hyperpnea at 3.0, 4.5, and 6.0 times quiet eucapnic minute ventilation (VE). In AGPs, hyperpnea caused significant bronchoconstriction that increased with VE; peak fractional increase of Rrs was 7.6 +/- 2.0 times BL. In contrast, hyperpnea caused insignificant bronchoconstriction in NGPs (1.4 +/- 0.2 times BL after the largest VE; P < 0.05 vs. AGP). Responses elicited by methacholine (10(-10)-10(-7) mol/kg) or capsaicin (0.01-10.0 microgram/kg) were similar in NGPs and AGPs. In AGPs, hyperpnea suppressed HIB until posthyperpnea. To determine whether the reduced HIB of NGPs was caused by enhanced suppression, NGPs and AGPs were administered acetylcholine (10(-10)-10(-7) mol/kg i.v.) during BL eucapnic ventilation and during eucapnic hyperpnea with warm humidified gas. Responses to acetylcholine were suppressed in AGPs and NGPs to a similar degree. We conclude that HIB is markedly diminished shortly after birth in guinea pigs and that it increases substantially during maturation.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1994

Airway reopening pressure in isolated rat lungs.

In a previous modeling study, we predicted that the yield pressure for airway reopening (Pyield) should depend on airway fluid surface tension (gamma) and airway radius (R), according to the relationship Pyield = 8.3 gamma/R. To test this prediction, we studied tantalum bronchograms of isolated perfused rat lungs from three rats by using microfocal X-ray imaging. Thirty-two airways with diameters ranging from 300 to 2,400 microns were recorded as the airways were collapsed and reinflated. Airway pressure was reduced transiently to -40 cmH2O to produce airway closure. Airway pressure was then slowly increased from 0 to 25 cmH2O. In each airway, the observed diameter remained constant until a Pyield was reached; at this pressure, airways were seen to "pop" open, allowing clear identification of airway reopening pressure. When Pyield was plotted against diameter at maximum inflation, the experimental data were in approximate agreement with predictions of Pyield made assuming a gamma of 35 dyn/cm. The close correspondence of the measured values with these predictions suggests that surfactant is present in these airways and facilitates airway reopening.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1994

Influences of parenchymal tethering on the reopening of closed pulmonary airways.

We investigated the influence of parenchymal tethering on the reopening of collapsed pulmonary airways. Reopening experiments were performed with freshly excised canine lobes placed in a vacuum chamber with pleural pressure (Ppl) set by vacuum pressure. Noncartilaginous 2- to 3-mm airways were collapsed by suction and remained collapsed on subsequent atmospheric pressure equalization. The airway was reopened by constant-flow insufflation, and peak pressure (Ppeak) needed to reopen the collapsed airway was measured. Yield pressure needed to begin axial meniscus motion decreased markedly at Ppl = -7.5 cmH2O, indicating a possible change in airway-meniscus configuration from compliant collapse to meniscus occlusion, thus promoting onset of reopening. Two distinct types of reopening behavior were observed: unstable low-frequency fluttering phenomenon characteristic of small magnitudes of Ppl in which airway tended to recollapse after being reopened and stable reopening phenomena at larger magnitudes of Ppl in which airway remained patent after it was reopened. Stable reopening was always observed at Ppl < or = -7.0 cmH2O. Effective transmural pressure (=Ppeak - Ppl) required to reopen airway and subsequent postreopening airway pressure, reflecting airway and collateral resistance, decreased with increasing magnitudes of Ppl due to increased influence of parenchymal tethering. However, at Ppl < -8.0 cmH2O, an increase in lung volume did not result in a reduction of effective transmural pressure, possibly indicating full airway distension and influence of airway wall hoop stress.

Air Pressure↗
PubMed1994

Recovery of airway structure and function after hyperoxic exposure in immature rats.

