CD14 is an essential mediator of LPS-induced airway disease

Chronic lipopolysaccharide (LPS) inhalation in rodents recapitulates many classic features of chronic obstructive pulmonary disease seen in humans, including airways hyperresponsiveness, neutrophilic inflammation, cytokine production in the lung, and small airways remodeling. CD14-deficient mice (C57BL/6(CD14-/-)) have an altered response to systemic LPS, and yet the role of CD14 in the response to inhaled LPS has not been defined. We observed that C57BL/6(CD14-/-) mice demonstrate no discernable physiological or inflammatory response to a single LPS inhalation challenge. However, the physiological (airways hyperresponsiveness) and inflammatory (presence of neutrophils and TNF-alpha in whole lung lavage fluid) responsiveness to inhaled LPS in C57BL/6(CD14-/-) mice was restored by instilling soluble CD14 intratracheally. Intratracheal instillation of wild-type macrophages into C57BL/6(CD14-/-) mice restored neutrophilic inflammation only and failed to restore airways hyperresponsiveness or TNF-alpha protein in whole lung lavage. These findings demonstrate that CD14 is critical to LPS-induced airway disease and that macrophage CD14 is sufficient to initiate neutrophil recruitment into the airways but that CD14 may need to interact with other cell types as well for the development of airways hyperresponsiveness and for cytokine production.     

ASTHMA,CHRONIC BRONCHITIS AND EMPHYSEMA—The Use of Intermittent Positive Pressure Breathing with Inspiratory Flow Rate Control: A Review of the Literature

In chronic obstructive lung disease (asthma, chronic bronchitis, obstructive emphysema) there is a segmental reduction in the caliber of the airways, which always results in obstruction to air-flow. Increased airway resistance is a physiological expression of airway obstruction.The addition of inspiratory flow rate control to an intermittent positive pressure breathing device permits slow filling of a lung with obstructed airways, and is presented as a simple means of reducing the high pulmonary flow resistance and increasing the tidal volume.     

A PAF receptor antagonist inhibits acute airway inflammation and late-phase responses but not chronic airway inflammation and hyperresponsiveness in a primate model of asthma

We have examined the effects of a PAF receptor antagonist, WEB 2170, on several indices of acute and chronic airway inflammation and associated changes in lung function in a primate model of allergic asthma. A single oral administration WEB 2170 provided dose related inhibition of the release of leukotriene C(4) (LTC(4)) and prostaglandin D(2) (PGD(2)) recovered and quantified in bronchoalveolar lavage (BAL) fluid obtained during the acute phase response to inhaled antigen. In addition, oral WEB 2170 treatment in dual responder primates blocked the acute influx of neutrophils into the airways as well as the associated late-phase airway obstruction occurring 6 h after antigen inhalation. In contrast, a multiple dosing regime with WEB 2170 (once a day for 7 consecutive days) failed to reduce the chronic airway inflammation (eosinophilic) and associated airway hyperresponsiveness to inhaled methacholine that is characteristic of dual responder monkeys. Thus, we conclude that the generation of PAF following antigen inhalation contributes to the development of lipid mediators, acute airway inflammation and associated late-phase airway obstruction in dual responder primates; however, PAF does not play a significant role in the maintenance of chronic airway inflammation and associated airway hyperresponsiveness in this primate model.     

O3-induced change in bronchial reactivity to methacholine and airway inflammation in humans

The increase in airway responsiveness induced by O3 exposure in dogs is associated with airway epithelial inflammation, as evidenced by an increase in the number of neutrophils (polymorphonuclear leukocytes) found in epithelial biopsies and in bronchoalveolar lavage fluid. We investigated in 10 healthy, human subjects whether O3-induced hyperresponsiveness was similarly associated with airway inflammation by examining changes in the types of cells recovered in bronchoalveolar lavage fluid obtained after exposure to air or to O3 (0.4 or 0.6 ppm). We also measured the concentrations of cyclooxygenase and lipoxygenase metabolites of arachidonic acid in lavage fluid. We measured airway responsiveness to inhaled methacholine aerosol before and after each exposure and performed bronchoalveolar lavage 3 h later. We found more neutrophils in the lavage fluid from O3-exposed subjects, especially in those in whom O3 exposure produced an increase in airway responsiveness. We also found significant increases in the concentrations of prostaglandins E2, F2 alpha, and thromboxane B2 in lavage fluid from O3-exposed subjects. These results show that in human subjects O3-induced hyperresponsiveness to methacholine is associated with an influx of neutrophils into the airways and with changes in the levels of some cyclooxygenase metabolites of arachidonic acid.     

