Platelet-activating factor receptor develops airway hyperresponsiveness independently of airway inflammation in a murine asthma model

Lipid mediators play an important role in modulating inflammatory responses. Platelet-activating factor (PAF) is a potent proinflammatory phospholipid with eosinophil chemotactic activity in vitro and in vivo. We show in this study that mice deficient in PAF receptor exhibited significantly reduced airway hyperresponsiveness to muscarinic cholinergic stimulation in an asthma model. However, PAF receptor-deficient mice developed an eosinophilic inflammatory response at a comparable level to that of wild-type mice. These results indicate an important role for PAF receptor, downstream of the eosinophilic inflammatory cascade, in regulating airway responsiveness after sensitization and aeroallergen challenge.     

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.     

P2Y12 antagonist attenuates eosinophilic inflammation and airway hyperresponsiveness in a mouse model of asthma

Leukotriene E4 (LTE4) that plays a key role in airway inflammation is expressed on platelets and eosinophils. We investigated whether blocking of the P2Y12 receptor can suppress eosinophilic inflammation in a mouse model of asthma because platelets and eosinophils share this receptor to be activated. BALB/c mice were sensitized by intraperitoneal injection of ovalbumin (OVA), followed by OVA nebulization. On each challenge day, clopidogrel, a P2Y12 antagonist was administered 30 min. before each challenge. Forty‐eight hours after the last OVA challenge, mice were assessed for airway hyperresponsiveness (AHR), cell composition and cytokine levels, including chemokine ligand 5 (CCL5), in bronchoalveolar lavage (BAL) fluid. EOL cells were treated with LTE4, with or without clopidogrel treatment, and intracellular and extracellular eosinophil cationic protein (ECP) expressions were measured to find the inhibiting function of P2Y12 antagonist on eosinophilic activation. The levels of P2Y12 expression were increased markedly in the lung homogenates of OVA‐sensitized and ‐challenged mice after platelet depletion. Administration of clopidogrel decreased AHR and the number of airway inflammatory cells, including eosinophils, in BAL fluid following OVA challenge. These results were associated with decreased levels of Th2 cytokines and CCL5. Histological examination showed that inflammatory cells as well as mucus‐containing goblet cells were reduced in clopidogrel‐administered mice compared to vehicle‐treated mice. Clopidogrel inhibited extracellular ECP secretion after LTE4 stimulation in EOL‐1 cells. Clopidogrel could prevent development of AHR and airway inflammation in a mouse model of asthma. P2Y12 can be a novel therapeutic target to the suppression of eosinophils in asthma.     

Thioredoxin suppresses airway hyperresponsiveness and airway inflammation in asthma

Thioredoxin (TRX) is a 12-kDa redox (reduction/oxidation)-active protein that has a highly conserved site (-Cys-Gly-Pro-Cys-) and scavenges reactive oxygen species. Here we examined whether exogenously administered TRX modulated airway hyperresponsiveness (AHR) and airway inflammation in a mouse asthma model. Increased AHR to inhaled acetylcholine and airway inflammation accompanied by eosinophilia were observed in OVA-sensitized mice. Administration of wild-type but not 32S/35S mutant TRX strongly suppressed AHR and airway inflammation, and upregulated expression of mRNA of several cytokines (e.g., IL-1alpha, IL-1beta, IL-1 receptor antagonist, and IL-18) in the lungs of OVA-sensitized mice. In contrast, TRX treatment at the time of OVA sensitization did not improve AHR or airway inflammation in OVA-sensitized mice. Thus, TRX inhibited the asthmatic response after sensitization, but did not prevent sensitization itself. TRX and redox-active protein may have clinical benefits in patients with asthma.     

Paeonol attenuates airway inflammation and hyperresponsiveness in a murine model of ovalbumin-induced asthma

Paeonol, the main active component isolated from Moutan Cortex, possesses extensive pharmacological activities such as anti-inflammatory, anti-allergic, and immunoregulatory effects. In the present study, we examined the effects of paeonol on airway inflammation and hyperresponsiveness in a mouse model of allergic asthma. BALB/c mice sensitized and challenged with ovalbumin were administered paeonol intragastrically at a dose of 100?mg/kg daily. Paeonol significantly suppressed ovalbumin-induced airway hyperresponsiveness to acetylcholine chloride. Paeonol administration significantly inhibited the total inflammatory cell and eosinophil count in bronchoalveolar lavage fluid. Treatment with paeonol significantly enhanced IFN-γ levels and decreased interleukin-4 and interleukin-13 levels in bronchoalveolar lavage fluid and total immunoglobulin E levels in serum. Histological examination of lung tissue demonstrated that paeonol significantly attenuated allergen-induced lung eosinophilic inflammation and mucus-producing goblet cells in the airway. These data suggest that paeonol exhibits anti-inflammatory activity in allergic mice and may possess new therapeutic potential for the treatment of allergic bronchial asthma.     

