Lung Tissue Resistance Measured in Saline-Filled Guinea Pig Lungs by Micropuncture

Lung tissue resistance (R_ti) measured in air-filled guinea pig lungs by the alveolar capsule technique was a large part of total lung resistance (R_l), and we wondered whether similar results applied to saline-filled lungs. We used the micropuncture method to measure alveolar pressure (P_alv) in saline-filled lungs of 21 guinea pigs. P_alv and airway opening pressure (P_ao) were measured before and after a sudden interruption of flow during an inflation or deflation maneuver. On stopping flow, there was an immediate large change in P_ao followed by a smaller slower change in P_ao. P_alv was nearly constant immediately after flow interruption but followed the slower change in P_ao. The initial change in P_ao on flow interruption was interpreted as the resistive pressure loss in the airways. The small change in P_ao and P_alv was interpreted as the pressure loss caused by tissue stress adaptation. Airway resistance (R_aw) and R_ti were obtained by dividing the pressure losses by the flow before the interruption. R_l was the sum of R_aw and R_ti. The calcium blocker nifedipine reduced both R_aw and R_ti and abolished the difference in R_ti between inflation and deflation. Values of R_ti were 10–29% of R_l. However, with correction for viscosity, R_ti predicted in air-filled lungs would dominate R_l. Accepted for publication: 21 February 1997     

Direct and Phagocyte-mediated Lipid Peroxidation of Lung Surfactant by Group B Streptococci

In newborn infants, group B streptococci (GBS) often cause pneumonia, with polymorphonuclear leukocytes (PMN) migrating into the lungs. Because surfactant therapy may be needed in such patients, we evaluated the interaction between GBS or GBS-stimulated PMN and a surfactant preparation (Curosurf) in vitro. The superoxide production of GBS strains or GBS-activated PMN was measured, using the nitroblue tetrazolium (NBT) test and the subsequent lipid peroxidation (LPO) as the content of malondialdehyde (MDA) and 4-hydroxyalkenals (4-HNE). The growth of GBS in surfactant was determined and related to the LPO. Finally, the effect of LPO on surfactant activity, caused by GBS-stimulated PMN, was assessed by measuring dynamic surface tension in a pulsating bubble surfactometer. Curosurf diminished the NBT reduction by both live GBS and GBS-stimulated PMN. Surfactant was peroxidized by reactive oxygen species (ROS) from both GBS and GBS-stimulated PMN in a time-dependent manner. Vitamin E significantly reduced the peroxidation level of surfactant in both cases. Surfactant peroxidation was associated with a reduction in the number of live bacteria. The biophysical activity of Curosurf was impaired by GBS-stimulated PMN, as reflected by increased minimum surface tension during cyclic compression. These findings indicate that Curosurf undergoes LPO by ROS produced by GBS and/or PMN. We speculate that exogenous surfactant preparations should be supplemented with vitamin E or another antioxidant, when given to infants with GBS pneumonia. Accepted for publication: 21 August 2000     

Atypical Adrenoceptor-mediated Relaxation of Canine Pulmonary Artery Through a Cyclic Adenosine Monophosphate–dependent Pathway

To determine whether functional atypical β-adrenoceptors (β₃-adrenoceptors) are present in pulmonary vascular smooth muscle, we studied isolated canine pulmonary arterial rings under isometric conditions in vitro. Addition of β-adrenoceptor agonists produced a concentration-dependent relaxation of noradrenaline-precontracted tissues, a rank order potency being isoproterenol (1) > salbutamol (0.95) > selective β₃-adrenoceptor agonists, CL 316243 (0.85), and BRL 37344 (0.83). A marked desensitization to salbutamol occurred by pretreatment with salbutamol but not with CL 316243. When β₁-adrenoceptors had been blocked, the relaxant responses to salbutamol were competitively antagonized by the β₂-adrenoceptor antagonist ICI 118551 with a pA₂ value of 7.67 ± 0.21 (mean ± S.E.), but the response to CL 316243 was weekly antagonized by ICI 118551 only at a high concentration of 10⁻⁵ M, where an apparent pA₂ value was 5.24. In contrast, cyanopindolol, a nonselective β-adrenoceptor antagonist, antagonized CL 316243–induced relaxation in a competitive manner with a pA₂ of 6.10 ± 0.11. This pA₂ value was lower than that when salbutamol was used as an agonist (6.69 ± 0.14, p < 0.01). Intracellular 3′,5′-cyclic adenosine monophosphate (cAMP) levels were increased by CL 316243 in a concentration-dependent fashion, an effect that was not altered by ICI 118551. These results suggest that β₃-adrenoceptors may exist in canine pulmonary artery smooth muscle and that stimulation of this atypical receptor causes vasodilation through a cAMP-dependent pathway. Accepted for publication: 17 June 1999     