Surfactant phospholipid changes after antigen challenge: a role for phosphatidylglycerol in dysfunction

In asthma, inflammation-mediated surfactant dysfunction contributes to increased airway resistance, but the mechanisms for dysfunction are not understood. To test mechanisms that alter surfactant function, atopic asthmatics underwent endobronchial antigen challenge and bronchoalveolar lavage (BAL). BAL fluids were sequentially separated into cells, surfactant, and supernatant, and multiple end points were analyzed. Each end point's unique relationship to surfactant dysfunction was determined. Our results demonstrate that minimum surface tension (gamma(min)) of surfactant after antigen challenge was significantly increased with a spectrum of responses that included dysfunction in 6 of 13 asthmatics. Antigen challenge significantly altered the partitioning of surfactant phospholipid measured as a decreased ratio of large surfactant aggregates (LA) to small surfactant aggregates (SA), LA/SA ratio. Phosphatidylglycerol (PG) was significantly reduced in the LA of the dysfunctional asthmatic BALs. There was a corresponding significant increase in the ratio of phosphatidylcholine to PG, which strongly correlated with both increased gamma(min) and decreased LA/SA. Altered surfactant phospholipid properties correlated with surfactant dysfunction as well or better than either increased eosinophils or protein. Secretory phospholipase activity, measured in vitro, increased after antigen challenge and may explain the decrease in surfactant PG. In summary, alteration of phospholipids, particularly depletion of PG, in the LA of surfactant may be an important mechanism in asthma-associated surfactant dysfunction.     

Lung epithelium damage in COPD – An unstoppable pathological event?

Chronic obstructive pulmonary disease (COPD) is a common term for alveolar septal wall destruction resulting in emphysema, and chronic bronchitis accompanied by conductive airway remodelling. In general, this disease is characterized by a disbalance of proteolytic/anti-proteolytic activity, augmented inflammatory response, increased oxidative/nitrosative stress, rise in number of apoptotic cells and decreased proliferation. As the first responder to the various environmental stimuli, epithelium occupies an important position in different lung pathologies, including COPD.Epithelium sequentially transitions from the upper airways in the direction of the gas exchange surface in the alveoli, and every cell type possesses a distinct role in the maintenance of the homeostasis. Basically, a thick ciliated structure of the airway epithelium has a major function in mucus secretion, whereas, alveolar epithelium which forms a thin barrier covered by surfactant has a function in gas exchange.Following this line, we will try to reveal whether or not the chronic bronchitis and emphysema, being two pathological phenotypes in COPD, could originate in two different types of epithelium. In addition, this review focuses on the role of lung epithelium in COPD pathology, and summarises underlying mechanisms and potential therapeutics.     

Cytological and biochemical indices of induced sputum in patients with bronchial asthma and chronic obstructive bronchitis

The aim of our research was to study the apoptotic index and the representativeness of CD95-receptor in the effector cells, in addition to estimation of the content of tumor necrosis factor-alpha in the induced sputum supernatant observed in patients with bronchial asthma and chronic obstructive bronchitis. These indices were evaluated in the disease dynamics and involves various treatment programs. The object of our research was induced sputum. The analysis has proven that apoptotic index of effector cell nuclei, representativeness of CD95-receptor and the content of tumor necrosis factor-alpha in the induced sputum differed, respectively, in patients with bronchial asthma and chronical obstructive bronchitis, and depended on the period of disease and employed treatment. The induced sputum analysis results can be used for the airway inflammation activity monitoring, with regard to these diseases and to treatment efficiency monitoring.     

Reassessment of inflammation of airways in chronic bronchitis.

