Cotton Smoke Inhalation Primes Alveolar Macrophages for Tumor Necrosis Factor-α Production and Suppresses Macrophage Antimicrobial Activities

The present study determined the effects of cotton smoke inhalation on the functioning of alveolar macrophages (mφ). Smoke inhalation led to dose-dependent impairment of respiratory gas exchange by 48 h postexposure and pulmonary edema by 96 h. Maximal effects were observed in animals ventilated with 54 breaths of cotton smoke (3-min exposure, 18 breaths/min). Macrophages were obtained at 48 h postexposure by bronchoalveolar lavage of rabbits subjected to 54 breaths of smoke or room air (control). Phagocytosis of opsonized bacteria and adherence to solid substratum were reduced in smoke-exposed mφ. Smoke inhalation primed mφ for release of tumor necrosis factor-α (TNF-α) induced by lipopolysaccharide (LPS). Smoke-exposed mφ were also primed for TNF-α release induced by phorbol myristate acetate, which suggests that the priming event occurred downstream of protein kinase C activation in the signal transduction pathway. Further, smoke exposure attenuated the inhibitory effects of phosphodiesterase inhibitors on LPS-induced TNF-α release. Thus, the priming event may be mediated through cAMP and/or protein kinase A. The data indicate that cotton smoke inhalation suppresses the antimicrobial activities of alveolar mφ and can lead to excessive mφ production of TNF-α. These mφ effects would be expected to contribute to the pathophysiological abnormalities associated with smoke inhalation injury. Accepted for publication: 19 February 1998     

High MW hyaluronan inhibits smoke inhalation‐induced lung injury and improves survival

Background and objective: High MW hyaluronan (HMW HA) as opposed to low MW hyaluronan (LMW HA) has been shown to have anti‐inflammatory and anti‐apoptotic effects. We hypothesized that treatment with HMW HA would block smoke inhalation lung injury by inhibiting smoke‐induced lung inflammation and airway epithelial cell apoptosis. Methods: Anesthetized, intubated male rats were randomly allocated to either control or smoke inhalation injury groups. Rats were treated with 3‐mL subcutaneous normal saline solution (sham) or LMW HA (35 kDa) or HMW HA (1600 kDa) 18 h before exposure to 15 min of cotton smoke (n = 5 each). Rats were also treated post smoke inhalation with 1600 kDa HA by intra‐peritoneal injection (3 mL) or intra‐tracheal nebulization (200 µL). Lung neutrophil infiltration, airway apoptosis, airway mucous plugging and lung injury were assessed 4 h after smoke inhalation injury. Results: Rats pretreated with 1600 kDa HA had significantly less smoke‐induced neutrophil infiltration, lung oedema, airway apoptosis and mucous plugging. Pretreatment with 35 kDa HA, in contrast, increased smoke‐induced neutrophil infiltration and lung injury score. Intra‐tracheal administration of a single dose 1600 kDa HA, but not intra‐peritoneal injection, significantly improved survival post smoke inhalation. Conclusions: High MW hyaluronan (1600 kDa) may prove to be a beneficial therapy for smoke inhalation through inhibition of smoke‐induced inflammation, lung oedema, airway epithelial cell apoptosis and airway mucous plugging.     

Lipopolysaccharide Tolerance in Relation to Intrabronchial Influx of Neutrophils in the Rat

