Aggravated Airway Inflammation Research Articles

Angiotensin-(1–7) Rescues Chronic Intermittent Hypoxia-Aggravated Transforming Growth Factor-β–Mediated Airway Remodeling in Murine and Cellular Models of Asthma

Renin-angiotensin system (RAS) is involved in TGF-β-mediated epithelial-to-mesenchymal transition (EMT) and is responsible for airway remodeling in refractory asthma. Obstructive sleep apnea (OSA), which affects RAS activity, is a risk factor for refractory asthma. We aimed to investigate how chronic intermittent hypoxia (IH), the main pathophysiology of OSA, exacerbates asthma and whether Ang-(1-7) protects against chronic IH-induced airway remodeling in asthma. We exposed ovalbumin (OVA)-challenged asthma mice to chronic IH and observed that chronic IH aggravated airway inflammation and collagen deposit in OVA-challenged mice. Compared with the OVA group, the OVA + chronic IH group had a lower expression level of epithelial marker E-cadherin and higher expression levels of mesenchymal markers α-smooth muscle actin and collagen IV in airway epithelia, accompanied with activation of TGF-β/Smad pathway. These changes were reversed by the administration of Ang-(1-7). Consistently, Ang-(1-7) mitigated chronic IH-induced activation of TGF-β-mediated EMT in lipopolysaccharide-treated bronchial epithelial cells in a dose-dependent manner, which was blocked by Ang-(1-7)-specific Mas receptor antagonist A779. Taken together, Ang-(1-7) rescued chronic IH-aggravated TGF-β-mediated EMT to suppress airway remodeling, implying that RAS activity is involved in the mechanisms of OSA-related airway dysfunction in asthma. SIGNIFICANCE STATEMENT: OSA is a risk factor for refractory asthma. In this study, we aimed to explore the mechanisms of how OSA exacerbates refractory asthma. We found that chronic IH induces TGF-β-mediated EMT and aggravates airway collagen deposit. We also found that Ang-(1-7) erased the aggravation of TGF-β-mediated EMT and epithelial fibrosis upon chronic IH exposure. These findings provided new insights that the ACE2/Ang-(1-7)/Mas axis might be considered as a potential therapeutic target for patients with asthma and OSA.

The Antioxidant Rosmarinic Acid Ameliorates Oxidative Lung Damage in Experimental Allergic Asthma via Modulation of NADPH Oxidases and Antioxidant Enzymes.

Oxidative stress can induce lung damage and aggravate airway inflammation in asthma. Previously, we reported that rosmarinic acid (RA) exerted strong anti-inflammatory effects in a mouse allergic asthma model. Therefore, we hypothesized that RA might also have antioxidative effects in a superimposed asthma mouse model with oxidative lung damage challenged with ovalbumin (Ova) and hydrogen peroxide (H2O2). We evaluated the antioxidative and anti-asthmatic activity of RA and explored its possible mechanisms of action. Mice sensitized to Ova and challenged with Ova and H2O2 were treated with RA 1h after challenge. RA treatment greatly diminished the number of inflammatory cells; decreased IL-4, IL-5, and IL-13 production; increased IFN-γ secretion; significantly downregulated ROS production; and markedly upregulated the activities of SOD, GPx, and CAT. Furthermore, RA treatment resulted in a significant increase in the expression of Cu/Zn SOD and a notable reduction in NOX-2 and NOX-4 expression in lung tissues. These findings suggest that RA may effectively alleviate oxidative lung damage and airway inflammation in asthma.