Limonene-induced activation of A2A adenosine receptors reduces airway inflammation and reactivity in a mouse model of asthma

Animal models of asthma have shown that limonene, a naturally occurring terpene in citrus fruits, can reduce inflammation and airway reactivity. However, the mechanism of these effects is unknown. We first performed computational and molecular docking analyses that showed limonene could bind to both A_2A and A_2B receptors. The pharmacological studies were carried out with A_2A adenosine receptor knock-out (A_2AKO) and wild-type (WT) mice using ovalbumin (OVA) to generate the asthma phenotype. We investigated the effects of limonene on lung inflammation and airway responsiveness to methacholine (MCh) and NECA (nonselective adenosine analog) by administering limonene as an inhalation prior to OVA aerosol challenges in one group of allergic mice for both WT and KO. In whole-body plethysmography studies, we observed that airway responsiveness to MCh in WT SEN group was significantly lowered upon limonene treatment but no effect was observed in A_2AKO. Limonene also attenuated NECA-induced airway responsiveness in WT allergic mice with no effect being observed in A_2AKO groups. Differential BAL analysis showed that limonene reduced levels of eosinophils in allergic WT mice but not in A_2AKO. However, limonene reduced neutrophils in sensitized A_2AKO mice, suggesting that it may activate A_2B receptors as well. These data indicate that limonene-induced reduction in airway inflammation and airway reactivity occurs mainly via activation of A_2AAR but A_2B receptors may also play a supporting role.

     

Resolvin E1 dampens airway inflammation and hyperresponsiveness in a murine model of asthma

Resolvin E1 (RvE1; 5S, 12R, 18R-trihydroxyeicosapentaenoic acid) is an anti-inflammatory lipid mediator derived from the omega-3 fatty acid eicosapentaenoic acid (EPA). It has been recently shown that RvE1 is involved in the resolution of inflammation. However, it is not known whether RvE1 is involved in the resolution of asthmatic inflammation. To investigate the anti-inflammatory effect of RvE1 in asthma, a murine model of asthma was studied. After RvE1 was administered to mice intraperitoneally, there were decreases in: airway eosinophil and lymphocyte recruitment, specific Th2 cytokine, IL-13, ovalbumin-specific IgE, and airway hyperresponsiveness (AHR) to inhaled methacholine. Moreover, RvE1-treated mice had significantly lower mucus scores compared to vehicle-treated mice based on the number of goblet cells stained with periodic acid-schiff (PAS). These findings provide evidence that RvE1 is a pivotal counterregulatory signal in allergic inflammation and offer novel multi-pronged therapeutic approaches for human asthma.     

Tryptase inhibition blocks airway inflammation in a mouse asthma model

Release of human lung mast cell tryptase may be important in the pathophysiology of asthma. We examined the effect of the reversible, nonelectrophilic tryptase inhibitor MOL 6131 on airway inflammation and hyper-reactivity in a murine model of asthma. MOL 6131 is a potent selective nonpeptide inhibitor of human lung mast cell tryptase based upon a beta-strand template (K(i) = 45 nM) that does not inhibit trypsin (K(i) = 1,061 nM), thrombin (K(i) = 23, 640 nM), or other serine proteases. BALB/c mice after i.p. OVA sensitization (day 0) were challenged intratracheally with OVA on days 8, 15, 18, and 21. MOL 6131, administered days 18-21, blocked the airway inflammatory response to OVA assessed 24 h after the last OVA challenge on day 22; intranasal delivery (10 mg/kg) had a greater anti-inflammatory effect than oral delivery (10 or 25 mg/kg) of MOL 6131. MOL 6131 reduced total cells and eosinophils in bronchoalveolar lavage fluid, airway tissue eosinophilia, goblet cell hyperplasia, mucus secretion, and peribronchial edema and also inhibited the release of IL-4 and IL-13 in bronchoalveolar lavage fluid. However, tryptase inhibition did not alter airway hyper-reactivity to methacholine in vivo. These results support tryptase as a therapeutic target in asthma and indicate that selective tryptase inhibitors can reduce allergic airway inflammation.     