Lipopolysaccharide (LPS) is a potent chemotactic component for polymorphonuclear leukocytes (PMN, neutrophils). Since LPS tolerance was first described, many studies have been reported about the hyporesponsiveness in vitro corresponding to attenuating production of proinflammatory cytokines. We hypothesized that in vivo daily exposure to LPS stimuli impairs neutrophil accumulation in the rat airway. Interleukin 8 (IL-8) and/or CXC-chemokine, a neutrophil chemoattractant and activating cytokine, have been implicated as proinflammatory mediators in gram-negative respiratory tract infections. It is possible that the tolerance to LPS has occurred in relation to this chemoattractant cytokine production. To settle this issue, we examined whether the neutrophil count in bronchoalveolar lavage fluid (BALF) decreases after daily inhalation of Pseudomonas aeruginosa LPS into the rat airway. Repeated inhalation of LPS into the airway resulted in reduction in neutrophil recruitment. We measured rat CXC-chemokine (rat GRO/CINC1) levels in recovered BALF. There were noted reductions of rat GRO corresponding to the diminished neutrophil trafficking. We also confirmed that the HLA-DR positive lymphocyte number in BALF gradually increased after daily inhalation of LPS. These results suggest that continuous stimuli of LPS mitigate the accumulation of inflammatory cells in the airway by reducing chemokine production with a consequent change in the appearance of local inflammation to a chronic state. Accepted for publication 25 May 2000     

The inducible nitric oxide synthase inhibitor BBS-2 prevents acute lung injury in sheep after burn and smoke inhalation injury

In this study we examined the role of inducible nitric oxide synthase (iNOS) in acute respiratory distress syndrome (ARDS) in sheep with severe combined burn and smoke inhalation injury. BBS-2, a potent and highly selective iNOS dimerization inhibitor, was used to exclude effects on the endothelial and neuronal NOS isoforms. Seven days after surgical recovery, sheep were given a burn (40% of total body surface, 3rd degree) and insufflated with cotton smoke (48 breaths, < 40 degrees C) under anesthesia. BBS-2 was provided by constant infusion at 100 microg/kg/hour, beginning 1 hour after injury. During 48 hours, control sheep developed multiple signs of ARDS. These included decreased pulmonary gas exchange, increased pulmonary edema, abnormal lung compliance, and extensive airway obstruction. These pathologies were associated with a large increase in tracheal blood flow and elevated plasma NO2-/NO3- (NOx) levels. These variables were all stable in sham animals. Treatment of injured sheep with BBS-2 attenuated the increases in tracheal blood flow and plasma NOx levels, and significantly attenuated all the pulmonary pathologies that were noted. The results provide definitive evidence that iNOS is a key mediator of pulmonary pathology in sheep with ARDS resulting from combined burn and smoke inhalation injury.     

Modulation of Airway Responsiveness to Acetylcholine by Nitric Oxide in a Rabbit Model

Nitric oxide (NO) is an important mediator in the regulation of bronchial muscle tone and airway responsiveness. We investigated the influence of exogenous NO on airway responsiveness to acetylcholine aerosols (ACH) in normal and in hyperresponsive rabbits. White New Zealand rabbits were anesthetized, intubated, and breathed room air spontaneously. Responses of respiratory parameters in ACH challenge tests were measured. In group A the influence of NO on ACH infusion-induced airway constriction was measured. Airway responses to aerosols from 0.25 to 8.0% ACH solutions in saline were measured with 150 and 300 ppm NO inhalation (groups B and C) and compared with the same animals' responses without NO. Moreover, we examined the influence of NO synthase inhibition on airway responsiveness (group D) and the modulatory effect of NO in hyperresponsive animals (group E). 300 ppm NO inhalation significantly decreased the bronchoconstrictor response to intravenously administered ACH (group A). However, the baseline value of dynamic elastance (E_dyn) was only marginally lower under the influence of 300 ppm NO. During inhalation of 150 or 300 ppm NO, responses to nebulized 2.0% and less ACH solutions remained nearly unaltered. Responses to aerosols of 4.0 and 8.0% diminished significantly (groups B and C). Following 40 min of aerosolized N-nitro-l-arginine-methyl ester (l-NAME) solution (a NO synthase inhibitor, 1.2 mM) inhalation, the response of E_dyn to ACH increased significantly in group D. In group E, animals inhaled 500 mg/m³ ammonium persulfate (APS), an oxidant with various industrial applications, after the first ACH challenge test (0.2, 1.0, and 2.0% ACH). After 2 h of APS exposure, the ACH-induced broncho constriction was increased significantly in the challenge test. After another 2 h of APS inhalation, the airway responsiveness to ACH was tested under the influence of 300 ppm NO. NO significantly decreased the response to ACH to almost the same level as before APS exposure. The results indicate that responses to high ACH concentrations as well as an APS-induced increase in ACH responsiveness were effectively reduced by high concentrations of inhaled NO. Accepted for publication: 11 February 1997     