The term chronic bronchitis has been criticised because it is associated with hypersecretion of mucus rather than bronchial inflammation. This study was designed to establish the presence or absence of clinical chronic bronchitis and measure pulmonary function in 45 patients about to undergo resection of the lung. The condition in the cartilaginous and small airways and the severity of the emphysema were then measured in the resected specimen. The results from 20 patients who had clinical chronic bronchitis were compared with those in 25 patients who did not. The data show that patients with chronic bronchitis had greater inflammation (a) on mucosal surfaces (p less than 0.05) of all bronchi larger than 2 mm luminal diameter and (b) around glands (p less than 0.005) and gland ducts (p less than 0.05) in bronchi larger than 4 mm diameter. A variable degree of inflammation was present in the submucosa of smaller bronchi. The groups had equivalent proportions of mucous glands and Reid''s indices in central airways, and no differences were noted in measurements of pulmonary function, condition of small airways, or emphysema. These data show that the term chronic bronchitis is justified by inflammation of cartilaginous airways and suggest that this abnormality may be the cause of the chronic productive cough.     

Sequential analysis of surfactant,lung function and inflammation in cystic fibrosis patients

Background

In a cross-sectional analysis of cystic fibrosis (CF) patients with mild lung disease, reduced surfactant activity was correlated to increased neutrophilic airway inflammation, but not to lung function. So far, longitudinal measurements of surfactant function in CF patients are lacking and it remains unclear how these alterations relate to the progression of airway inflammation as well as decline in pulmonary function over time.

Methods

As part of the BEAT trial, a longitudinal study to assess the course of airway inflammation in CF, we studied lung function, surfactant function and endobronchial inflammation using bronchoalveolar lavage fluid from 20 CF patients with normal pulmonary function (median FEV₁ 94% of predicted) at three times over a three year period.

Results

There was a progressive loss of surfactant function, assessed as minimal surface tension. The decline in surfactant function was negatively correlated to an increase in neutrophilic inflammation and a decrease in lung function, assessed by FEV₁, MEF_75/25%VC, and MEF_25%VC. The concentrations of the surfactant specific proteins A, C and D did not change, whereas SP-B increased during this time period.

Conclusion

Our findings suggest a link between loss of surfactant function driven by progressive airway inflammation and loss of small airway function in CF patients with limited lung disease.     

Vascular endothelial growth factor: an angiogenic factor reflecting airway inflammation in healthy smokers and in patients with bronchitis type of chronic obstructive pulmonary disease?

BackgroundPatients with bronchitis type of chronic obstructive pulmonary disease (COPD) have raised vascular endothelial growth factor (VEGF) levels in induced sputum. This has been associated with the pathogenesis of COPD through apoptotic and oxidative stress mechanisms. Since, chronic airway inflammation is an important pathological feature of COPD mainly initiated by cigarette smoking, aim of this study was to assess smoking as a potential cause of raised airway VEGF levels in bronchitis type COPD and to test the association between VEGF levels in induced sputum and airway inflammation in these patients.Methods14 current smokers with bronchitis type COPD, 17 asymptomatic current smokers with normal spirometry and 16 non-smokers were included in the study. VEGF, IL-8, and TNF-α levels in induced sputum were measured and the correlations between these markers, as well as between VEGF levels and pulmonary function were assessed.ResultsThe median concentrations of VEGF, IL-8, and TNF-α were significantly higher in induced sputum of COPD patients (1,070 pg/ml, 5.6 ng/ml and 50 pg/ml, respectively) compared to nonsmokers (260 pg/ml, 0.73 ng/ml, and 15.4 pg/ml, respectively, p < 0.05) and asymptomatic smokers (421 pg/ml, 1.27 ng/ml, p < 0.05, and 18.6 pg/ml, p > 0.05, respectively). Significant correlations were found between VEGF levels and pack years (r = 0.56, p = 0.046), IL-8 (r = 0.64, p = 0.026) and TNF-α (r = 0.62, p = 0.031) levels both in asymptomatic and COPD smokers (r = 0.66, p = 0.027, r = 0.67, p = 0.023, and r = 0.82, p = 0.002, respectively). No correlation was found between VEGF levels in sputum and pulmonary function parameters.ConclusionVEGF levels are raised in the airways of both asymptomatic and COPD smokers. The close correlation observed between VEGF levels in the airways and markers of airway inflammation in healthy smokers and in smokers with bronchitis type of COPD is suggestive of VEGF as a marker reflecting the inflammatory process that occurs in smoking subjects without alveolar destruction.     