Inhibition of phosphodiesterase activity, airway inflammation and hyperresponsiveness by PDE4 inhibitor and glucocorticoid in a murine model of allergic asthma

Phosphodiesterase 4 (PDE4) isozyme plays important roles in inflammatory and immunomodulatory cells. In this study, piclamilast, a selective PDE4 inhibitor, was used to investigate the role of PDE4 in respiratory function and inflammation in a murine asthma model. Sensitized mice were challenged with aerosolized ovalbumin for 7 days, piclamilast (1, 3 and 10 mg/kg) and dexamethasone (2 mg/kg) were orally administered once daily during the period of challenge. Twenty-four hours after the last challenge, airway hyperresponsiveness to methacholine was determined by whole-body plethysmography, airway inflammation and mucus secretion by histomorphometry, pulmonary cAMP-PDE activity by HPLC, cytokine levels in bronchoalveolar lavage fluid and their mRNA expression in lung by ELISA and RT-PCR, respectively. In control mice, significant induction of cAMP-PDE activity was parallel to the increases of hyperresponsiveness, inflammatory cells, cytokine levels, mRNA expression as well as goblet cell hyperplasia. However, piclamilast dose-dependently and significantly improved airway resistance and dynamic compliance, and the maximal effect was similar to that of dexamethasone. Piclamilast treatment dose-dependently and significantly prevented the increase in inflammatory cell number and goblet cell hyperplasia, as well as production of cytokines, including eotaxin, TNFalpha and IL-4. Piclamilast exerted a weaker inhibitory effect than dexamethasone on eosinophils and neutrophils, had no effect on lymphocyte accumulation. Moreover, piclamilast inhibited up-regulation of cAMP-PDE activity and cytokine mRNA expression; the maximal inhibition of cAMP-PDE was greater than that exerted by dexamethasone, and was similar to dexamethasone on cytokine mRNA expression. This study suggests that inhibition of PDE4 by piclamilast robustly improves the pulmonary function, airway inflammation and goblet cell hyperplasia in murine allergenic asthma.     

Soluble IL-4 receptor inhibits airway inflammation following allergen challenge in a mouse model of asthma

In vitro and in vivo studies, in both animal models and human asthmatics, have implicated IL-4 as an important inflammatory mediator in asthma. In a murine asthma model, we examined the anti-inflammatory activities of soluble IL-4R (sIL-4R). In this model, mice sensitized to OVA by i.p. and intranasal (i.n.) routes are challenged with the allergen by i.n. administration. The OVA challenge elicits an eosinophil infiltration into the lungs, with widespread mucus occlusion of the airways, and results in bronchial hyperreactivity. sIL-4R (0.1-100 microgram) was administered by either i.n. or i.p. routes before OVA challenge in OVA-sensitized mice. Both blood and bronchoalveolar lavage fluid levels of sIL-4R were significantly elevated compared with controls by i.n. delivery of 100 microgram sIL-4R; i.p. delivery of 100 microgram sIL-4R only raised blood levels of sIL-4R. The i.n. administration of 100 microgram sIL-4R before allergen challenge significantly reduced late phase pulmonary inflammation, blocking airway eosinophil infiltration, VCAM-1 expression, and mucus hypersecretion. In contrast, i.p. delivery of 100 microgram sIL-4R inhibited only the influx of eosinophils into the lungs, but not airway mucus release. Furthermore, sIL-4R treatment by either i.n. or i.p. routes did not reduce airway hyperreactivity in response to methacholine challenge. Thus, elevating airway levels of sIL-4R through the administration of exogenous sIL-4R is effective in blocking the late phase pulmonary inflammation that occurs in this murine allergen-challenge asthma model. These results suggest that sIL-4R may have beneficial anti-inflammatory effects in asthmatic patients.     