The induction of carbon monoxide-mediated airway relaxation by PACAP 38 in isolated guinea pig airways

Pituitary adenylate cyclase–activating peptide 38 (PACAP 38) displays several biologic activities relevant to obstructive airway disease. Carbon monoxide (CO) has recently emerged as a potent, endogenously produced mediator of bronchodilation. In this study, we have analyzed the occurrence of PACAP 38 and the corresponding occurrence of heme oxygenase (HO), the rate-limiting enzyme for CO production, in guinea pig trachea, using immunocytochemistry. We have also investigated whether the dilatory effects of PACAP 38 are dependent on CO, using an in vitro setup for tracheal studies. A moderate supply of PACAP-like immunoreactive nerve fibers was seen in association with tracheal smooth muscle. HO-like immunoreactivity was observed in the respiratory epithelium and in association with smooth muscle bundles. PACAP 38 induced a concentration-dependent relaxation of precontracted tracheal segments. This dilation was nearly abolished after pretreatment with zincprotoporphyrine, an inhibitor of heme oxygenase. The same effect was accomplished with Rp-8Br-cyclicGMPS, an inhibitor of cyclicGMP, whereas the nitric oxide synthase inhibitor N^G-monomethyl-l-arginine had no effect on the PACAP 38–induced dilation. The presented data suggest that PACAP 38 can induce bronchodilation by means of a CO-dependent, cyclicGMP-related mechanism, thereby providing a link between neurotransmission and local CO release in the airway smooth muscle. Accepted for publication: 10 January 2001     

The Importance of Polymorphonuclear Leukocytes in Lipopolysaccharide-Induced Superoxide Anion Production and Lung Injury: Ex Vivo Observation in Rat Lungs

The purpose of this study is to determine if the polymorphonuclear leukocyte (PMN) is a major causative agent for lipopolysaccharide (LPS)-induced lung injury and responsible for the excess production of superoxide anion in the lung. We measured superoxide anion production from the lung and pulmonary capillary permeability in rats with and without PMN depletion. The superoxide anion production from the lung was measured using a purpose-built ex vivo chemiluminescence apparatus. Pulmonary capillary permeability was evaluated by the Evans blue dye extravasation method. PMN sequestration was determined by counting PMNs in histologic tissue specimens using microscopy. All rats received 3 mg/kg LPS intravenously. Examinations were undertaken at 2, 6, and 12 h after the LPS injection. The PMN-depleted group received cyclophosphamide 4 days before the LPS injection, which resulted in a PMN count of less than 200 cells/μl. In rats without PMN depletion, Evans blue dye extravasation increased significantly at 12 h after the LPS injection; PMN sequestration increased at 2, 6, and 12 h after the LPS injection; and superoxide anion production increased at 6 h and remained elevated at 12 h after the LPS injection. The increased permeability, PMN sequestration, and superoxide anion production were not seen in the PMN-depleted group. The contribution of the xanthine/xanthine oxidase system and alveolar macrophages to the observed superoxide anion production was negligible. We conclude that, in rats, the PMN is a major causative agent in LPS-induced lung injury and is responsible for the excess production of superoxide anion in the lung. Accepted for publication: 3 March 1997     

Effect of Silica Inhalation on the Pulmonary Clearance of a Bacterial Pathogen in Fischer 344 Rats