Long Term Cigarette Smoke Exposure Does Not Increase Airway Responsiveness in Rats

To ascertain whether chronic cigarette smoke exposure induces increased airway responsiveness, we performed methacholine response tests in Sprague-Dawley rats by calculating pulmonary resistance after nebulization of saline followed by an increasing concentration of methacholine. We also calculated the concentration of methacholine which doubled the baseline resistance (R200). Tests were performed at baseline and after 2, 4, 8, and 12 months of exposure to the smoke of seven cigarettes per day, 5 days each week; control animals were exposed to room air. At the completion of the study, there were 13 rats in the smoke-exposed group and 7 rats remaining in the control group. Airway morphology was assessed using a point counting technique. We found that (1) chronic exposure to cigarette smoke did not alter either the baseline resistance or the R200; (2) the saline baseline resistance decreased over time in the control animals; and (3) at the 12-month time point, smokers with increased baseline airway resistance had greater amounts of airway smooth muscle compared with the smoke-exposed animals without increased resistance. We conclude that in this animal model, long term exposure to cigarette smoke did not alter the response to methacholine but did increase airway smooth muscle and baseline resistance in some but not all animals. Accepted for publication: 4 December 1997     

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     

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     

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     

Reflex bradypnea elicited by cigarette smoke inhaled through an isolated larynx

The respiratory reflex responses elicited by laryngeal exposure to cigarette smoke were studied in 23 chloralose anesthetized dogs. A balloon-in-box system was connected to the breathing circuit, which allowed smoke to be inhaled spontaneously through an isolated larynx while preserving its normal respiratory flow and pressure. Our results in this study showed the following. (1) Two tidal breaths of cigarette smoke inhaled through the larynx triggered a mild but consistent bradypnea: expiratory duration (TE) increased from a control of 3.13 +/- 0.18 sec (mean +/- SEM) to a peak of 4.07 +/- 0.24 sec during smoke inhalation. The slowing of respiration occurred only during the period of smoke inhalation and returned quickly toward control after resuming air breathing. (2) No concomitant cardiovascular response was detected in these animals. (3) There was no significant difference in the prolongation of TE between responses to low- and high-nicotine cigarette smoke. (4) The bradypneic response to smoke was completely abolished by application of topical anesthetic (lidocaine hydrochloride) to the mucosa of this airway segment. These results suggest that the smoke-induced reflex bradypnea is probably elicited by a stimulation of laryngeal afferents.     

Predictive role of arterial carboxyhemoglobin concentrations in ovine burn and smoke inhalation-induced lung injury

Inhalation injury frequently occurs in burn patients and contributes to the morbidity and mortality of these injuries. Arterial carboxyhemoglobin has been proposed as an indicator of the severity of inhalation injury; however, the interrelation between arterial carboxyhemoglobin and histological alterations has not yet been investigated. Chronically instrumented sheep were subjected to a third degree burn of 40% of the total body surface area and inhalation of 48 breaths of cotton smoke. Carboxyhemoglobin was measured immediately after injury and correlated to clinical parameters of pulmonary function as well as histopathology scores from lung tissue harvested 24 hours after the injury. The injury was associated with a significant decline in pulmonary oxygenation and increases in pulmonary shunting, lung lymph flow, wet/dry weight ratio, congestion score, edema score, inflammation score, and airway obstruction scores. Carboxyhemoglobin was negatively correlated to pulmonary oxygenation and positively correlated to pulmonary shunting, lung lymph flow, and lung wet/dry weight ratio. No significant correlations could be detected between carboxyhemoglobin and histopathology scores and airway obstruction scores. Arterial carboxyhemoglobin in sheep with combined burn and inhalation injury are correlated with the degree of pulmonary failure and edema formation, but not with certain histological alterations including airway obstruction scores.     

