Airway Oxidative Stress Research Articles

Oxidative Stress and Inflammation in Acute and Chronic Lung Injuries.

Acute and chronic lung injuries are among the leading causes of mortality worldwide. Lung injury can affect several components of the respiratory system, including the airways, parenchyma, and pulmonary vasculature. Although acute and chronic lung injuries represent an enormous economic and clinical burden, currently available therapies primarily focus on alleviating disease symptoms rather than reversing and/or preventing lung pathology. Moreover, some supportive interventions, such as oxygen and mechanical ventilation, can lead to (further) deterioration of lung function and even the development of permanent injuries. Lastly, sepsis, which can originate extrapulmonary or in the respiratory system itself, contributes to many cases of lung-associated deaths. Considering these challenges, we aim to summarize molecular and cellular mechanisms, with a particular focus on airway inflammation and oxidative stress that lead to the characteristic pathophysiology of acute and chronic lung injuries. In addition, we will highlight the limitations of current therapeutic strategies and explore new antioxidant-based drug options that could potentially be effective in managing acute and chronic lung injuries.

Integrative analysis of the expression profiles of whole coding and non-coding RNA transcriptomes and construction of the competing endogenous RNA networks for chronic obstructive pulmonary disease.

The pathogenesis of Chronic Obstructive Pulmonary Disease (COPD) is implicated in airway inflammation, oxidative stress, protease/anti-protease and emphysema. Abnormally expressed non-coding RNAs (ncRNAs) play a vital role in regulation of COPD occurrence and progression. The regulatory mechanisms of the circRNA/lncRNA-miRNA-mRNA (competing endogenous RNA, ceRNA) networks might facilitate our cognition of RNA interactions in COPD. This study aimed to identified novel RNA transcripts and constructed the potential ceRNA networks of COPD patients. Total transcriptome sequencing of the tissues from patients with COPD (COPD) (n = 7) and non-COPD control subjects (Normal) (n = 6) was performed, and the expression profiles of differentially expressed genes (DEGs), including mRNAs, lncRNAs, circRNAs, and miRNAs, were analyzed. The ceRNA network was established based on the miRcode and miRanda databases. Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), Gene Set Enrichment Analysis (GSEA), and Gene set variation analysis (GSVA) were implemented for functional enrichment analysis of DEGs. Finally, CIBERSORTx was extracted to analyze the relevance between hub genes and various immune cells.The Starbase and JASPAR databases were used to construct hub-RNA binding proteins (RBPs) and lncRNA-transcription factor (TF) interaction networks. A total of 1,796 mRNAs, 2,207 lncRNAs, and 11 miRNAs showed differentially expression between the lung tissue samples from the normal and COPD groups. Based on these DEGs, lncRNA/circRNA-miRNA-mRNA ceRNA networks were constructed respectively. In addition, ten hub genes were identified. Among them, RPS11, RPL32, RPL5, and RPL27A were associated with the proliferation, differentiation, and apoptosis of the lung tissue. The biological function revealed that TNF-α via NF-kB and IL6/JAK/STAT3 signaling pathways were involved in COPD. Our research constructed the lncRNA/circRNA-miRNA-mRNA ceRNA networks, filtrated ten hub genes may regulate the TNF-α/NF-κB, IL6/JAK/STAT3 signally pathways, which indirectly elucidated the post-transcriptional regulation mechanism of COPD and lay the foundation for excavating the novel targets of diagnosis and treatment in COPD.