Silica inhalation predisposes workers to bacterial infection and impairments in pulmonary defense function. In this study, we evaluated the effect of pre-exposure to silica on lung defense mechanisms by use of a rat pulmonary Listeria monocytogenes infection model. Male Fischer 344 rats were exposed by inhalation to filtered air or silica (15 mg/m³× 6 h/day × 5 days/wk). After 21 or 59 days of silica exposure, the rats were inoculated intratracheally with 5 × 10³ L. monocytogenes. At 0 (noninfected controls), 3, and 7 days after infection, the left lungs were removed, homogenized, and the number of viable L. monocytogenes was counted after an overnight culture at 37° C. Bronchoalveolar lavage (BAL) was performed on the right lungs. Alveolar macrophages (AM) were collected, and the AM production of chemiluminescence (CL), an index of reactive oxygen species generation, was measured. The number of lavagable neutrophils (PMNs) and acellular BAL lactate dehydrogenase (LDH) activity were determined as indices of inflammation and injury, respectively. Pre-exposure to silica for 59 days caused substantial increases in PMN number and LDH activity compared with the air controls, whereas silica inhalation for both 21 and 59 days significantly enhanced the pulmonary clearance of L. monocytogenes compared with air controls. Dramatic elevations were also observed in zymosan- and phorbol myristate acetate (PMA)–stimulated CL production by lung phagocytes recovered from rats pre-exposed to silica for 59 days. These results demonstrate that short-term exposure to inhaled silica particles activates lung phagocytes, as evidenced by increases in reactive oxygen species. This up-regulation in the production of antimicrobial oxidants is likely responsible for the enhancement in pulmonary clearance of L. monocytogenes observed with short-term silica inhalation. Accepted for publication: 2 October 2000     

Dose Dependence and Time Course of Smoke Inhalation Injury in a Rabbit Model

The dose dependence and time course of smoke inhalation injury were determined in a rabbit model. Animals were insufflated with 18–90 breaths of cotton smoke or room air (control) at a rate of 18 breaths/min and tidal volume of 12 ml/kg. Smoke-exposed animals exhibited dose-related histologic effects with progressive deterioration of respiratory function during the postexposure period of observation (96 h). The smoke-exposed rabbits had reproducible injuries to both airway mucosa and lung parenchyma, manifested by disruption and sloughing of airway and alveolar epithelia, and exudation of protein-rich fluid and leukocytes into the airway and alveolar spaces. Significant effects were evident by 24 h postexposure. Smoke inhalation also affected the respiratory burst of alveolar macrophages. Generation of superoxide anions by alveolar macrophages at 48 h postexposure was increased significantly after smoke inhalation (54 breaths). The present rabbit model should be useful for studying the interactions between pulmonary epithelial cells and leukocytes after smoke inhalation and for determining the role that abnormal functioning of alveolar macrophages plays in the development of smoke inhalation injury. Accepted for publication: 8 October 1998     

Development of Monocrotaline-Induced Pulmonary Hypertension Is Attenuated by a Serotonin Receptor Antagonist

The significance of serotonin in the pathogenesis of monocrotaline-induced pulmonary hypertension (MCT-PH) in rats, plasma serotonin concentrations, and the effect of a serotonin receptor antagonist administration in association with the number of proliferative cells were investigated. The thickness of the media of the small pulmonary arteries and the weight ratio of the RV to that of LV + S (RV/[LV + S] weight ratio) were used as indices of the severity of PH. Plasma serotonin concentrations were measured by high-performance liquid chromatography. Histopathologic analysis of the lung tissue was performed by hematoxylin-eosin and elastin van Gieson staining. Immunohistopathologic staining for proliferating cell nuclear antigen (PCNA) was performed to identify proliferative cells. The severity of PH as determined by the medial thickness of the small pulmonary arteries and RV/(LV + S) weight ratio in rats with MCT-PH was significantly reduced after treatment with MCI-9042 (p < 0.01 and p < 0.05, respectively). The serotonin concentration was significantly greater in MCT-PH rats than in normal control rats (p < 0.05). The scores for histopathologic changes, such as thickening of the alveolar walls and interstitial inflammatory cell infiltration in MCT-PH rats, were significantly reduced after treatment with MCI-9042 (p < 0.05 and p < 0.01, respectively). The number of PCNA-positive cells was significantly greater in MCT-PH rats than in normal control rats (p < 0.0001) and was reduced after treatment with MCI-9042 (p < 0.0001). Treatment with MCI-9042 significantly inhibited the development of MCT-PH along with a decrease in the number of PCNA-positive cells, suggesting a pivotal role of serotonin in the development of PH induced by MCT. Accepted for publication: 10 November 1999     