Altered allergen-induced eosinophil trafficking and physiological dysfunction in airways with preexisting virus-induced injury

Although both asthmatics and allergic rhinitics develop an acute inflammatory response to lower airway allergen challenge, only asthmatics experience airway obstruction resulting from chronic environmental allergen exposure. Hypothesizing that asthmatic airways have an altered response to chronic allergic inflammation, we compared the effects of repeated low-level exposures to inhaled Alternaria extract in sensitized rats with preexisting chronic postbronchiolitis airway dysfunction versus sensitized controls with normal airways. Measurements of air space (bronchoalveolar lavage) inflammatory cells, airway goblet cells, airway wall collagen, airway wall eosinophils, airway alveolar attachments, and pulmonary physiology were conducted after six weekly exposures to aerosolized saline or Alternaria extract. Postbronchiolitis rats, but not those starting with normal airways, had persistent increases in airway wall eosinophils, goblet cell hyperplasia in small airways, and loss of lung elastic recoil after repeated exposure to aerosolized Alternaria extract. Despite having elevated airway wall eosinophils, the postbronchiolitis rats had no eosinophils in bronchoalveolar lavage at 5 days after the last allergen exposure, suggesting altered egression of tissue eosinophils into the air space. In conclusion, rats with preexisting airway pathology had altered eosinophil trafficking and allergen-induced changes in airway epithelium and lung mechanics that were absent in sensitized control rats that had normal airways before the allergen exposures.     

The dendritic cell niche in chronic obstructive pulmonary disease

The pulmonary innate immune system is heavily implicated in the perpetual airway inflammation and impaired host defense characterizing Chronic Obstructive Pulmonary Disease (COPD). The airways of patients suffering from COPD are infiltrated by various immune and inflammatory cells including macrophages, neutrophils, T lymphocytes, and dendritic cells. While the role of macrophages, neutrophils and T lymphocytes is well characterized, the contribution of dendritic cells to COPD pathogenesis is still the subject of emerging research. A paper by Botelho and colleagues in the current issue of Respiratory Research investigates the importance of dendritic cell recruitment in cigarette-smoke induced acute and chronic inflammation in mice. Dendritic cells of the healthy lung parenchyma and airways perform an important sentinel function and regulate immune homeostasis. During inflammatory responses the function and migration pattern of these cells is dramatically altered but the underlying mechanisms are incompletely understood. Botelho and colleagues demonstrate here the importance of IL-1R1/IL-1α related mechanisms including CCL20 production in cigarette-smoke induced recruitment of dendritic cells and T cell activation in the mouse lung.     

How does airway inflammation modulate asthmatic airway constriction? An antigen challenge study.

During the late-phase (LP) response to inhaled allergen, mediators from neutrophils and eosinophils are released within the airways, resembling what occurs during an asthma attack. We compared the distribution of obstruction and degree of reversibility that follows a deep inspiration (DI) during early-phase (EP) and LP responses in nine asthmatic subjects challenged with allergen. Heterogeneity of constriction was assayed by determining frequency dependence of dynamic lung resistance and elastance, airway caliber by tracking airway resistance during a DI, and airway inflammation by measuring inflammatory cells in induced sputum postchallenge. Despite a paucity of eosinophils in the sputum at baseline (<1% of nonsquamous cells), asthmatic subjects showed a substantial EP response with highly heterogeneous constriction and reduced capacity to maximally dilate airways. The LP was associated with substantial airway inflammation in all subjects. However, five subjects showed only mild LP constriction, whereas four showed more marked LP constriction characterized by heterogeneous constriction similar to EP. Bronchoconstriction during LP was fully alleviated by administration of a bronchodilator. These findings, together with the impaired bronchodilatory response during a DI, indicate a physiological abnormality in asthma at the smooth muscle level and indicate that airway inflammation in asthma is associated with a highly nonuniform pattern of constriction. These data support the hypothesis that variability in responsiveness among asthmatic subjects derives from intrinsic differences in smooth muscle response to inflammation.     

15(S)-HETE modulates LTB(4) production and neutrophil chemotaxis in chronic bronchitis