Endogenous hydrogen sulfide reduces airway inflammation and remodeling in a rat model of asthma

Endogenous hydrogen sulfide (H₂S) is hypothesized to have an important role in systemic inflammation. We investigated if endogenous H₂S may be a crucial mediator in airway inflammation and airway remodeling in a rat model of asthma and if endogenous H₂S may exert its anti-inflammatory effect by inhibiting inducible nitric oxide synthase (iNOS)/NO pathway. Cystathionine-γ-lyase (CSE; a H₂S-synthesizing enzyme) was mainly expressed in airway and vascular smooth muscle cells in rat lung tissue. Levels of endogenous H₂S was decreased in pulmonary tissue in ovalbumin (OVA)-treated rats. Exogenous administration of NaHS alleviated airway inflammation and airway remodeling: peak expiratory flow (PEF) increased, goblet cell hyperplasia and collagen deposition score decreased, with decreased total cells recovered from bronchoalveolar fluid (BALF) and influx of eosinophils and neutrophils. The H₂S levels of serum and lung tissue were positively correlated with PEF and negatively correlated with the level of eosinophils and neutrophils in BALF, score of lung pathology. NaHS treatment significantly attenuated pulmonary iNOS activation in OVA-treated rats. These results suggest that the CSE/H₂S pathway plays an anti-inflammatory and anti-remodeling part in asthma pathogenesis and could be a novel target in prevention and treatment of asthma.     

Alcohol reduces airway hyperresponsiveness (AHR) and allergic airway inflammation in mice

There is very limited knowledge about the effects of alcohol on airway hyperresponsiveness and inflammation in asthma. Historical accounts of alcohol administration to patients with breathing problems suggest that alcohol may have bronchodilating properties. We hypothesized that alcohol exposure will alter airway hyperresponsiveness (AHR) and pulmonary inflammation in a mouse model of allergic asthma. To test this hypothesis, BALB/c mice were fed either 18% alcohol or water and then sensitized and challenged with ovalbumin (OVA). AHR was assessed by means of ventilation or barometric plethysmography and reported as either total lung resistance or enhanced pause, respectively. Airway inflammation was assessed by total and differential cell counts in bronchoalveolar lavage fluid (BALF), cytokine levels in BALF, lung histology, and serum immunoglobulin E (IgE) levels. Alcohol feeding significantly blocked methacholine-induced increases in AHR compared with water-fed controls. Alcohol feeding significantly reduced total cell numbers (64%) as well as the number of eosinophils (84%) recruited to the lungs of these mice. Modest changes in lung pathology were also observed. Alcohol exposure led to a reduction of IgE in the serum of the EtOH OVA mice. These data demonstrate that alcohol exposure blunts AHR and dampens allergic airway inflammation indices in allergic mice and suggest that there may be an important role for alcohol in the modulation of asthma. These data provide an in vivo basis for previous clinical observations in humans substantiating the bronchodilator properties of alcohol and for the first time demonstrates an alcohol-induced reduction of allergic inflammatory cells in a mouse model of allergic asthma.     

Neovastat (AE-941) inhibits the airway inflammation and hyperresponsiveness in a murine model of asthma

Matrix metalloproteinase (MMP)-9 plays an important role in the pathogenesis of bronchial asthma. Neovastat, having significant antitumor and antimetastatic properties, is classified as a naturally occurring multifunctional antiangiogenic agent. We evaluated the therapeutic effect of Neovastat on airway inflammation in a mouse model of asthma. BALB/c mice were immunized subcutaneously with ovalbumin (OVA) on days 0, 7, 14, and 21 and challenged with inhaled OVA on days 26, 29, and 31. Neovastat was administrated by gavage (5 mg/kg body weight) three times with 12 h intervals, beginning 30 min before OVA inhalation. On day 32, mice were challenged with inhaled methacholine, and enhanced pause (Penh) was measured as an index of airway hyperresponsiveness. The severity of airway inflammation was determined by differential cell count of bronchoalveolar lavage (BAL) fluid. The MMP-9 concentration in BAL fluid samples was measured by ELISA, and MMP-9 activity was measured by zymography. The untreated asthma group showed an increased inflammatory cell count in BAL fluid and Penh value compared with the normal control group. Mice treated with Neovastat had significantly reduced Penh values and inflammatory cell counts in BAL fluid compared with untreated asthmatic mice. Furthermore, mice treated with Neovastat showed significantly reduced MMP-9 concentrations and activity in BAL fluid. These results demonstrate that Neovastat might have new therapeutic potential for airway asthmatic inflammation.     