Suppressive Effect of Prostaglandin E1 on Pulmonary Hypertension Induced by Monocrotaline in Rats

The effect of administering prostaglandin E₁ (PGE₁) on the extent of monocrotaline (MCT)-induced pulmonary hypertension and cytokine production [interleukins (IL) 1 and 6 and tumor necrosis factor (TNF)] by macrophages during MCT induction of pulmonary hypertension was studied. Right ventricle/left ventricle plus septum weight ratios (RV/LV + S) were used as an index of the development of pulmonary hypertension. Administering PGE₁ at a dose of 0.2 mg/kg/day for 4 weeks reduced significantly the RV/LV + S ratio from 0.428 ± 0.070 to 0.243 ± 0.059 (p < 0.01) and decreased the production of these cytokines: IL-1, from 4.675 ± 3.558 to 1.800 ± 0.722 units; IL-6, from 0.322 ± 0.121 to 0.060 ± 0.039 units; and TNF, from 0.578 ± 0.369 to 0.004 ± 0.004 units. In another series of experiments, a significant reduction of the RV/LV + S ratio was noted for only 1 week when we administered PGE₁ immediately after the injection of MCT. We confirmed that histopathologic improvements of lungs were noted by administering 0.2 mg/kg PGE₁ for 4 weeks. In another experiment, PGE₁ at a concentration of 2 μg/ml suppressed a rise in the cytosolic Ca²⁺ concentration of lipopolysaccharide-stimulated peritoneal macrophages of rats in vitro, suggesting that PGE₁ suppressed cytokine production by macrophages through the suppression of the Ca²⁺ influx. These results suggest that administering PGE₁ may be effective in the treatment of some forms of pulmonary hypertension in humans. Accepted for publication: 20 August 1998     

Elimination of Neutrophils by Apoptosis During the Resolution of Acute Pulmonary Inflammation in Rats

We evaluated the apoptosis of neutrophils during the resolution of acute pulmonary inflammation induced by exposure to ozone. The inflammatory response was assessed in rat lungs 0, 1, 3, and 7 days after 4-h exposure to air or 2 ppm ozone. Analysis of bronchoalveolar lavage fluid demonstrated significant increases in albumin concentrations on days 0 and 1 and in the number of lavageable neutrophils on days 0, 1, and 3, indicating the presence of acute pulmonary inflammation. These parameters returned to control values on day 7, which suggests that the acute pulmonary inflammation induced by ozone was reversible. On days 1 and 3, but not on day 0, the neutrophils showed morphologic evidence of apoptosis. Based on morphologic analysis, the proportion of apoptotic neutrophils was 23.3 ± 2.2% on day 1 and 55.7 ± 3.2% on day 3. Terminal deoxynucleotidyl transferase-mediated dUTP end labeling (TUNEL), in contrast, revealed that the proportion of apoptotic cells was 59.7 ± 9.1% on day 1 and 68.0 ± 4.3% on day 3. On day 3, light microscopy and electron microscopy demonstrated engulfment of the neutrophils by macrophages. These findings indicate that the apoptosis of neutrophils followed by their engulfment by macrophages contributes to the clearance of neutrophils from the sites of inflammation. Moreover, TUNEL detected apoptotic neutrophils with greater sensitivity compared with morphologic assessment. Accepted for publication: 4 June 1997     

Mediators and Oxygen Radicals in Hyperpnea-Induced Airway Constriction of Guinea Pigs