We have previously demonstrated that hyperoxic exposure (> 95% O2 for 8 d) induces airway cholinergic hyperresponsiveness and remodeling in 21-d-old rats. To examine the potential relationship between airway hyperresponsiveness and remodeling in these animals, we exposed rats to air or hyperoxia for 8 d, returned them to air-breathing, and measured airway responsiveness to inhaled acetylcholine (ACh) and layer thicknesses immediately after or 16 or 48 d after cessation of air or O2 exposure. The ACh concentration required to increase resistance by 100% (EC200ACh) was calculated by linear interpolation. Small airway (circumference < 1,000 microns) and medium-sized, conducting airway (1,000 to 3,000 microns) epithelial and smooth muscle layer mean thicknesses and fractional areas (layer area/luminal cross-sectional area) were determined from lung sections by contour tracing using a digitizing pad and computer. As we reported previously, after 8 d of O2 exposure, group mean log EC200ACh was significantly reduced relative to that in control animals (p < 0.001). Similarly, hyperoxic exposure was associated with significant increases in all parameters of airway layer thickness assessed (p < 0.05). However, by 16 d after cessation of O2 exposure, there were no longer statistically significant differences in log EC200ACh, airway layer thickness, or fractional area between control and O2-exposed animals. Further studies, in a second cohort of animals killed 0, 3, 6, 8, or 13 d after cessation of O2 exposure, demonstrated progressive reductions in small airway epithelial and smooth muscle layer thicknesses, confirming that hyperoxia-induced airway remodeling resolves by approximately 2 wk after termination of O2 exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1994

Hyperoxia increases airway cell S-phase traversal in immature rats in vivo.

Exposure of 21-day-old Sprague-Dawley rats to hyperoxia (> 95% O2 for 8 days) causes thickening of the airway epithelial and smooth muscle layers. To test the hypothesis that hyperoxic exposure increases airway layer DNA synthesis, we labeled the nuclei of cells undergoing S-phase by administering the thymidine analog bromodeoxyuridine (BrdU). BrdU was administered on days 3 and 4, 5 and 6, or 7 and 8 of air or O2 exposure, and the lungs were harvested immediately thereafter. Histologic sections were stained with an avidin-biotin-immunoperoxidase stain that revealed BrdU incorporation into nuclei, and a hematoxylin counterstain. After 4 days of air or O2 exposure, there was no difference in BrdU fractional labeling between control and hyperoxic animals. Thereafter, fractional BrdU labeling of the small airway (circumference < 1,000 microns) epithelium and smooth muscle layer was significantly increased in O2-exposed animals (P < 0.01, unpaired t test). The fractional labeling of larger, central airway smooth muscle layer cells was also increased after 8 days of O2 exposure (P < 0.01). In another cohort of O2-exposed animals, measurements of airway layer dimensions demonstrated increases in small airway epithelial and smooth muscle layer thickness that paralleled the time course seen for BrdU incorporation. We conclude that O2 exposure of immature rats increases airway epithelial and smooth muscle layer cellular DNA synthesis. These data suggest that hyperplasia of airway epithelial and smooth muscle layer cells may contribute to hyperoxia-induced airway remodeling.

Animals↗
PubMed1994

Hydrogen peroxide stimulates mitogen-activated protein kinase in bovine tracheal myocytes: implications for human airway disease.

We have shown that hyperoxic exposure of immature rats induces airway smooth muscle layer thickening and cell turnover parallel to that found in the airways of patients with bronchopulmonary dysplasia and chronic, severe asthma. We hypothesized that reactive oxygen species could promote the observed airway remodeling by directly stimulating signal transduction pathways that regulate cell growth. To test this hypothesis in cultured cells, we assessed the effects of hydrogen peroxide (H2O2) on mitogen-activated protein (MAP) kinase activation in bovine tracheal myocytes. The MAP kinases are a family of 40 to 46 kD cytosolic serine/threonine kinases that participate in the transduction of mitogenic signals to the cell nucleus. Quiescent cells were exposed to H2O2 (25 to 200 microns; 2 to 60 min), after which SDS-PAGE of cell extracts was performed. Western analysis using an anti-MAP kinase antiserum revealed a decrease in the mobility of the 42 and 44 kD MAP kinase bands after H2O2 exposures of 5 to 30 min, reflecting the phosphorylation at threonine and tyrosine residues required for enzymatic activity. MAP kinase activation was demonstrated by kinase renaturation assays, which showed an almost 4-fold increase in 42 and 44 kD MAP kinase activity. Down-regulation of protein kinase C (PKC) with phorbol 12,13-dibutyrate (PDBu) partially reduced H2O2-stimulated MAP kinase activity, suggesting that H2O2 induces MAP kinase activation via both PKC-dependent and PKC-independent pathways. Western analysis using a phosphotyrosine monoclonal antibody revealed increased tyrosine phosphorylation of proteins with approximate molecular weights of 72 and 125 kD after H2O2 exposure, demonstrating that H2O2 can stimulate the tyrosine phosphorylation of multiple cytosolic proteins, including MAP kinase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Activation of tracheal smooth muscle responsiveness by fMLP-treated HL-60 cells and neutrophils.