MiR-223 plays a protecting role in neutrophilic asthmatic mice through the inhibition of NLRP3 inflammasome

BackgroundNeutrophilic subtype asthma occurs in approximately 15–25% of the asthma cases and is associated with severe airflow obstruction, corticosteroid resistance. MicroRNA plays a vital role in regulating many immune processes, but how miRNA circuits coordinate airway inflammation during neutrophilic asthma is unclear.MethodsTo investigate the molecular mechanism of miR-223 in regulation of neutrophilic airway inflammation, miR-223 knockout mice were used to the OVA/CFA-induced neutrophilic asthma or treated with NLRP3 inhibitor and IL-1β receptor antagonist. Based on the results obtained, wide-type mice were subsequently treated with miR-223 agomirs or negative control agomirs, and the effects on airway inflammation were assessed using morphometric techniques, quantitative RT-PCR, western blot, ELISA and other molecular approaches.ResultsThe expression of miR-223 was upregulated in lung tissues of experimental mice model. Furthermore, miR-223−/− mice led to aggravated neutrophilic airway inflammation with heightened histopathological, inflammatory cells and cytokines readouts. Moreover, miR-223−/− mice also presented with enhanced NLRP3 inflammasome level with elevated IL-1β. Blocking NLRP3 or IL-1β diminished this phenotype. Finally, overexpression of miR-223 via treatment with miR-223 agomirs attenuated airway inflammation, NLRP3 levels and IL-1β release.ConclusionsThe findings of this study revealed a crucial role for miR-223 in regulating the immunoinflammatory responses by depressing the NLRP3/ IL-1β axis in neutrophilic asthma.

Disruption of the Notch pathway aggravates airway inflammation by inhibiting regulatory T cell differentiation via regulation of plasmacytoid dendritic cells.

Plasmacytoid dendritic cells (pDCs) regulate immunity and promote tolerance in asthma. Notch signalling is a highly conserved pathway that regulates the immune response; however, its role in pDC-mediated asthmatic airway inflammation is unclear. This study clarified the effects of Notch signalling on pDC-mediated airway inflammation using murine models of ovalbumin-sensitized allergic asthma. RBP-J-deficient pDCs (RBP-J-/- pDCs) were co-cultured with naïve CD4+ T cells and supernatants and T cell subtypes were analysed. RBP-J-/- pDCs were intranasally transferred to the airways of ovalbumin-sensitized recipient mice. Lung samples of all mice were subjected to tests for histopathology, cytokine profile of bronchoalveolar lavage fluid, airway hyperactivity and expression of T helper type 1 (Th1)/Th2 cells, regulatory T cells and type 2 innate lymphoid cells (ILC2s). The results showed that pDCs with and without RBP-J deficiency significantly differed in expression levels of cluster of differentiation 83 (CD83), but not CD80, CD86 and major histocompatibility complex class II. Co-culturing pDCs with naïve T cells revealed a poorer immunosuppressive effect of RBP-J-/- pDCs. This may be attributed to the lower expression levels of inducible co-stimulator ligand and lower production of interleukin 10 in RBP-J-/- pDCs than in control pDCs, which impeded T cell activation and Treg suppression. RBP-J-/- pDCs were associated with high ILC2 expression and severe Th2 immune responses and airway inflammation. Therefore, Notch signalling is critical for pDC-dependent immunoregulation, and RBP-J deficiency reduces pDC-based immunosuppression via T cell activation and Th cell differentiation. Thus, this pathway may be a therapeutic target for pDC-based anti-asthma immunotherapy.

Apolipoprotein E negatively regulates murine allergic airway inflammation via suppressing the activation of NLRP3 inflammasome and oxidative stress

Apolipoprotein E (ApoE) has been reported as a steroid unresponsive gene and functions as a negative regulator of airway hyperreactivity (AHR) and goblet cell hyperplasia in house dust mite (HDM)-challenged mice. However, the role of ApoE in Ovalbumin (OVA)-induced allergic airway inflammation disease and the underlying mechanism are still unknown. In the present study, murine allergic airway inflammation was induced by inhaled OVA for consecutive 7 days in wild type (WT) and ApoE−/− mice. In the OVA-induced model, the ApoE level in the bronchoalveolar lavage fluid (BALF) and lung tissues was significantly higher than that of control mice. And ApoE deficiency aggravated airway inflammation including leukocytes infiltration, goblet cell hyperplasia and IgE production as compared to those of WT mice after OVA- challenged, suggesting ApoE servers as an endogenous negative regulator of airway inflammation. Furthermore, OVA challenge elevated the activation of NLRP3 inflammasome with higher protein expression of NLRP3, caspase1 and IL-1β, enhanced oxidative stress with higher expression of 8-OHdG, nitrotyrosine and SOD2, increased the expression of mitochondrial fusion/fission markers including Optic Atrophy 1 (OPA1), Mitofusion 2 (Mfn2), dynamin-related protein 1 (DRP1) and Fission 1 (Fis1). However, these OVA-induced changes were augmented in ApoE−/− mice. Collectively, our results demonstrated that the OVA-induced airway inflammation was aggravated in ApoE−/− mice, and suggested that the underlying mechanism may be associated with the augmented activation of NLRP3 inflammasome and oxidative stress in ApoE−/− mice, therefore targeting ApoE pathway might be a novel therapy approach for allergic airway diseases such as asthma.