Comparative evaluation of two intranasal forms of Curcumin: Quantitation and impact on mouse model of asthma

Aim of the studyPresent study aimed to investigate impact of two different intranasal forms of curcumin on mouse model of asthma and detection of its absorption after different time points of administration. Since the systemic bioavailability of curcumin is very low, therefore, intranasal route of administration has been explored here where systemic absorption of two intranasal forms of curcumin was evaluated. Materials and methodsTo explore the possibilities of its absorption and role in amelioration of asthma, two intranasal forms of curcumin, nasal drop and aerosol were administered to control and asthmatic mice. Blood plasma and lungs were collected at different time points of curcumin administration. Separation was done by using isocratic reversed phase high performance liquid chromatography (HPLC). Airway inflammation and oxidative stress parameters like SOD, Catalase, ROS, lipid peroxidation, and total inflammatory cell recruitments were analyzed to study efficacy of two intranasal forms of curcumin. ResultsMaximum absorption was noted at 3 hrs of different intranasal forms of curcumin, administration, i.e., nasal drop (1.93 ± 0.050 plasma, 2.87 ± 0.26 in lungs) and aerosol form of curcumin where better absorption was noted in aerosol form as compared to nasal drop (Lungs 3.08 ± 0.12 aerosol, 2.05 ± 0.020 nasal drop) at 1 h. Both, curcumin aerosol and nasal drops were effective in ameliorating oxidative stress (p < 0.05) associated with asthma in mice model. The present study may pave the way towards the development of intranasal curcumin as complementary medication because of its better absorption in plasma and lungs.

Oxidative Stress, Environmental Pollution, and Lifestyle as Determinants of Asthma in Children.

Exposure to cigarette smoke, allergens, viruses, and other environmental contaminants, as well as a detrimental lifestyle, are the main factors supporting elevated levels of airway oxidative stress. Elevated oxidative stress results from an imbalance in reactive oxygen species (ROS) production and efficiency in antioxidant defense systems. Uncontrolled increased oxidative stress amplifies inflammatory processes and tissue damage and alters innate and adaptive immunity, thus compromising airway homeostasis. Oxidative stress events reduce responsiveness to corticosteroids. These events can increase risk of asthma into adolescence and prompt evolution of asthma toward its most severe forms. Development of new therapies aimed to restore oxidant/antioxidant balance and active interventions aimed to improve physical activity and quality/quantity of food are all necessary strategies to prevent asthma onset and avoid in asthmatics evolution toward severe forms of the disease.

Mitoquinone mesylate attenuates pathological features of lean and obese allergic asthma in mice.

Obesity is associated with severe, difficult-to-control asthma, and increased airway oxidative stress. Mitochondrial reactive oxygen species (mROS) are an important source of oxidative stress in asthma, leading us to hypothesize that targeting mROS in obese allergic asthma might be an effective treatment. Using a mouse model of house dust mite (HDM)-induced allergic airway disease in mice fed a low- (LFD) or high-fat diet (HFD), and the mitochondrial antioxidant MitoQuinone (MitoQ), we investigated the effects of obesity and ROS on HDM-induced airway inflammation, remodeling, and airway hyperresponsiveness (AHR). Obese allergic mice showed increased lung tissue eotaxin, airway tissue eosinophilia, and AHR compared with lean allergic mice. MitoQ reduced airway inflammation, remodeling, and hyperreactivity in both lean and obese allergic mice, and tissue eosinophilia in obese-allergic mice. Similar effects were observed with decyl triphosphonium (dTPP+), the hydrophobic cationic moiety of MitoQ lacking ubiquinone. HDM-induced oxidative sulfenylation of proteins was increased particularly in HFD mice. Although only MitoQ reduced sulfenylation of proteins involved in protein folding in the endoplasmic reticulum (ER), ER stress was attenuated by both MitoQ and dTPP+ suggesting the anti-allergic effects of MitoQ are mediated in part by effects of its hydrophobic dTPP+ moiety reducing ER stress. In summary, oxidative signaling is an important mediator of allergic airway disease. MitoQ, likely through reducing protein oxidation and affecting the UPR pathway, might be effective for the treatment of asthma and specific features of obese asthma.