Leukotrienes (LTs), tachykinins (TKs), and oxygen radicals have been suggested to be important modulating factors for the hyperpnea-induced bronchoconstriction (HIB) of guinea pigs. In this study, we tested the hypothesis that LTs and oxygen radicals modulate HIB by triggering TK release. Eighty-five Hartley guinea pigs were divided into four groups: control, dimethylthiourea (DMTU), FPL 55712, and A63162. DMTU is the scavenger for hydroxyl radical. FPL 55712 is an antagonist of LT receptor, whereas A63162 is an inhibitor of lipoxygenase. Each group was further divided into three subgroups: baseline, hyperpnea, and recovery. Each animal was anesthetized, cannulated, paralyzed, and artificially ventilated. We measured dynamic respiratory compliance (Crs), maximal expiratory flow at 50% total lung capacity (V_max50), and forced expiratory volume in 0.1 s (FEV_0.1) during the baseline and recovery periods. Hyperpnea caused significant decreases in Crs, V_max50, and FEV_0.1, indicating HIB in the control group. Pretreatment with DMTU, FPL 5712, or A63162 attenuated HIB. Plasma substance P (SP) levels increased progressively during the experiment in all groups. However, both FPL 55712 and A63162, but not DMTU, significantly decreased SP levels. Similarly, lung malondialdehyde (MDA) contents increased progressively during the experiment in the control group. Neither FPL 55712 nor A63162 significantly affected the increase. On the contrary, DMTU significantly attenuated the increase in MDA during the recovery period. These results suggest that inhibition of LTs leads to suppression at SP levels and HIB, whereas DMTU attenuates HIB by means of other mechanisms. Accepted for publication: 25 April 2000     

一氧化氮及一氧化氮合酶在低氧性肺动脉高压中的研究进展

一氧化氮可调节肺血管张力,维持肺血管正常结构和肺循环的低阻力状态,在低氧性肺动脉高压的发生机制中起重要作用.由于一氧化氮具有独特的理化性质和生物学活性,因此目前研究主要集中在对其合成的关键酶一氧化氮合酶.下面就一氧化氮、一氧化氮合酶在低氧性肺动脉高压发病中的作用机制及临床应用的研究作一简单综述.     

Effects of Recycled Paper Dust Extracts on Isolated Guinea Pig Trachea

The effect of paper dust collected at two different locations in a paper recycling plant (PD1 and PD2) on isolated nonsensitized guinea pig tracheal smooth muscle was studied in vitro. Dust extracts were prepared as a 1:10 w/v aqueous solution. Dose-related contractions of guinea pig tracheal rings were elicited with both PD1 and PD2. Pharmacologic studies were performed with atropine (10⁻⁶ M), indometacin (10⁻⁶ M), pyrilamine (10⁻⁶ M), LY171883 (10⁻⁵ M), nordihydroguaiaretic acid (10⁻⁵ M), and TMB8 (10⁻⁵ M). The possible role of endogenous neuropeptides in this constrictor process was studied by depleting neural mediators with capsaicin (5 × 10⁻⁶ M) before challenge with dust extracts. Constrictor effects were partially inhibited by a wide variety of the mediator blocking agents. The effects of both extracts were almost totally inhibited by the anticholinergic agent atropine, suggesting that a principal pathway mediating this response may involve the parasympathetic nervous system. The intracellular calcium-blocking agent TMB8 also induced a reduction of the contractile responses to PD1 and PD2 concsistent with the well established role of intracellular calcium in smooth muscle constriction. Pretreatment with capsaicin significantly increased the contractile activity of paper dust extracts but only at the higher doses of these extracts. This suggests that the effect of paper dust is not initiated by the release of mediators stored in sensory nerves but that the prerelease of these mediators may enhance the constrictor effects of these dusts. We suggest that paper dust extracts cause dose-related airway smooth muscle constriction possibly associated with the release of cholinergic as well as other mediators. The constrictor effect does not require tissue presensitization or the release of neuropeptides from sensory nerves. Accepted for publication: 21 March 1997     

Effects of Age, Gender, Disease, and Multisystem Involvement on Oxygen Saturation Levels in Dysphagic Persons

The purpose of this study was to examine the effects of age, gender, disease, and multisystem involvement on SpO₂ levels of 104 dysphagic patients and 77 nondysphagic persons. Results indicated that solid aspirators had lower SpO₂ levels than liquid aspirators, penetrators, and nondysphagics. In addition, SpO₂ levels varied by age, with older persons having lower levels than younger persons among dysphagics but not among nondysphagics. Patients with COPD had lower SpO₂ levels than dysphagics with other disorders. Significant interactions were found among age, gender, and disease. Multisystem involvement was found not to be a factor in SpO₂ levels. It was concluded that although normal aging processes reduce swallowing and pulmonary functioning, it became a significant factor only when combined with an assault to the system, such as CVA or COPD.     