Study of vitamins, antioxidant and trace elements on various spirometric parameters and quality of life in patients of bronchial asthma

Study of vitamins, antioxidant and trace elements on various spirometric parameters and quality of life in patients of bronchial asthma - IJCAAP- Print ISSN No: - 2581-5555 Online ISSN No:- 2456-9542 Article DOI No:- 10.18231/j.ijcaap.2019.030, IP International Journal of Comprehensive and Advanced Pharmacology-IP Int

High and low temperatures aggravate airway inflammation of asthma: Evidence in a mouse model

Epidemiology suggests ambient temperature is the triggers and potential activator of asthma. The role of high and low temperatures on airway inflammation of asthma, and the underlying molecular mechanism are not yet understood. A mouse model of asthma was adopted in our experiment. The BALB/c mice were exposed at different temperature for 4 h (2 h in the morning and 2 h in the afternoon) on weekday. The exposure temperatures were 10 °C, 24 °C and 40 °C. Ovalbumin (OVA) was used to sensitize the mice on days 14, 18, 22, 26, and 30, followed by an aerosol challenge for 30 min from day 32–38. After the final OVA challenge, lung function, serum protein and pulmonary inflammation were assessed. Comparing the OVA with the saline group at 24 °C, we saw a significant increase in: serum Total-IgE (p < 0.05); OVA-sIgE (p < 0.01); IL-4 (p < 0.05); IL-1β (p < 0.01); IL-6 (p < 0.01); TNF-α (p < 0.01); and the ratio of IL-4/IFN-γ (p < 0.01). At the same time, there was a significant decrease in IFN-γ (p < 0.01). As the temperature increase, there is a U shape for immune proteins and pro-inflammatory factors with a peak value at 24 °C, exception for IFN-γ (inverted U-shape). After the high and low temperature exposure, the Ri and Re increased significantly, while Cldyn decreased significantly compared with the 24 °C group. Histopathological analysis of the OVA groups showed airway remodeling, airway wall thickening and deforming, and subepithelial fibrosis. More obvious changes were found in the high and low temperature exposure groups. The immunohistochemistry suggested that TRPs changed with temperatures. High and low temperatures can aggravate airway inflammation in a mouse model of asthma. TRPs play an important role in temperature aggravation of allergic asthma. The results suggest that asthmatics should avoid exposure to high and low temperatures for too long time.

Tobacco smoking aggravates airway inflammation by upregulating endothelin-2 and activating the c-Jun amino terminal kinase pathway in asthma