Apelin-13 facilitates mitochondria homeostasis via mitophagy to prevent against airway oxidative injury in asthma

Oxidative stress is a major mediator in the pathogenesis of allergens-induced asthma. Mitochondria damage and dysfunction is considered to be closely related with oxidative stress. Apelin-13 is a novel multifunctional protein with anti-inflammatory and anti-oxidative properties in neuroinflammation and ischemia-reperfusion injury. However, its role in mitochondria homeostasis under asthma-associated airway oxidative injury and the potential mechanisms have not been elucidated. A murine model of asthma was established by house dust mite (HDM) allergen sensitization and challenge. The mice were received Apelin-13 protein through intraperitoneal administration before HDM challenge. Airway inflammation, histopathological changes and oxidative stress were examined. The regulatory effects of Apelin-13 on mitochondria function were evaluated using airway epithelial BEAS-2B cells, including mitochondria membrane potential (MMP), mitophagy and the possible signaling pathway. The HDM-challenged mice group exhibited robust inflammation and apoptosis in airway epithelium compared to the control group. The airway impairment in asthmatic mice was partly lessened after Apelin-13 administration. Meanwhile, protein expressions of mitophagy-related markers PINK1, Parkin, Tomm20 and LC3 were significantly increased in the lungs of Apelin-13-treated asthmatic mice. In vitro, Apelin-13 treatment significantly improved MMP levels and reduced ROS production in BEAS-2B cells exposed to HDM, accompanied with the increase of cell viability. Furthermore, Apelin-13 was found to promote the activation of PINK1/Parkin signaling in BEAS-2B cells, thereby increasing mitophagy activity and facilitating mitochondria homeostasis. These results demonstrate that Apelin-13 acts as a regulator of mitochondria homeostasis by driving mitophagy to protect against HDM allergen-induced airway oxidative injury. Apelin-13 may serve as a promising protective agent for treating asthma.

The effect of N-acetylcysteine in patients with non-cystic fibrosis bronchiectasis (NINCFB): study protocol for a multicentre, double-blind, randomised, placebo-controlled trial

BackgroundN-acetylcysteine (NAC), which is specifically involved in airway mucus clearance and antioxidation, is recommended by the treatment guideline for non-cystic fibrosis bronchiectasis (NCFB). However, there is little clinical evidence of its long-term efficacy concerning quality of life (QoL) and exacerbation in patients with NCFB. In addition, the influences of NAC on airway bacterial colonization, chronic inflammation and oxidative stress in NCFB are also unclear.MethodsNINCFB is a prospective, multicentre, double-blind, randomised, placebo-controlled trial that will recruit 119 patients with NCFB and randomly divide them into an NAC group (n = 79) and a control group (n = 40). Participants in the NAC group will receive 600 mg oral NAC twice daily for 52 weeks, while patients in the control group will receive 600 mg placebo twice daily for 52 weeks. The information at baseline will be collected once participants are enrolled. The primary endpoints are the changes in St George’s Respiratory Questionnaire scores and the number of exacerbations in 52 weeks. The secondary endpoints are the 16S rRNA of sputum and the levels of inflammatory factors and oxidative stressors in sputum and serum. Other data related to radiography, lung function tests, number of oral and/or intravenous antibiotic therapies and adverse events (AEs) will also be analysed. Further subgroup analysis distinguished by the severity of disease, severity of lung function, airway bacterial colonization and exacerbation frequency will be performed.DiscussionThe objective of this study is to determine the long-term efficacy of NAC on QoL and exacerbation of NCFB and to explore the effectiveness of NAC for antibiosis, anti-inflammation and antioxidation in NCFB. The study results will provide high-quality clinical proof for the revision and optimization of treatment guidelines and for expert consensus on NCFB treatment.Trial registrationThe trial was registered on the Chinese Clinical Trial Register at April 11, 2020 (chictr.org.cn, ChiCTR2000031817).

Dexmedetomidine attenuates airway inflammation and oxidative stress in asthma via the Nrf2 signaling pathway.