We assessed the effects of cultured human promyelocytic leukemia (HL-60) cells and polymorphonuclear leukocytes (neutrophils) isolated from peripheral human blood on tracheal smooth muscle responsiveness in 40 male Hartley guinea pigs. Undifferentiated HL-60 cells (16-25 passages) were activated in vitro by incubation with 1 microM f-Met-Leu-Phe (fMLP), and force of contraction was measured isometrically using an in situ preparation of tracheal smooth muscle. Increasing concentrations of acetylcholine (ACh; 10(-10) to 10(-6) mol/cm2 tracheal surface) were applied topically to the epithelial surface pretreated with 4 x 10(6) fMLP-activated HL-60 cells, 4 x 10(6) fMLP-activated neutrophils, 4 x 10(6) sham-activated HL-60 cells, fMLP+vehicle, or vehicle control. Topical application of fMLP-activated HL-60 cells caused a maximum active tension (AT) of 1.13 +/- 0.2 g/cm after 5 min; fMLP-activated neutrophils, sham-activated HL-60 cells, or fMLP+vehicle had no effect. The fMLP-activated HL-60 cells also caused substantial augmentation of tracheal contraction to ACh (P < 0.05 vs. sham-activated cells for all concentrations > 10(-9) mol/cm2). Although fMLP treatment caused 247 +/- 28% increase from baseline level in O2-. production, neither direct contraction nor augmentation of muscarinic stimulation was demonstrated after topical application of 4 x 10(6) neutrophils. In 12 other preparations, fMLP-activated HL-60 cells were pretreated with either 10 microM indomethacin (Indo) or 100 microM A63162, a 5-lipoxygenase inhibitor. Pretreatment with Indo caused complete blockade of direct tracheal contraction and 88 +/- 13% blockade of muscarinic augmentation; there was no effect after A63162.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetamides↗
PubMed1993

Effect of airway inflammation on smooth muscle shortening and contractility in guinea pig trachealis.

We studied the effect of either 1) immunogenic inflammation caused by aerosolized ovalbumin or 2) neurogenic inflammation caused by aerosolized capsaicin in vivo on guinea pig tracheal smooth muscle (TSM) contractility in vitro. Force-velocity relationships were determined for nine epithelium-intact TSM strips from ovalbumin-sensitized (OAS) vs. seven sham-sensitized controls and TSM strips for seven animals treated with capsaicin aerosol (Cap-Aer) vs. eight sham controls. Muscle strips were tethered to an electromagnetic lever system, which allowed isotonic shortening when load clamps [from 0 to maximal isometric force (Po)] were applied at specific times after onset of contraction. Contractions were elicited by supramaximal electrical field stimulation (60 Hz, 10-s duration, 18 V). Optimal length for each muscle was determined during equilibration. Maximal shortening velocity (Vmax) was increased in TSM from OAS (1.72 +/- 0.46 mm/s) compared with sham-sensitized animals (0.90 +/- 0.15 mm/s, P < 0.05); Vmax for TSM from Cap-Aer (0.88 +/- 0.11 mm/s) was not different from control TSM (1.13 +/- 0.08 mm/s, P = NS). Similarly, maximal shortening (delta max) was augmented in TSM from OAS (1.01 +/- 0.15 mm) compared with sham-sensitized animals (0.72 +/- 0.14 mm, P < 0.05); delta max for TSM from Cap-Aer animals (0.65 +/- 0.11 mm) was not different from saline aerosol controls (0.71 +/- 0.15 mm, P = NS). We demonstrate Vmax and delta max are augmented in TSM after ovalbumin sensitization; in contrast, neurogenic inflammation caused by capsaicin has no effect on isolated TSM contractility in vitro. These data suggest that airway hyperresponsiveness in vivo that occurs in association with immunogenic or neurogenic inflammation may result from different effects of these types of inflammation on airway smooth muscle.

Aerosols↗
PubMed1993

Construction and uses of a concentric catheter for gas sampling in lung airways.