BackgroundAsthma is closely associated with tobacco smoking (TS) and is more difficult to effectively treat after exposure to TS. ObjectiveTo observe the effects of TS on the expression of endothelin-2 (ET-2) and airway inflammation in asthmatic rats and to explore the related mechanisms. MethodsWe established an animal model of asthma with ovalbumin (OVA)/Al(OH)3 and subjected different animal groups to TS and/or dexamethasone/bosentan. The differences in the inflammatory cell infiltration, the pathological changes to the bronchial wall and the bronchial smooth muscle thickness, and the expression of ET-2, c-Jun amino terminal kinase (JNK1/2), malondialdehyde (MDA), and glutathione peroxidase (GSH) in the lung tissue and of interleukin (IL)-7 in bronchoalveolar lavage fluid (BALF) were assessed. ResultsExposure to TS or OVA caused an obvious increase in the inflammatory cells in the BALF over what was observed in the control group. In asthma models, the expression of ET-1, JNK1/2, MDA, and GSH in the lung tissues, as well as that of IL-17 in the BALF, was increased. After treatment with dexamethasone/bosentan, the expression of IL-17, JNK1/2, MDA, and GSH decreased compared to the smoking group; airway inflammation and the staining intensity in the lung tissue were also reduced. ConclusionTS exposure can clearly exacerbate airway inflammation in asthmatic rats, while bosentan can alleviate airway inflammation through regulation of the ET-2/JNK1/2 signalling pathway.

Effects of epigallocatechin-3-gallate on the HMGB1/RAGE pathway in PM2.5-exposed asthmatic rats

Current studies have shown that long-term exposure to fine particulate matter (PM2.5) can aggravate lung injury in asthmatic children. The HMGB1/RAGE pathway may play an important role, but few studies on the HMGB1/RAGE signaling pathway in PM2.5-induced asthma have been performed. Epigallocatechin-3-gallate (EGCG), which has antioxidant, anti-inflammatory and immunomodulatory effects, has not been examined in studies at home and abroad. In this study, we established an animal model of asthma and observed that the lung tissue was damaged, inflammatory cells infiltrated, bronchial wall thickness (WTt) and bronchial smooth muscle thickness (WTm) increased and the HMGB1 and RAGE mRNA and protein expression increased. The asthmatic rats exposed to PM2.5 showed significantly increased lung injury and inflammatory cell infiltration, WTt and WTm further increased, and HMGB1 and RAGE mRNA and protein levels were higher than those in the asthma group. The asthmatic rats exposed to PM2.5 were treated with EGCG, which alleviated the lung injury, reduced the number of inflammatory cells, decreased WTt and WTm, and reduced the expression of HMGB1 and RAGE mRNA and protein. The high-dose group showed more significant effects than the other groups. In conclusion, our results suggest that HMGB1 and RAGE are involved in the pathogenesis of asthma. PM2.5 exposure significantly aggravated airway inflammation injury in asthmatic rats. EGCG can reduce lung injury and airway remodeling in PM2.5-exposed asthmatic rats and has lung protective effects. The mechanism may be related to regulation of the HMGB1/RAGE signaling pathway. Our results may provide new ideas and methods for the prevention and treatment of PM2.5-induced asthma.

Dose dependency PM2.5 aggravated airway inflammation in asthmatic mice via down-regulating expression of ITGB4.

We aimed to investigate whether PM2.5 has the potential to exacerbate neutrophil airway inflammation and to analyze the underlying mechanisms. The high-volume air sampler (Laoying 2033B, Qingdao, China) was used to collect PM2.5 from January 01, 2016 to December 21, 2016 in Yantai, Shandong Province, China. BALB/c mice were divided into the following four groups: control group, ovalbumin (OVA) group, low-dose PM2.5 group and high-dose PM2.5 group. Mice except for control group were sensitized and challenged by OVA, and those in low-dose PM2.5 group and high-dose PM2.5 group were intranasally administered by PM2.5 suspension. Airway responsiveness of mice was measured. Enzyme-linked immunosorbent assay (ELISA) kit was used to evaluate the expressions of interleukin 17 (IL-17) and tumor necrosis factor-α (TNF-α) in bronchoalveolar lavage fluid (BALF) and serum samples. Cell counting in BALF and histological examination were measured to explore PM2.5-induced airway inflammation. Protein expression of Integrin β4 (ITGB4) was assessed by Western blot. Airway hyperresponsiveness (AHR) exacerbated in PM2.5 exposed asthmatic mice in progressively increased doses of acetylcholine chloride (ACH). Levels of IL-17 and TNF-αin BALF and serum increased significantly in PM2.5 groups compared with other groups with significant differences between two PM2.5 groups. PM2.5 exposure exacerbated inflammatory cell infiltration and mucus secretion in airways of asthmatic mice. Percentage of neutrophils in PM2.5 groups was significantly higher in dose-dependent manner. OVA and PM2.5 co-exposure inhibited the expression of ITGB4. In particular, ITGB4 expression in mice of high-dose PM2.5 group was significantly lowered than the low-dose PM2.5 group. We showed that PM2.5 exposure exacerbates neutrophil airway inflammation in asthmatic mice though up-regulating expressions of IL-17 and TNF-α but down-regulating the expression of ITGB4.