Effects of Initial Low Flow Reperfusion and Surfactant Administration on the Viability of Perfused Cadaveric Rat Lungs

To expand the cadaveric lung donor pool, protecting the endothelium and alveoli from warm ischemia and reperfusion injury is important. The effects of initial low flow reperfusion and surfactant administration were studied in non–heart-beating donor lungs. The rat heart-lung bloc was excised immediately (group 1) or 30 min (groups 2–4) after euthanasia (n= 6 in each group). The graft was ventilated and reperfused (50 ml/min) immediately after excision for 1 h in groups 1 and 2. In groups 3 and 4, the reperfusion flow rate was increased gradually to 50 ml/min, while ensuring that the pulmonary arterial pressure did not exceed 40 mmHg. Then the graft was reperfused for 1 h. Surfactant was introduced into the airway in group 4 before reperfusion. Airway pressure (AWP) and pulmonary arterial pressure were monitored during reperfusion. After reperfusion, the wet/dry weight ratio (W/D) of the right lung was calculated, and histologic examination using trypan blue staining of the left lung was performed. In group 2, lung failure appeared in all animals during reperfusion. In group 3, although all lungs were reperfused for 1 h, AWP and W/D were higher than in group 1. In group 4, AWP and W/D were lower than in group 3. Histologic examination showed that surfactant administration had attenuated the alveolar cell death. To avoid damage caused by high pulmonary arterial pressure associated with graft reperfusion, iniital low flow reperfusion was beneficial in cadaveric lungs. Surfactant administration before reperfusion was effective in preventing pulmonary edema. Accepted for publication: 16 July 1998     

COPD: a dust-induced disease?

Various reports have demonstrated the importance of small airway inflammation in the development of airflow limitation and progression of COPD. This hypothesis proposes that the pathogenesis of COPD mirrors a chronic inhalational dust-induced disease. The putative inorganic dust in cigarette smoke is aluminum silicate or kaolinite, a common component of clay soils. Kaolinite has been recovered in the alveolar macrophages of smokers and has been reported as a constituent of tobacco products. The origin of kaolinite in tobacco products remains unknown, and possible potential sources are proposed. On inhalation, kaolinite deposition in the distal lung may promote macrophage accumulation within the terminal airways leading to a respiratory bronchiolitis. In the susceptible smoker, important genetic, environmental, immunologic, and mechanical factors interact and modulate this small airway inflammation, ultimately leading to the pathologic lesion of emphysema. Further studies into the effects of kaolinite on macrophage function and the subsequent development of respiratory bronchiolitis could lead to prevention of COPD at its precursor lesion.     

Inhibitory effect of gas phase cigarette smoke on breathing: role of hydroxyl radical

Inhaling cigarette smoke evokes immediate bradypnea in rats, resulting from stimulation of vagal bronchopulmonary C-fiber afferents by smoke constituent(s) other than nicotine. To determine the contribution of the gas phase of smoke to this irritant effect, the acute respiratory responses to both cigarette smoke and gas phase smoke were studied and compared in anesthetized Sprague-Dawley rats; smoke (6 ml, 50%) was generated by a machine from low-nicotine research cigarettes and the gas phase was obtained by passing the smoke through a glass-fiber Cambridge filter. Inhalation of gas phase smoke alone evoked a transient inhibitory effect on breathing, prolonging expiratory time (Te) to a peak of 159 +/- 6% of the base line; this response was very similar to that triggered by inhaling the unfiltered smoke (Te = 177 +/- 12%). The bradypnea started within 1-4 breaths after the onset of smoke inhalation, lasted for 3-5 breaths and was completely abolished by vagotomy. This inhibitory effect of gas phase smoke on breathing was also largely prevented after a pretreatment with either intravenous infusion or aerosol inhalation of a hydroxyl radical scavenger, dimethylthiourea. These results suggest that the gas phase is primarily responsible for eliciting the reflexogenic bradypneic response to cigarette smoke in anesthetized rats and that hydroxyl radicals released endogenously in the lungs may be involved.     