Allergic asthma is a chronic inflammatory disease in which oxidative stress serves a pivotal role. In clinical practice, dexmedetomidine (DEX), an α‑2‑adrenergic receptor agonist, is used as a sedative. DEX exhibits antioxidative and organ‑protective properties. In a murine model of asthma, DEX has a therapeutic effect via the toll like receptor 4/NF‑кB signaling pathway; however, whether DEX can exert an antioxidative effect on asthma has yet to be elucidated. In the present study, a T helper (Th)2‑dominant murine asthma model was established. DEX treatment significantly reduced eosinophilic airway inflammation, mucus overproduction and airway hyperresponsiveness, as well as the concentrations of Th2 cytokines. The lung tissues of mice with asthma were characterized by redox imbalance (increased oxidative stress and impaired antioxidant capacity). DEX treatment alleviated this imbalance by decreasing the levels of malondialdehyde and reactive oxygen species, and increasing the levels of glutathione. Furthermore, the nuclear factor erythroid 2‑related factor 2 (Nrf2) signaling pathway was inhibited in the lung tissues of asthmatic mice; these effects were noted in its downstream genes, heme oxygenase 1 and glutathione peroxidase 4. In mice with asthma, DEX treatment induced the expression of these antioxidant genes and the activation of Nrf2, whereas ML385 (an inhibitor of Nrf2) partially abrogated the antioxidative and therapeutic effects of DEX. To the best of our knowledge, the present study is the first to demonstrate the protective effect of DEX on Th2‑dominant asthma through the activation of the Nrf2 signaling pathway. The results suggested that the antioxidative properties of DEX could be beneficial in clinical application of DEX for the relief of asthmatic symptoms.

Exhaled breath condensate markers of oxidative stress in male storekeepers of chemical stores in the Ariaria international market Aba Abia state Nigeria.

In most developing countries, stores, where chemical substances are sold, are poorly ventilated, and best practices are not followed. This can result in the contamination of the ambient air inside the stores with toxicological implications for the lungs. This work aimed at determining the risk of pulmonary disease in chemical storekeepers in the Ariaria international market Aba by the evaluation of exhaled breath condensate (EBC) biomarkers of oxidative stress. A gas monitor was used for gas sampling while an Aerocet analyzer was used for particulate matter determinations. Exposed filter paper was used for the sampling of heavy metals in the air, and the determination was done using atomic absorption spectrophotometry. The exhaled breath condensate was collected with a refrigerated condenser, and the markers of oxidative stress were determined spectrophotometrically. Concentrations of particulate matter (PM1, PM2.5, PM4, PM7, PM10) were elevated in all the chemical stores studied. Our findings also showed that the indoor air of the chemical stores studied was polluted with SO2, NO2, NH3 and H2S, as their concentrations were respectively higher than the WHO standard values. Concentrations of all the heavy metals present in the ambient air of the chemical stores were also higher than the Nigerian Environmental Standard and Regulation Enforcement Agency (NESREA) standard values. Chemical storekeepers at the Ariaria international market exhaled increased concentrations of thiobarbituric acid reactive substances (TBARS), H2O2, and lower concentrations of glutathione (GSH). The pH values of the exhaled breath condensates were decreased and slightly acidic. It therefore means that the storekeepers were exposed to polluted ambient air inside the stores. This resulted to airway oxidative stress in the storekeepers as reported herein. Therefore, storekeepers of chemical stores in the Ariaria international market, Aba Nigeria were at risk of pulmonary disease(s).

Dimethylarginine dimethylaminohydrolase 1 protects PM2.5 exposure-induced lung injury in mice by repressing inflammation and oxidative stress