A catheter for intra-airway sampling of gas concentrations was constructed from concentric polyethylene tubes. The internal tube (0.58 mm ID, 0.91 mm OD) was connected to a gas analyzer while the external tube (1.20 mm ID, 1.75 mm OD) was constantly flushed by air or a calibration gas, except during sampling. Injection and sampling dead spaces were 0.35 and 0.28 ml, respectively. Delay at 4-ml/min sampling rate was 4.0 +/- 0.2 s. The 0-90% step response to a sudden change in gas composition was 0.24 s when connected to a mass spectrometer. This catheter was used to assess tracer gas dispersion during oscillatory flow (1-20 Hz) in a straight long tube. Local concentrations measured through the catheter, after a small bolus of tracer gas was injected through the external tube, compared favorably with direct measurements through needles inserted via the tube wall and with theoretical predictions. The catheter was also used to measure intra-airway gas concentrations in dog airways during spontaneous breathing, conventional mechanical ventilation, high-frequency ventilation, high-frequency vibration ventilation, and constant-flow ventilation. It ws placed by a fiber-optic bronchoscope and used to measure local quasi-steady concentrations of CO2 and local dispersion with the bolus method. The occurrence of catheter clogging with secretions was substantially reduced with flow through the external tube. Transmitting a calibration gas through the external tube facilitated in situ recalibration of the gas analyzer without removing the catheter. The use of this catheter improved the efficiency and accuracy of measurements of gas concentrations inside lung airways.

Animals↗
PubMed1993

Role of eicosanoids in hyperpnea-induced airway responses in guinea pigs.

Guinea pigs mechanically hyperventilated with dry gas exhibit hyperpnea-induced bronchoconstriction (HIB) and hyperpnea-induced bronchovascular hyperpermeability (HIBVH). Tachykinins released from airway C-fiber neurons are the central mediators of guinea pig HIB but play only a contributory role in HIBVH. Recent studies suggest that eicosanoid mediators can provoke bronchoconstriction and bronchovascular hyperpermeability, are released by dry gas hyperpnea, and can themselves elicit or modulate tachykinin release. We therefore hypothesized that eicosanoids may participate in HIB and/or HIBVH. To test these hypotheses, we analyzed respiratory system resistance changes and Evans blue-labeled albumin extravasation into the airways of 60 tracheostomized and mechanically ventilated guinea pigs. Animals were subjected to 10 min of isocapnic dry gas hyperpnea or to quiet breathing of humidified gas and received as pretreatment either piroxicam, a cyclooxygenase (CO) inhibitor; A-63162, a 5-lipoxygenase (5-LO) inhibitor; BW-755c, a combined CO and 5-LO inhibitor; ICI-198,615, a leukotriene D4 receptor antagonist; or no drug. HIB was substantially (50-80%) reduced by each of the four eicosanoid-modulating drugs. In contrast, HIBVH was reduced only by BW-755c, and this effect occurred only within the extrapulmonary airways (42% reduction). These data indicate that both CO and 5-LO products, including leukotriene D4, participate in the pathogenesis of HIB but that, like tachykinins, they play only a small contributory role in HIBVH. Together with our previous demonstration that sensory neuropeptide release is critical for the occurrence of HIB, we conclude that the roles of eicosanoids and tachykinins in guinea pig HIB are interdependent.

Animals↗
PubMed1993

Augmented muscarinic responsiveness caused by 5-lipoxygenase products secreted from alveolar macrophages in isolated-perfused rat lung.

We examined the effect of activated alveolar macrophages (AM) on airway responsiveness to muscarinic stimulation in 33 adult Sprague-Dawley rats. An isolated-perfused lung preparation was used to ensure precise and uniform delivery of cells into peripheral airways. The bronchoconstrictor response to acetylcholine (ACh) delivered into the pulmonary arterial circulation was augmented in 8 rats after infusion of 3 x 10(6) AM activated with 10(-6) M f-met-leu-phe and 5 micrograms/ml of cytochalasin B. Lung resistance (RL) caused by 10(-6) mol ACh increased 2.5-fold from 0.10 +/- 0.004 cm H2O/ml/s before infusion of activated AM to 0.35 +/- 0.05 cm H2O/ml/s after infusion of activated AM (N = 8; p < 0.05); the response to ACh was not augmented after infusion of nonactivated AM (N = 7) or vehicle control (N = 6). Baseline RL before ACh was similar in all three groups (p NS). Perfusion with activated AM also significantly increased the wet/dry (W/D) lung weight ratios (7.1 +/- 0.5) compared with nonactivated AM (5.2 +/- 0.1) or vehicle control (5.5 +/- 0.3) (p < 0.05 versus either nonactivated AM or vehicle control). A63162, a 5-lipoxygenase inhibitor, but not indomethacin, a cyclooxygenase inhibitor, completely inhibited augmentation of bronchoconstrictor responses to ACh caused by activated AM and also completely attenuated the increase in W/D lung weight ratios. A highly significant (p < 0.01) correlation (R = 0.76) between W/D lung weight ratios and RL was observed after 10(-6) mol ACh (the greatest dose of ACh administered). Baseline RL was equivalent for all groups before and after infusion of cells or vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