Neonatal Streptococcus pneumoniae Pneumonia Induces an Aberrant Airway Smooth Muscle Phenotype and AHR in Mice Model.

Our previous study showed that neonatal S. pneumoniae infection aggravated airway inflammation and airway hyperresponsiveness (AHR) in an OVA-induced allergic asthma model. As airway smooth muscle (ASM) plays a pivotal role in AHR development, we aim to investigate the effects of neonatal S. pneumoniae pneumonia on ASM structure and AHR development. Non-lethal neonatal pneumonia was established by intranasally infecting 1-week-old BALB/C mice with the S. pneumoniae strain D39. Five weeks after infection, the lungs were collected to assess the levels of α-SMA and the contractile proteins of ASM. Our results indicate that neonatal S. pneumoniae pneumonia significantly increased adulthood lung α-SMA and SMMHC proteins production and aggravated airway inflammatory cells infiltration and cytokines release. In addition, the neonatal S. pneumoniae pneumonia group had significantly higher Penh values compared to the uninfected controls. These data suggest that neonatal S. pneumoniae pneumonia promoted an aberrant ASM phenotype and AHR development in mice model.

Downregulation of Sfrp5 in insulin resistant rats promotes macrophage-mediated pulmonary inflammation through activation of Wnt5a/JNK1 signaling

BackgroundInsulin resistance (IR), a common co-morbidity of chronic obstructive pulmonary disease (COPD), aggravates airway inflammation in COPD patients, but its mechanism is unclear. Sfrp5, a novel anti-inflammatory adipocytokine, inhibits macrophage-mediated inflammation of adipose tissue and abrogates IR. However, few studies have been conducted on the regulatory role of Sfrp5 in lung inflammation. MethodsIn the present study, 30 SD rats were divided into two groups: the normal food (NF) group and the high-fat diet (HFD) group. Oral glucose tolerance test (OGTT) and insulin release test were performed to assess whether a successful IR rat model was established. The expression of Sfrp5 and key downstream moleculars of Wnt5a/JNKl signaling was detected. Lung tissue pathomorphology and macrophage activation were observed. In addition, we counted the number of inflammatory cells and measured inflammatory cytokines in bronchoalveolar lavage fluid (BALF). In vitro, rat lung macrophages were isolated and treated with Wnt5a, Sfrp5, and/or JNK inhibitor SP600125. JNK activity and inflammatory cytokines expression were examined. ResultsWe found that in a rat model of IR, Sfrp5 expression of lung tissue was downregulated, while the Wnt5a/JNKl pathway was activated and the lung inflammatory response was enhanced. Meanwhile, Sfrp5 significantly suppressed Wnt5a/JNKl-induced macrophage activation. ConclusionsCollectively, IR reduces Sfrp5 expression of lung tissue and activates the Wnt5a/JNK1 pathway, promoting macrophage activation and contributing to the lung's inflammatory response. In contrast, Sfrp5 suppresses the inflammatory response by inhibiting the Wnt5a/JNKl pathway, which could be a target of treatment of COPD.