We evaluated the levels of15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE] and the expression of15-lipoxygenase (15-LO) mRNA in induced sputum obtained from 10 controland 15 chronic bronchitis subjects. 15(S)-HETE was evaluated by reversephase high-performance liquid chromatography separationfollowed by specific RIA. 15-LO mRNA expression was determined byprimed in situ labeling. The levels of both soluble and cell-associated 15(S)-HETE resulted significantly higher in chronic bronchitis than incontrol subjects. The percentage of cells expressing 15-LO mRNA wassignificantly higher in chronic bronchitis than in control subjects(P < 0.01). Double staining for specific cell typemarkers and 15-LO mRNA showed macrophages and neutrophils positive for 15-LO, whereas similar staining of peripheral blood neutrophils did notshow evidence for 15-LO expression, suggesting that expression of 15-LOin neutrophils takes place on migration into the airways. Because15(S)-HETE inversely correlated with the percentage of neutrophils insputum of chronic bronchitis subjects, we studied the effect of15(S)-HETE on leukotriene B₄ (LTB₄) productionin vitro and evaluated the concentration of LTB₄ in inducedsputum and the contribution of LTB₄ to the chemotacticactivity of induced sputum samples ex vivo. The results obtainedindicate that macrophages and neutrophils present within the airways ofchronic bronchitis subjects express 15-LO mRNA; increased basal levelsof 15(S)-HETE may contribute to modulate, through the inhibition of5-lipoxygenase metabolites production, neutrophil infiltration andairway inflammation associated with chronic bronchitis.

     

Interaction of tgf-beta with immune cells in airway disease

Asthma, chronic obstructive pulmonary disorder (COPD), and cystic fibrosis (CF), chronic diseases of the airways, are characterized by symptoms such as inflammation of the lung tissue, mucus hypersecretion, constriction of the airways, and excessive fibrosis of airway tissue. Transforming growth factor (TGF)-beta, a cytokine that affects many different cell processes, has an important role in the lungs of patients with some of these chronic airway diseases, especially with respect to airway remodeling. Eosinophils can be activated by and are a major source of TGF-beta in asthma. The action of TGF-beta also shows associations with other cell types, such as T cells and neutrophils, which are involved in the pathogenesis of asthma. TGF-beta can perpetuate the pathogenesis of COPD and CF, as well, through its induction of inflammation via release from and action on different cells. The intracellular signaling induced by TGF-beta in various cell types has been elucidated and may point to mechanisms of action by TGF-beta on different structural or immune cells in these airway diseases. Some possible treatments, especially that prevent the deleterious airway changes induced by the action of either eosinophils or TGF-beta in asthma, have been investigated. TGF-beta-induced signaling pathways, especially those in different cell types in asthma, COPD, or CF, may provide potential therapeutic targets for the treatment of some of the most devastating airway diseases.     

豚鼠气道炎症中Eotaxin基因表达的意义

通过气管内滴注葡聚糖诱导豚鼠气道炎症,研究嗜酸细胞在气道炎症中的意义。用葡聚糖G200(5mg/kg)滴注形成气道炎症,进行支气管肺泡灌洗,通过RTPCR方法,检测气道炎症时肺匀浆Eotaxin基因的表达。结果可见,葡聚糖G200所致豚鼠肺损伤后Eotaxin的mRNA表达水平随葡聚糖G200刺激时间延长而明显升高(P<0.05),同时支气管肺泡灌洗液中白细胞数及上清液中Th2型细胞因子IL4也随之升高(P<0.05);试验中采用甲强龙琥珀酸钠抑制气道炎症,与盐水对照组比较P>0.05。可见,用葡聚糖G200进行气管滴注是形成气管炎症简单而实用的动物模型;Eotaxin在聚集、活化炎性细胞过程中起重要作用;糖皮质激素类药物能有效抑制Eotaxin的表达。     

Cigarette smoke-induced pulmonary inflammation and emphysema are attenuated in CCR6-deficient mice

Chronic obstructive pulmonary disease (COPD) is mainly caused by cigarette smoking, and is characterized by an increase in inflammatory cells in the airways and pulmonary tissue. The chemokine receptor CCR6 and its ligand MIP-3alpha/CCL20 may be involved in the recruitment of these inflammatory cells. To investigate the role of CCR6 in the pathogenesis of COPD, we analyzed the inflammatory responses of CCR6 knockout (KO) and wild-type mice upon cigarette smoke (CS) exposure. Both subacute and chronic exposure to CS induced an increase in cells of the innate and adaptive immune system in the bronchoalveolar lavage, both in CCR6 KO and wild-type mice. However, the accumulation of dendritic cells, neutrophils, and T lymphocytes, which express CCR6, was significantly attenuated in the CCR6 KO mice, compared with their wild-type littermates. In the lung tissue of CCR6 KO mice, there was an impaired increase in dendritic cells, activated CD8(+) T lymphocytes, and granulocytes. Moreover, this attenuated inflammatory response in CCR6 KO mice offered a partial protection against pulmonary emphysema, which correlated with an impaired production of MMP-12. Importantly, protein levels of MIP-3alpha/CCL20, the only chemokine ligand of the CCR6 receptor, and MCP-1/CCL2 were significantly increased upon CS exposure in wild-type, but not in CCR6 KO mice. In contrast, CCR6 deficiency had no effect on the development of airway wall remodeling upon chronic CS exposure. These results indicate that the interaction of CCR6 with its ligand MIP-3alpha contributes to the pathogenesis of CS-induced pulmonary inflammation and emphysema in this murine model of COPD.     