Impaired alveolar macrophage chemotaxis in patients with acute smoke inhalation.

Pulmonary infection is a leading cause of death in patients with smoke inhalation; however, few studies have evaluated the effects of inhaled smoke on the host defense mechanisms of the lung. In this study we investigated the effects of acute smoke inhalation on the random and chemotactic (stimulated unidirectional) migration of human pulmonary alveolar macrophages. Fiberoptic subsegmental pulmonary lavage was performed in 19 normal subjects (12 nonsmokers and 7 smokers) and 7 patients with smoke inhalation. After quantification of lavaged cell populations, random and chemotactic migration was measured using modified Boyden chambers. Zymosan-activated serum was used as a chemotactic stimulant. Mean +/- SE random migration was 6.2 +/- 0.8 cells per 20 microscopic fields in smoking control subjects, 5.7 +/- 0.7 in nonsmoking control subjects, and 5.2 +/- 0.7 in patients with smoke inhalation. These values are not significantly different. In contrast, the mean directed (chemotactic) migration of pulmonary alveolar macrophages was 26.5 +/- 1.9 in smoking control subjects, 22.7 +/- 3.0 in nonsmoking control subjects, and 11.4 +/- 1.4 in patients with smoke inhalation; the latter response was significantly different from that of the smoking (P less than 0.001) and nonsmoking (P less than 0.025) control subjects and the combined average of the 2 control groups (P less than 0.001. In vitro exposure of pulmonary alveolar macrophages to nontoxic doses of smoke produced similar impairment of chemotaxis. These findings may partially explain the enhanced susceptibility of patients with smoke inhalation to pulmonary infection.     

烟雾吸入性急性肺损伤/急性呼吸窘迫综合征的研究进展

目前烟雾吸入性急性肺损伤（ALI）／急性呼吸窘迫综合征（ARDS）的发病机制尚未完全明确,可能与烟雾所致的氧化性损伤、肺表面活性物质变化、细胞因子改变、细胞凋亡的发生有关。与机制相应的治疗方法仍未找到,常见的临床治疗方法（如：机械通气,肺泡灌洗,药物治疗）虽然已被证明有一定疗效,但仍然无法治愈烟雾吸入性ALI／ARDS。体外二氧化碳排除及一氧化氮治疗等新方法的尝试为我们进一步研究烟雾吸入性ALI／ARDS提供了新的思路。     

Airway resistance and deposition of particles in the lung

The percentage 24-h lung retention of 4-micrometers monodispersed Teflon particles, aerodynamic diameter about 6 micrometers, was studied twice in 8 healthy nonsmokers. The particles were inhaled at 0.5 liter/sec with maximally deep breaths. Bronchoconstriction was induced by inhalation of a methacholine-bromide aerosol for one exposure before and for the other 20-30 min after the inhalation of the Teflon particles. For both exposures, airway resistance (Raw) was measured with a whole body plethysmograph before and after the induction of the bronchoconstriction and was found on an average to increase with a factor of 2-3. For the exposure when bronchoconstriction was induced after the inhalation of the Teflon particles, Raw and 24-h lung retention correlated significantly. Retention at 24 h was markedly lower when bronchoconstriction was induced before inhalation of the Teflon particles than when bronchoconstriction was induced after, the ranges being 13-24% and 38-68%, respectively. The experimental data agreed well with theoretical data from a lung model wherein the diameters of the airways were varied. The results indicate that the magnitude of bronchoconstriction occurring in real life can protect the alveolar part of the lung by reducing the amount of inhaled particles that deposit there.     