Caffeic acid phenethyl ester attenuates allergic airway inflammation and hyperresponsiveness in murine model of ovalbumin-induced asthma

Caffeic acid phenethyl ester (CAPE) is a biologically active ingredient of propolis, which has several interesting biological properties, including antioxidant and anti-inflammatory; however, its anti-allergic effects are poorly understood. The objective of this study was to determine whether treatment with CAPE results in significant inhibition of asthmatic reactions in a mouse model. Mice sensitized and challenged with ovalbumin (OVA) had the following typical asthmatic reactions: an increase in the number of eosinophils in bronchoalveolar lavage (BAL) fluid; a marked influx of inflammatory cells into the lung around blood vessels and airways, and airway luminal narrowing; the development of airway hyperresponsiveness (AHR); the presence of tumor necrosis factor-alpha (TNF-alpha) and Th2 cytokines, including IL-4 and IL-5, in the BAL fluid; and the presence of allergen-specific IgE in the serum. Five successive intraperitoneal administrations of CAPE before the last airway OVA challenge resulted in significant inhibition of characteristic asthmatic reactions. We determined that increased generation of reactive oxygen species (ROS) by inhalation of OVA was diminished via the administration of CAPE in BAL fluid, as well as nuclear factor-kappaB (NF-kappaB) DNA binding activity. These findings indicate that oxidative stress may have a crucial function in the pathogenesis of bronchial asthma, and that CAPE may be useful as an adjuvant therapy for the treatment of bronchial asthma.     

Meconium aspiration produces airway hyperresponsiveness and eosinophilic inflammation in a murine model

Meconium aspiration syndrome is a cause of significant morbidity and mortality in the perinatal period and has been implicated in the pathogenesis of airway dysfunction. In this study, we developed a murine model to evaluate the effects of meconium aspiration on airway physiology and lung cellular responses. Under light anesthesia, BALB/c mice received a single intratracheal instillation of meconium or physiological saline. Respiratory mechanics were measured in unrestrained animals and expressed as percent increase in enhanced pause to increasing concentrations of methacholine (MCh). Furthermore, we assessed the changes in cells and cytokines into the bronchoalveolar lavage fluid (BALF). We found meconium aspiration produced increased airway responsiveness to MCh at 7 days. These functional changes were associated with lymphocytic/eosinophilic inflammation, goblet cell metaplasia, and increased concentrations of IL-5 and IL-13 in the BALF. Our findings suggest meconium aspiration leads to alterations of airway function, lung eosinophilia, goblet cell metaplasia, and cytokine imbalance, thus providing the first evidence of meconium-induced airway dysfunction in a mouse model.     

Contribution of vascular endothelial growth factor to airway hyperresponsiveness and inflammation in a murine model of toluene diisocyanate-induced asthma

Isocyanate chemicals, including toluene diisocyanate (TDI), are currently the most common causes of occupational asthma. Although considerable controversy remains regarding its pathogenesis, TDI-induced asthma is characterized by hyperresponsiveness and inflammation of the airways. One of the histological hallmarks of inflammation is angiogenesis, but the possible role of vascular endothelial growth factor (VEGF), a potent angiogenic cytokine, in TDI-induced asthma is unknown. We developed a murine model to investigate TDI-induced asthma by performing two courses of sensitization with 3% TDI and one challenge with 1% TDI using ultrasonic nebulization to examine the potential involvement of VEGF in that disease. These mice develop the following typical pathophysiological features: airway hyperresponsiveness, airway inflammation, and increased VEGF levels in the airway. Administration of VEGFR inhibitors reduced all these pathophysiological symptoms. These results suggest that VEGF is one of the major determinants of TDI-induced asthma and that the inhibition of VEGF may be a good therapeutic strategy.     

Nitrogen dioxide enhances allergic airway inflammation and hyperresponsiveness in the mouse

In addition to being an air pollutant, NO2 is a potent inflammatory oxidant generated endogenously by myeloperoxidase and eosinophil peroxidase. In these studies, we sought to determine the effects of NO2 exposure on mice with ongoing allergic airway disease pathology. Mice were sensitized and challenged with the antigen ovalbumin (OVA) to generate airway inflammation and subsequently exposed to 5 or 25 ppm NO2 for 3 days or 5 days followed by a 20-day recovery period. Whereas 5 ppm NO2 elicited no pathological changes, inhalation of 25 ppm NO2 alone induced acute lung injury, which peaked after 3 days and was characterized by increases in protein, LDH, and neutrophils recovered by BAL, as well as lesions within terminal bronchioles. Importantly, 25 ppm NO2 was also sufficient to cause AHR in mice, a cardinal feature of asthma. The inflammatory changes were ameliorated after 5 days of inhalation and completely resolved after 20 days of recovery after the 5-day inhalation. In contrast, in mice immunized and challenged with OVA, inhalation of 25 ppm NO2 caused a marked augmentation of eosinophilic inflammation and terminal bronchiolar lesions, which extended significantly into the alveoli. Moreover, 20 days postcessation of the 5-day 25 ppm NO2 inhalation regimen, eosinophilic and neutrophilic inflammation, pulmonary lesions, and AHR were still present in mice immunized and challenged with OVA. Collectively, these observations suggest an important role for NO2 in airway pathologies associated with asthma, both in modulation of degree and duration of inflammatory response, as well as in induction of AHR.     