Brg1 aggravates airway inflammation in asthma via inhibition of the PI3K/Akt/mTOR pathway

The PI3K/Akt/mTOR pathway is thought to be closely associated with airway inflammation and is regulated by various upstream proteins. Brahma-related gene 1 (Brg1) plays an important role in chromatin remodeling and facilitates recruitment of essential transcription factors, leading to regulation of gene expression. Thus, the present study aimed at evaluating the anti-inflammatory role of Brg1 on house dust mite (HDM)-induced asthma through regulating the PI3K/Akt/mTOR pathway. The Brgfl/fl mice were crossbred with the SFTPC-Cre mice to generate bronchial epithelial cell specific Brg1 knockout mice, and LY294002 was used to inhibit PI3K. Western blot, immunofluorescence, immunoprecipitation, and immunohistochemical staining were used to detect the expression of proteins. An increase in Brg1 and a decrease in the PI3K/Akt/mTOR pathway activity were detected in asthmatic mice, but not in control mice. When Brg1 was knocked out, the asthma severity was ameliorated and the PI3K/Akt/mTOR pathway was activated. However, this protective effect could be suppressed by LY294002. Additionally, we observed that Brg1 was co-localized and co-immunoprecipitated with PI3K, using immunofluorescence and immunoprecipitation assays. Our results suggest that Brg1 might play an essential role in maintaining airway inflammation and affect the PI3K/Akt/mTOR pathway in asthma.

HMGB1 regulates T helper 2 and T helper17 cell differentiation both directly and indirectly in asthmatic mice

The Th (T helper) 2 response is characteristic of allergic asthma, and Th17 cells are involved in more severe asthma. Recent studies demonstrated that HMGB1 (High mobility group box 1 protein) regulates airway inflammation and the Th2, Th17 inflammatory response in asthma. HMGB1 can interact with Toll-like receptors (TLR) 2 and 4, and the receptor for advanced glycation end products (RAGE), activating the NF-κB (nuclear factor kappa B) signaling pathway and inducing the release of downstream inflammatory mediators. Both Th cells and dendritic cells express TLR2, TLR4, and RAGE receptors. Therefore, we speculate that HMGB1 could regulate the differentiation of Th2, Th17 cells in asthma through direct and indirect mechanisms. An ovalbumin (OVA)-induced mouse asthmatic model was established. Anti-HMGB1 antibody or rHMGB1 was administered to OVA-sensitized mice 30 min prior to each challenge. For in vitro studies, magnetically separated CD4+ naive T cells were stimulated with or without rHMGB1 and/or anti-HMGB1 antibody. BMDCs (bone marrow-derived dendritic cells)-stimulated with or without rHMGB1 and/or anti-HMGB1 antibody were cocultured with CD4+ naive T cells. Our study showed that administration of rHMGB1 aggravated airway inflammation and mucus production, and induced Th2, Th17 polarization in asthmatic mice, and that anti-HMGB1 antibody weakened characteristic features of asthma and blocked the Th2, Th17 inflammatory responses. HMGB1 could directly act on naive T cells to induce differentiation of Th2, Th17 cells in vitro through activating the TLR2, TLR4, RAGE-NF-κB signal pathway in CD4+ naive T cells. HMGB1 could also indirectly promote Th2, Th17 differentiation via activating the TLR2, TLR4, RAGE-NF-κB signal pathway in DCs to mediate their maturation and antigen-presenting ability in vitro.

ATP/P2X7-NLRP3 axis of dendritic cells participates in the regulation of airway inflammation and hyper-responsiveness in asthma by mediating HMGB1 expression and secretion

The ATP/P2X7 axis of dendritic cells (DCs) mediates the activation of NLRP3 inflammasome and promotes secretion of interleukin (IL)−1β and IL-18 to induce T helper (Th) 2, Th17 differentiation in the pathogenesis of asthma. NLRP3 inflammasome also regulates high mobility protein 1 (HMGB1) release in DCs. Recent studies demonstrated the correlation between HMGB1 expression and airway inflammation and hyper-responsiveness (AHR) in asthma. However, the relationship between the ATP/P2X7-NLRP3 axis and HMGB1 in DCs in asthma is still unclear. ATP, apyrase, Brilliant Blue G, BzATP, glibenclamide, and Z-YVAD-FMK were administered to ovalbumin (OVA)-induced murine asthmatic model. For in vitro studies, bone marrow-derived mononuclear cells (BMDCs) were primed with LPS and stimulated with the same reagents. Activation of the ATP/P2X7 axis aggravated airway inflammation and AHR in the lung and induced Th2, Th17 polarization in asthmatic mice. Inhibition of NLRP3 inflammasome weakened cardinal features of asthma and blocked Th2, Th17 polarization. In vitro and vivo, ATP/P2X7 axis activated NLRP3 inflammasome and induced HMGB1 expression and release from DCs. Inhibition of NLRP3 inflammasome reduced HMGB1 expression and release. The ATP/P2X7-NLRP3 axis of DCs participates in mediating airway inflammation, AHR, and promoting Th2, Th17 inflammatory responses in asthmatic mice by inducing HMGB1 expression and secretion.