BackgroundAirborne fine particulate matter with aerodynamic diameter ≤ 2.5 μm (PM2.5) pollution is associated with the prevalence of respiratory diseases, including asthma, bronchitis and chronic obstructive pulmonary disease. In patients with those diseases, circulating asymmetric dimethylarginine (ADMA) levels are increased, which contributes to airway nitric oxide deficiency, oxidative stress and inflammation. Overexpression of dimethylarginine dimethylaminohydrolase 1 (DDAH1), an enzyme degrading ADMA, exerts protective effects in animal models. However, the impact of DDAH1/ADMA on PM2.5-induced lung injury has not been investigated.MethodsDdah1−/− and DDAH1-transgenic mice, as well as their respective wild-type (WT) littermates, were exposed to either filtered air or airborne PM2.5 (mean daily concentration ~ 50 µg/m3) for 6 months through a whole-body exposure system. Mice were also acutely exposed to 10 mg/kg PM2.5 and/or exogenous ADMA (2 mg/kg) via intratracheal instillation every other day for 2 weeks. Inflammatory response, oxidative stress and related gene expressions in the lungs were examined. In addition, RAW264.7 cells were exposed to PM2.5 and/or ADMA and the changes in intracellular oxidative stress and inflammatory response were determined.ResultsDdah1−/− mice developed more severe lung injury than WT mice after long-term PM2.5 exposure, which was associated with greater induction of pulmonary oxidative stress and inflammation. In the lungs of PM2.5-exposed mice, Ddah1 deficiency increased protein expression of p-p65, iNOS and Bax, and decreased protein expression of Bcl-2, SOD1 and peroxiredoxin 4. Conversely, DDAH1 overexpression significantly alleviated lung injury, attenuated pulmonary oxidative stress and inflammation, and exerted opposite effects on those proteins in PM2.5-exposed mice. In addition, exogenous ADMA administration could mimic the effect of Ddah1 deficiency on PM2.5-induced lung injury, oxidative stress and inflammation. In PM2.5-exposed macrophages, ADMA aggravated the inflammatory response and oxidative stress in an iNOS-dependent manner.ConclusionOur data revealed that DDAH1 has a marked protective effect on long-term PM2.5 exposure-induced lung injury.

The effect of beetroot juice on airway inflammation in a murine model of asthma.

The effects of beetroot juice on airways inflammation, cytokine levels, and oxidative stress biomarkers were evaluated using an allergen-induced murine model of asthma. Ovalbumin (OVA)-sensitized and challenged BALB/c mice were used as an asthma model. BALB/c mice were randomly assigned into four groups: control (Ova sensitization and normal saline challenge), control and beetroot (Ova sensitization and normal saline challenge plus beetroot juice), Ova S/C [Ova sensitization and challenge (Ova S/C)], Ova S/C and beetroot juice (Ova S/C plus beetroot juice). The bronchoalveolar lavage fluid (BALF) was analyzed for total and differential inflammatory cells count. The levels of cytokines [interleukin (IL)-10, IL-13, and IL-18], and oxidative stress biomarkers [glutathione peroxidase (GPx), catalase, and thiobarbituric acid reactive substances (TBARS)] were analyzed in the lung tissue. Simultaneous administration of beetroot juice and Ova S/C significantly increased the total inflammatory cells compared to the control (p=.0001) and Ova S/C (p=.013) groups and significantly increased the number of eosinophils (p ˂ .0001) and macrophages (p ˂ .0001) compared to the control. Moreover, the simultaneous administration of beetroot juice and Ova S/C did not affect the level of IL-10, IL-13, IL-18, GPx, or TBARS compared to the control (p > .05), but it significantly increased the level of catalase (p=.002). Results suggest that beetroot juice aggravates asthma by enhancing airway inflammation. However, it does not affect airway inflammation in healthy mice. PRACTICAL APPLICATIONS: Asthma is a chronic airway inflammatory disease that is characterized by variable degrees of airways inflammation and obstruction. Paradox data are reported in the literature regarding beetroot and asthma. The present study revealed that beetroot juice exacerbates asthma by enhancing airway inflammation. However, it is safe and has no effects on airway inflammation in healthy mice. Patients having asthma or a history of asthma are advised to avoid the consumption of beetroot.

Inhalation of Salvianolic Acid B Prevents Fine Particulate Matter-Induced Acute Airway Inflammation and Oxidative Stress by Downregulating the LTR4/MyD88/NLRP3 Pathway.