Effects of Lidocaine on Cytosolic pH Regulation and Stimulus-Induced Effector Functions in Alveolar Macrophages

Local anesthetics influence a variety of stimulus-induced effector functions in leukocytes. The present study determined the effects of lidocaine on intracellular pH (pH_i) regulation, superoxide production, and tumor necrosis factor-α (TNF-α) release in alveolar macrophages (mφ). Resident mφ were obtained by bronchoalveolar lavage of rabbits. The cells were subjected to an intracellular acid load, and subsequent pH_i recovery was followed in the presence or absence of bafilomycin A₁, a specific inhibitor of V-type H⁺-translocating ATPase (V-ATPase) or amiloride, an inhibitor of Na⁺/H⁺ exchange. Lidocaine slowed pH_i recovery in a dose-dependent manner. Pretreatment (1 h) with 2.5 mM lidocaine abolished Na⁺/H⁺ exchange and reduced the V-ATPase-mediated component of pH_i recovery. Lidocaine also significantly depressed the superoxide production induced by phorbol ester. TNF-α release induced by endotoxin was not affected significantly by the local anesthetic. Macrophage viability (trypan blue exclusion) and cellular ATP concentration were unaffected. These results indicate that lidocaine inhibits pH_i regulatory mechanisms in alveolar mφ. This disruption of pH_i regulation could contribute to inhibitory actions of lidocaine on mφ effector functions. Accepted for publication: 28 January 1997     

Characterization of the lower respiratory tract inflammation of nonsmoking individuals with interstitial lung disease associated with chronic inhalation of inorganic dusts

The pneumoconioses, interstitial lung disorders resulting from the inhalation of inorganic dusts, are associated with chronic inflammatory processes in the lower respiratory tract. To characterize these inflammatory processes in relation to the pathogenesis of these disorders, we studied 39 nonsmoking individuals with long-term occupational exposures to inorganic dust and functional evidence of interstitial disease (asbestosis, n = 18; coal workers' pneumoconiosis, n = 15; silicosis, n = 6). In all 3 disorders, the inflammation was dominated by alveolar macrophages. Because a common feature of these interstitial lung diseases is concurrent injury and fibrosis of alveolar walls, we assessed whether these alveolar macrophages were spontaneously releasing mediators capable of giving rise to these changes. Alveolar macrophages from the study population were spontaneously releasing increased amounts of superoxide anion and hydrogen peroxide (both p less than 0.01 compared to normals), oxidants capable of injuring lung parenchymal cells. The alveolar macrophages were also spontaneously releasing significantly increased amounts of fibronectin and alveolar macrophage-derived growth factor (both p less than 0.01 compared to normals), mediators that act synergistically to signal fibroblast replication. Taken together, these findings define a major role for the alveolar macrophage in mediating the alveolar wall injury and fibrosis that characterize the common pneumoconioses and suggest that the alveolar macrophage is an important "target" for developing strategies designed to prevent loss of lung function in these individuals.     

Effects of Vagal and Carotid Chemoreceptor Afferents on the Frequency and Pattern of Spontaneous Augmented Breaths in Rabbits

We investigated the effects of vagal afferents and carotid chemoreceptors on the frequency and pattern of spontaneous augmented breaths in anesthetized rabbits by analyzing the changes in the phrenic nerve discharge. Blockade of vagal C-fiber conduction by capsaicin treatment greatly reduced the frequency of spontaneous augmented breaths but had no significant effect on the pattern of the augmented breaths. Inhalation of sulfur dioxide, which abolished the Hering-Breuer inflation reflex, suppressed the frequency of spontaneous augmented breaths but did not significantly alter the pattern of the augmented breaths. Carotid sinus denervation diminished both the frequency and amplitude of spontaneous augmented breaths. The occurrence of spontaneous augmented breaths was not observed in rabbits after bilateral vagotomy. In other experiments we examined the relationship between rapidly adapting pulmonary stretch receptors (RARs) and dynamic lung compliance during the spontaneous augmented breath. The stimulation of RARs occurred at the first phase of spontaneous augmented breaths, and augmentation of transpulmonary pressure seen at the second phase coincided with vigorous stimulation of the receptor activity. These results suggest that spontaneous augmented breaths may be mediated by the summation of several facilitatory inputs from vagal and carotid chemoreceptor afferents. Accepted for publication: 8 October 1996