LIPID PROFILE AND LIPID PEROXIDATION IN BRONCHIAL ASTHMA

Background: Bronchial asthma, a chronic inflammatory condition, often triggered by allergy & oxidative stress, initiate lipid peroxidation& enhanced release of arachidonic acid from cell membrane. Regarding lipid profile in bronchial asthma patients many conflicting data were reported. Therefore we have conducted this study. Methodology: 50 clinically diagnosed bronchial asthma cases for lipid profile and lipid peroxidation levels were compared with 50 healthy controls. Results: In our study fasting serum HDL and LDL cholesterol level of cases respectively (52.32mg/dl ±3.58), (99.21mg/dl ±12.49) were found to be significantly higher when compared to controls (44.58mg/dl ±2.58), (103.44mg/dl ±10.55) (p-value <0.05). Mean plasma SOD level of cases (3.42 U/mL±0.74) was significantly lowered than controls (7.16 U/mL±0.52). Serum MDA level of cases (5.91nmol/L±0.88) was higher as compared to controls (3.00nmol/L±0.40). (p-value <0.001) Conclusion: Lipid profile in bronchial asthma patients (raised HDL& decreased LDL) provides some degree of protection to this patients against ischemic heart disease (IHD). But increased in lipid peroxidation as evidenced by decrease plasma SOD & raised serum MDA aggravate airway inflammation, smooth muscle contraction & increased vascular permeability Keywords: Asthma; Oxidative stress; Lipid peroxidation; Lipid profile.

KIF3A knockdown sensitizes bronchial epithelia to apoptosis and aggravates airway inflammation in asthma

BackgroundKIF3A expression was decreased in asthmatic child patients and animal. Impaired KIF3A expression resulted in increased Th2 inflammation in mice and apoptosis in renal tubular epithelium and photoreceptor cells. This work aimed to investigate the role of KIF3A in epithelium apoptosis and bronchial inflammation in asthma. MethodsAfter establishment of ovalbumin induced asthma, the mice were infected with KIF3A adenovirus through nasal cavity inhalation. KIF3A expression and apoptosis in epithelia of nasal mucosa and bronchia were determined using qRT-PCR, western blotting, immunohistochemistry and TUNEL staining. The mRNA expression of COX-2, IL-4, IL-5, IL-13, IL-6, IL-10 and TNF-α was also measured. In vitro, human bronchial epithelial cell line 16HBE 14o- was stimulated with IL-4, IL-13 and TNF-α, accompanied by KIF3A knockdown or overexpression using siRNA or KIF3A adenovirus respectively. Apoptosis, mRNA expression of CCL17, CCL26, IL-5 and IL-8, and protein expression of COX-2 and β-catenin were determined using flow cytometry, qRT-PCR and western blotting. ResultsKIF3A expression was reduced in epithelia of nasal mucosa and bronchia of asthmatic mice, and overexpression of KIF3A ameliorated epithelial cell apoptosis and bronchial inflammation in asthmatic mice. In vitro, KIF3A knockdown significantly promoted epithelium apoptosis, facilitated the transcription of CCL17, CCL26, IL-5 and IL-8, and increased the protein levels of COX-2 and β-catenin translocation, whereas overexpression of KIF3A exhibited the opposite effect. ConclusionKIF3A plays an important role in epithelium apoptosis and bronchial inflammation in asthma, and may be a potential target for asthma treatment.