Daily exposure to dust alters innate immunity

Pig farmers are exposed to organic material in pig barns on a daily basis and have signs of an ongoing chronic airway inflammation and increased prevalence of chronic inflammatory airway diseases, predominantly chronic bronchitis. Interestingly, the inflammatory response to acute exposure to organic dust is attenuated in farmers. The aim of the study was to closer characterize innate immunity features in blood and airways in farmers and in naïve, non-exposed, controls. The expression of pattern recognition receptors (TLR2, TLR4 and CD14) whose ligands are abundant in pig barn dust and adhesion proteins (CD11b, CD62L and CD162L) on blood and sputum neutrophils in pig farmers and soluble TLR2 and CD14 (sTLR2 and sCD14) in blood and sputum were assessed in pig farmers and previously unexposed controls. The release of pro-inflammatory cytokines from blood cells stimulated with LPS ex vivo was measured in the absence and presence of anti-ST2. We also examined, in a separate study population, serum levels of soluble ST2 (sST2), before and after exposure in a pig barn and a bronchial LPS challenge. Farmers had signs of ongoing chronic inflammation with increased number of blood monocytes, and decreased expression of CD62L and CD162 on blood neutrophils. Farmers also had lower levels of sTLR2 and sCD14 in sputum and reduced expression of CD14 on sputum neutrophils than controls. Exposure to organic dust and LPS induced increase of serum sST2 in controls but not in farmers. In conclusion, farmers have signs of local and systemic inflammation associated with altered innate immunity characteristics.     

Chronic mild prenatal stress exacerbates the allergen-induced airway inflammation in rats

The effects of chronic mild prenatal stress on leukocyte infiltration into the airways was investigated in rat offspring. The chronic prenatal stress consisted of transitory and variable changes in the rat's living conditions. Offspring at adult age were actively sensitized (day 0) and intratracheally challenged (day 14) with ovalbumin. Bronchoalveolar lavage was performed in the offspring at 48 h after intratracheal challenge with ovalbumin. A significant increase in total leukocyte infiltration was observed in the non-stressed offspring group and this was associated with a marked recruitment of eosinophils without a significant effect on the influx of neutrophils and mononuclear cells. In the prenatal stressed offspring, the counts of both total leukocyte and eosinophils, as well as mononuclear cells, was increased by 50% compared to the non-stressed offspring. We provide here the first experimental evidence that chronic mild unpredictable prenatal stress produces a marked increase in the allergen-induced airway inflammation in the rat offspring.     

PAF mediates cigarette smoke-induced goblet cell metaplasia in guinea pig airways

Goblet cell metaplasia is an important morphological feature in the airways of patients with chronic airway diseases; however, the precise mechanisms that cause this feature are unknown. We investigated the role of endogenous platelet-activating factor (PAF) in airway goblet cell metaplasia induced by cigarette smoke in vivo. Guinea pigs were exposed repeatedly to cigarette smoke for 14 consecutive days. The number of goblet cells in each trachea was determined with Alcian blue-periodic acid-Schiff staining. Differential cell counts and PAF levels in bronchoalveolar lavage fluid were also evaluated. Cigarette smoke exposure significantly increased the number of goblet cells. Eosinophils, neutrophils, and PAF levels in bronchoalveolar lavage fluid were also significantly increased after cigarette smoke. Treatment with a specific PAF receptor antagonist, E-6123, significantly attenuated the increases in the number of airway goblet cells, eosinophils, and neutrophils observed after cigarette smoke exposure. These results suggest that endogenous PAF may play a key role in goblet cell metaplasia induced by cigarette smoke and that potential roles exist for inhibitors of PAF receptor in the treatment of hypersecretory airway diseases.