Air pollution is a serious threat to human health. Inhaled fine particulate matter (PM2.5) can cause inflammation and oxidative stress in the airway; however, the mechanisms responsible for this effect have yet to be elucidated and there are no specific drugs that can prevent and treat this condition. In the present study, we investigated the effects and mechanisms underlying the inhalation of salvianolic acid B (SalB) on PM2.5-induced airway inflammation and oxidative stress. We used a PM2.5-induced mouse model of airway inflammation and oxidative stress, along with a human epithelial cell model, to study the action and mechanisms of SalB by histopathology, real-time PCR, enzyme-linked immunosorbent assays, flow cytometry, and western blotting. SalB treatment markedly inhibited the PM2.5-induced increase in the number of neutrophils and macrophages in bronchoalveolar lavage fluid, improved the infiltration of inflammatory cells in lung tissue, and reduced injury in the alveolar septum. Furthermore, SalB reduced the mRNA and protein levels of interleukin- (IL-) 1β, tumor necrosis factor- (TNF-) α, keratinocyte (KC), and transforming growth factor- (TGF-) β1 in lung tissues and the protein levels of IL-1β, TNF-α, IL-8, IL-6, and TGF-β1 in human epithelial cells. SalB treatment also significantly prevented the reduction of levels of superoxide dismutase, catalase, glutathione, and glutathione peroxidase in lung tissue and reduced the levels of reactive oxygen species in human epithelial cells induced by PM2.5. Furthermore, SalB and the myeloid differentiation primary response 88 (MyD88) inhibitor ST2825 inhibited the expression levels of toll-like receptor 4 (TLR4), MyD88, tumor necrosis factor receptor associated factor 6 (TRAF-6), and NOD-like receptor protein 3 (NLRP3), as well as the phosphorylation of downstream Erk1/2 and P38 in lung tissue and epithelial cells. SalB protects against PM2.5-induced airway inflammation and oxidative stress in a manner that is associated with the inhibition of the TLR4/MyD88/TRAF-6/NLRP3 pathway and downstream signals ERK1/2 and P38.

Serum Proteomic Profile of Asthmatic Patients after Six Months of Benralizumab and Mepolizumab Treatment.

Severe eosinophilic asthma is characterized by chronic airway inflammation, oxidative stress, and elevated proinflammatory cytokines, especially IL-5. Mepolizumab and benralizumab are both humanized IgG antibodies directed against IL-5 signaling, directly acting on eosinophils count. Together with the complexity of severe asthma classification and patient selection for the targeted treatment, there is also the urgency to clarify the follow-up of therapy to identify biomarkers, in addition to eosinophils, for the optimal duration of treatment, persistence of effectiveness, and safety. To this purpose, here we performed a follow-up study using differential proteomic analysis on serum samples after 1 and 6 months of both therapies and sera from healthy patients. Statistical analysis by PCA and heatmap analyses were performed, and identified proteins were used for enrichment analysis by MetaCore software. The analysis highlighted 82 differences among all considered conditions. In particular, 30 referred to benralizumab time point (T0, T1B, T6B) and 24 to mepolizumab time point (T0, T1M, T6M) analyses. t-SNE and heatmap analyses evidence that the differential serum protein profile at 6 months of both treatments is more similar to that of the healthy subjects. Among the identified proteins, APOAI, APOC-II, and APOC-III are upregulated principally after 6 months of benralizumab treatment, plasminogen is upregulated after 6 months of both treatments and ceruloplasmin, upregulated already after 1 month of benralizumab, becoming higher after 6 months of mepolizumab. Using enrichment analysis, identified proteins were related to lipid metabolism and transport, blood coagulation, and ECM remodeling.

Airway epithelial Paraoxonase-2 in obese asthma.