Interleukin 33 exacerbates antigen driven airway hyperresponsiveness, inflammation and remodeling in a mouse model of asthma

Interleukin 33 (IL-33) represents a potential link between the airway epithelium and induction of Th2-type inflammatory responses associated with the development of asthma. This study investigated the potential of IL-33 to exacerbate antigen driven asthma responses. An ovalbumin (OVA) asthma model was used in which sensitized C57BL/6 mice were exposed to IL-33 before each OVA challenge. IL-33 given to sensitized mice acted synergistically with antigen and aggravated airway inflammation, hyperresponsiveness and remodeling compared with mice that were only OVA sensitized and challenged and mice that were only exposed to IL-33. Elevated levels of local and systemic mast cell protease mMCP-1, as well as antigen-specific IgE production, were observed following IL-33 administration to sensitized mice. Similarly, exposing OVA-sensitized mice to IL-33 increased the Th2 cytokine levels, including IL-4, IL-5 and IL-13. Furthermore, IL-33 and OVA administration to OVA-sensitized mice increased ILC2s in the lung, suggesting a role for ILC2s in IL-33-mediated exacerbation of OVA-induced airway responses. Collectively, these findings show that IL-33 aggravates important features of antigen-driven asthma, which may have implications for asthma exacerbations.

Impaired TNF/TNFR2 signaling enhances Th2 and Th17 polarization and aggravates allergic airway inflammation.

CD4+ T-cell differentiation plays an important role in allergic airway diseases. Tumor necrosis factor receptor 2 (TNFR2) has been shown to regulate CD4+ T-lymphocyte differentiation, but its role in allergic airway inflammation is not clear. Here, we investigated the role of TNFR2 in allergic airway inflammation. The mouse model was generated by immunization with ovalbumin and intranasal administration of TNFR2 antibody. Airway inflammation and CD4+ T-cell differentiation were measured in vivo and in vitro. Inhibited TNFR2 signaling aggravated airway inflammation and increased the expression of inflammatory cytokines (IL-4, IL-5, IL-17, and TNF-α) in serum and bronchoalveolar lavage fluid. Impaired TNFR2 signaling promoted Th2 and Th17 polarization but inhibited Th1 and CD4+CD25+ T-cell differentiation in vivo. Furthermore, TNFR2 signaling inhibition promoted Th2 and Th17 polarization in vitro, which may occur through the activation of TNF receptor-associated factor 2 and NF-κB signaling. Therefore, our findings indicate that impaired TNF/TNFR2 signaling enhances Th2 and Th17 polarization and aggravates allergic airway inflammation.

Effects of Asian Dust Particles on the Early-Stage Antigen-Induced Immune Response of Asthma in NC/Nga Mice.

Asian dust (AD) can aggravate airway inflammation in asthma, but the association between AD and the development of asthma remains unclear. This study aimed to investigate the effects of AD on the early stage of antigen sensitization using a mouse model of asthma, as well as the role of leukotrienes (LTs) in antigen-induced airway inflammation potentiated by AD particles. NC/Nga mice were co-sensitized by intranasal instillation of AD particles and/or Dermatophagoides farinae (Df) for five consecutive days. Df-sensitized mice were stimulated with an intranasal Df challenge at seven days. Mice were treated with the type 1 cysteinyl LT (CysLT1) receptor antagonist orally 4 h before and 1 h after the allergen challenge. At 24 h post-challenge, the differential leukocyte count, inflammatory cytokines, and LTs in bronchoalveolar lavage fluid were assessed, and airway inflammation was evaluated histopathologically. AD augmented neutrophilic and eosinophilic airway inflammation with increased CysLTs and dihydroxy-LT in a mouse model of asthma. The CysLT1 receptor antagonist was shown to attenuate both neutrophilic and eosinophilic airway inflammation augmented by AD. Therefore, exposure to AD may be associated with the development of asthma and LTs may play important roles in airway inflammation augmented by AD.