The Role of the Insular Cortex in Dysphagia

Recent data indicate that dysphagia may occur following unilateral cortical stroke; however, the elucidation of specific cytoarchitectonic sites that produce deglutition disorders remains unclear. In a previous study of unilateral cortical stroke patients with dysphagia, Daniels et al. [8] proposed that the insula may be important in swallowing as it was the most common lesion site in the patients studied. Therefore, 4 unilateral stroke patients with discrete lesions of the insular cortex were studied to further facilitate understanding of the role of the insula in swallowing. Dysphagia, as confirmed by videofluoroscopy, was evident in 3 of the 4 patients; all had lesions that involved the anterior insula, whereas the only patient without dysphagia had a lesion restricted to the posterior insula. These data suggest that the anterior insula may be an important cortical substrate in swallowing. The anterior insula has connections to the primary and supplementary motor cortices, the ventroposterior medial nucleus of the thalamus, and to the nucleus tractus solitarius, all of which are important regions in the mediation of oropharyngeal swallowing. Therefore, discrete lesions of the anterior insula may disrupt these connections and, thereby, produce dysphagia.     

Interaction of Vagal Lung Afferents with Inhalation of Histamine Aerosol in Anesthetized Dogs

In seven alpha-chloralose anesthetized dogs we examined the contribution of lung afferents to the rapid, shallow breathing induced by inhalation of 10 breaths of histamine aerosol. In four spontaneously breathing dogs, the inhalation of histamine caused an increased respiratory frequency, decreased tidal volume, and decreased dynamic lung compliance. Selective blockade of pulmonary C-fibers abolished a reflex-induced increase in respiratory frequency but did not significantly affect the reductions in tidal volume or lung compliance. Terbutaline treatment in combination with C-fiber blockade abolished the reductions in tidal volume and lung compliance induced by histamine. In three separate alpha-chloralose anesthetized, open-chest, mechanically ventilated dogs, we recorded an increase in the inspiratory activity of rapidly adapting pulmonary stretch receptors (RARs) induced by the inhalation of histamine aerosol. Selective C-fiber blockade abolished histamine-induced increases in RAR activity while only partially attenuating reductions in lung compliance. We conclude that the increase in RAR activity induced by histamine depends on intact C-fibers and not on a direct effect of histamine on RARs or an indirect effect of histamine reducing lung compliance. In addition, our data illustrate the multiple interactions that occur between the various vagal afferents and their roles in the reflexes induced by histamine inhalation. Accepted for publication: 2 December 1999     

Non-Invasive Estimation of Pulmonary Arterial Hypertension in Chronic Obstructive Pulmonary Disease

The feasibility and reliability of the combination of several noninvasive methods using a multivariate method of analysis to predict pulmonary artery hypertension (PAH) is evaluated in 20 patients with chronic obstructive pulmonary disease. These methods comprised arterial blood gases (Pao ₂, Paco ₂), pulmonary functional parameters (FEV₁), echo-Doppler parameters (tricuspid regurgitation jets, acceleration time on pulmonary valve), computed tomography measurements (transhilar distance, hilar thoracic index, and measurement of the descending branch of the right pulmonary artery to the lower lobe). A multiple stepwise regression analysis (including one Doppler parameter, two parameters of arterial blood gases, and one functional parameter) revealed a coefficient of determination (R ²) equal to 0.954 for mean pulmonary artery pressure (MPAP) with a standard error of estimate (S.E.E.) of 5.25 mmHg. A stepwise regression analysis including computed tomography and radiographic parameters revealed an R ² equal to 0.970 for PAP with a S.E.E. of 4.26 mmHg. Logistical regression analysis classified correctly 80% of patients with PAH using noninvasive methods such as the diameter of the main pulmonary artery and the diameter of the left pulmonary arterial branch calculated by computed tomography. Not only the presence of PAH but also the level of MPAP can be estimated by the combination of multiple stepwise and logistical regression analyses. Accepted for publication: 13 August 1998     

Angiotensin-converting Enzyme Activity by Canine Pulmonary Microvascular and Central Pulmonary Artery Endothelial Cells Exposed to Hypoxia