Protectin D1 is generated in asthma and dampens airway inflammation and hyperresponsiveness

Protectins are newly identified natural chemical mediators that counter leukocyte activation to promote resolution of inflammation. In this study, we provide the first evidence for protectin D1 (PD1, 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid) formation from docosahexaenoic acid in human asthma in vivo and PD1 counterregulatory actions in allergic airway inflammation. PD1 and 17S-hydroxy-docosahexaenoic acid were present in exhaled breath condensates from healthy subjects. Of interest, levels of PD1 were significantly lower in exhaled breath condensates from subjects with asthma exacerbations. PD1 was also present in extracts of murine lungs from both control animals and those sensitized and aerosol challenged with allergen. When PD1 was administered before aeroallergen challenge, airway eosinophil and T lymphocyte recruitment were decreased, as were airway mucus, levels of specific proinflammatory mediators, including IL-13, cysteinyl leukotrienes, and PGD(2), and airway hyperresponsiveness to inhaled methacholine. Of interest, PD1 treatment after aeroallergen challenge markedly accelerated the resolution of airway inflammation. Together, these findings provide evidence for endogenous PD1 as a pivotal counterregulatory signal in allergic airway inflammation and point to new therapeutic strategies for modulating inflammation in asthmatic lung.     

GITR signaling potentiates airway hyperresponsiveness by enhancing Th2 cell activity in a mouse model of asthma

Background

Anxiety and depression are common and treatable risk factors for re-hospitalisation and death in patients with COPD. The degree of lung function impairment does not sufficiently explain anxiety and depression. The BODE index allows a functional classification of COPD beyond FEV₁. The aim of this cross-sectional study was (1) to test whether the BODE index is superior to the GOLD classification for explaining anxious and depressive symptoms; and (2) to assess which components of the BODE index are associated with these psychological aspects of COPD.

Methods

COPD was classified according to the GOLD stages based on FEV_1%predicted in 122 stable patients with COPD. An additional four stage classification was constructed based on the quartiles of the BODE index. The hospital anxiety and depression scale was used to assess anxious and depressive symptoms.

Results

The overall prevalence of anxious and depressive symptoms was 49% and 52%, respectively. The prevalence of anxious symptoms increased with increasing BODE stages but not with increasing GOLD stages. The prevalence of depressive symptoms increased with both increasing GOLD and BODE stages. The BODE index was superior to FEV_1%predicted for explaining anxious and depressive symptoms. Anxious symptoms were explained by dyspnoea. Depressive symptoms were explained by both dyspnoea and reduced exercise capacity.

Conclusion

The BODE index is superior to the GOLD classification for explaining anxious and depressive symptoms in COPD patients. These psychological consequences of the disease may play a role in future classification systems of COPD.     

Anti-inflammatory effects of Tat-Annexin protein on ovalbumin-induced airway inflammation in a mouse model of asthma

Chronic airway inflammation is a key feature of bronchial asthma. Annexin-1 (ANX1) is an anti-inflammatory protein that is an important modulator and plays a key role in inflammation. Although the precise action of ANX1 remains unclear, it has emerged as a potential drug target for inflammatory diseases such as asthma. To examine the protective effects of ANX1 protein on ovalbumin (OVA)-induced asthma in animal models, we used a cell-permeable Tat-ANX1 protein. Mice sensitized and challenged with OVA antigen had an increased amount of cytokines and eosinophils in their bronchoalveolar lavage (BAL) fluid. However, administration of Tat-ANX1 protein before OVA challenge significantly decreased the levels of cytokines (interleukin (IL)-4, IL-5, and IL-13) and BAL fluid in lung tissues. Furthermore, OVA significantly increased the activation of mitogen-activated protein kinase (MAPK) in lung tissues, whereas Tat-ANX1 protein markedly reduced phosphorylation of MAPKs such as extracellular signal-regulated protein kinase, p38, and stress-activated protein kinase/c-Jun N-terminal kinase. These results suggest that transduced Tat-ANX1 protein may be a potential protein therapeutic agent for the treatment of lung disorders including asthma.