To compare the amount of angiotensin-converting enzyme (ACE) activity in pulmonary artery endothelial cells from different sites and to examine the effect of severe hypoxia (less than 1% of O₂ in 5% CO₂ and 95% N₂) on the ACE activity expressed by these cells, endothelial cells were harvested and cultured from canine main pulmonary artery by scraping the luminal surface of the artery and from canine pulmonary artery microvessels by infusing chilled buffer with microcarrier beads and 0.02% ethylenediamine tetraacetic acid (EDTA). ACE activity in cell lysates and culture medium was evaluated by fluorometric assay with hippuryl-L-histidyl-L-leucine as a substrate. ACE activity in cell lysates and postculture medium of pulmonary microvascular endothelial cells (PMVEC) was higher than in cell lysates and culture medium of central pulmonary artery endothelial cells (PAEC). However, hypoxia suppressed cellular ACE activity in both PAEC and PMVEC. The degree of suppression of ACE activity by hypoxia, which was determined as (ACE activity in normoxia − ACE activity in hypoxia)/ACE activity in normoxia × 100(%), was larger in PMVEC than in PAEC. The pulmonary microvasculature may be a greater source of ACE than central pulmonary artery, and the ACE activity of pulmonary microvascular endothelial cells seem to be sensitive to hypoxia, although the small diameter of the vessels improves conditions for interaction of blood-borne substance with endothelial enzymes. Accepted for publication 10 July 2000     

A Murine Model of Latex Allergy-Induced Airway Hyperreactivity

Sensitization to latex proteins can cause immediate IgE mast cell-mediated reactions. Health care workers have been found to be particularly at risk because of high exposure. Latex allergy can be produced in mice as demonstrated by IgE and eosinophil responses. Thus the mouse is a potential animal model for studying this disease, but the airway response to latex sensitization in mice has not been evaluated previously. In the present study, we immunized BALB/c mice intranasally with nonammoniated latex proteins. Animals were anesthetized, and lung mechanics were evaluated plethysmographically. Changes in pulmonary conductance (G_L) and compliance (C_dyn) were measured in response to a nonspecific challenge with methacholine or to a direct challenge with intravenous latex antigen. Latex sensitization resulted in elevated levels of IgE and latex-specific IgG₁ as well as interstitial infiltrates consistent with an allergic response. The methacholine dose-response ED₅₀ for G_L was 116.4 μg for the control mice and fell significantly to 20.9 μg for latex-sensitized mice. The ED₅₀ calculated for C_dyn was also significantly lower after latex sensitization. The G_L in latex-sensitized mice challenged with latex antigen fell significantly from a prechallenge value of 1.87 ± 0.41 (S.E.) to 0.198 ± 0.03 ml · s⁻¹· cmH₂O after latex antigen challenge. The results indicate that latex-sensitized mice did exhibit increased airway reactivity in the methacholine challenge test. The latex allergic response in mice is unique in that direct challenge with latex antigen itself also resulted in a significant airway response. Accepted for publication: 10 September 1998     

Effects of Halothane, Enflurane, Isoflurane, and Sevoflurane on Slowly Adapting Pulmonary Stretch Receptor Activity in Anesthetized Dogs

The aim of this study was to evaluate the effects of halothane, enflurane, isoflurane, and sevoflurane on slowly adapting pulmonary stretch receptor (SAR) activity in dogs. Eight beagles were anesthetized with an intravenous injection of a mixture of urethane and α-chloralose as a basal anesthesia, then vagotomized, artificially ventilated, and chest opened. Single afferent activities from SARs were recorded from the peripheral nerve cut end of the left vagus. Changes in SAR activities with inhalation of halothane, enflurane, isoflurane, and sevoflurane at 1, 1.5, and 2 times the minimal alveolar anesthetic concentration (MAC) were measured, and differences in the discharges within and among four anesthetics were evaluated. As a result, two different types of SARs, low threshold SARs and high threshold SARs, were detected in this study. In all anesthetics, expiratory discharges of low threshold SARs decreased significantly in a dose-dependent manner, whereas inspiratory discharges did not change significantly at any anesthetic level. Discharges of high threshold SARs tended to decrease with increasing anesthetic level; however, no statistical significance was observed at any anesthetic level. Only one exception to these changes was observed at 1 MAC of halothane where no significant decrease in the expiratory discharge of low threshold SARs or significant increase in the discharge of high threshold SARs was induced against a control value. In conclusion, recent inhalation anesthetics, except for halothane at the light anesthetic level, tended to decrease SAR activities depending on the anesthetic level, suggesting attenuation of the Hering-Breuer inflation reflex.