BackgroundObesity in asthmatics has been associated with higher airway oxidative stress in which dysfunctional mitochondria are a potential contributing source of excess free radicals. Paraoxonase 2 (PON2) plays an important role in reducing mitochondrial-derived oxidative stress and could, therefore, have therapeutic potential in these patients.ObjectivesWe used primary human bronchial epithelial cells (HBECs) from asthmatics and healthy controls to evaluate: a) protein levels of Paraoxonase 2 and b) to test the potential protective effect of quercetin supplementation in cells under oxidative stress conditions.ResultsCompared to lean controls, obese asthmatics had significantly lower PON2 airway epithelial levels (respectively, 1.08 vs. 0.47 relative units normalized by GAPDH) (p-value < 0.006). Treating HBECs in vitro for 24 hrs. with 25μM quercetin significantly increased PON2 protein levels: 15.5 treated cells vs. 9.8 untreated cells (relative units normalized by GAPDH) (p value = 0.004). Notably, compared to untreated cells, quercetin supplementation reduces mitochondrial superoxide and hydrogen peroxide production on HBECs cells exposed to different oxidative stress triggers such as 1–2 Naphthoquinone (1–2 NQ) and hydrogen peroxide, suggesting that PON2 might play a protective role ameliorating oxidative injury on human airway epithelium.ConclusionCompared to lean controls, obese asthmatics have significantly reduced PON2 levels in airway epithelial cells. Treatment with quercetin in vitro increased PON2 protein levels and prevented oxidative stress from different types of stimuli. Hence, quercetin supplementation may be a potential therapeutic strategy to prevent obesity-mediated airway oxidative stress in obese asthmatics.

Extracellular Matrix Oxidised by the Granulocyte Oxidants Hypochlorous and Hypobromous Acid Reduces Lung Fibroblast Adhesion and Proliferation In Vitro.

Chronic airway inflammation and oxidative stress play crucial roles in the pathogenesis of chronic inflammatory lung diseases, with airway inflammation being a key driving mechanism of oxidative stress in the lungs. Inflammatory responses in the lungs activate neutrophils and/or eosinophils, leading to the generation of hypohalous acids (HOX). These HOX oxidants can damage the extracellular matrix (ECM) structure and may influence cell–ECM interactions. The ECM of the lung provides structural, mechanical, and biochemical support for cells and determines the airway structure. One of the critical cells in chronic respiratory disease is the fibroblast. Thus, we hypothesised that primary human lung fibroblasts (PHLF) exposed to an oxidised cell-derived ECM will result in functional changes to the PHLF. Here, we show that PHLF adhesion, proliferation, and inflammatory cytokine secretion is affected by exposure to HOX-induced oxidisation of the cell-derived ECM. Furthermore, we investigated the impact on fibroblast function from the presence of haloamines in the ECM. Haloamines are chemical by-products of HOX and, like the HOX, haloamines can also modify the ECM. In conclusion, this study revealed that oxidising the cell-derived ECM might contribute to functional changes in PHLF, a key mechanism behind the pathogenesis of inflammatory lung diseases.

Continuous positive airway pressure affects mitochondrial function and exhaled PGC1-α levels in obstructive sleep apnea

Purpose: Subjects with obstructive sleep apnea (OSA) exhibit systemic and upper airway oxidative stress and inflammation, which cause mitochondrial dysfunction. The intend of this study is to estimate mitochondrial function (mitochondrial DNA/nuclear DNA [Mt/N] ratio) and protein levels of peroxisome proliferator-coactivated receptor gamma co-activator 1-alpha (PGC1-α) in the exhaled breath condensate (EBC) and plasma before and after continuous positive airway pressure (CPAP) treatment. Materials and methods: Twenty healthy individuals (control) and 40 subjects with severe or moderate OSA were recruited to undergo CPAP treatment and evaluation in a sleep study. The Mt/N ratio in the EBC and blood were assayed by quantitative real-time polymerase chain reaction. Enzyme-linked immunosorbent assay was used to measure the protein concentration of PGC1-α in the EBC and plasma. All experiments were performed after 3 months of CPAP treatment in subjects with OSA. Results: We observed no noteworthy differences between the control and treatment groups. Moreover, there were no differences in the Mt/N ratio in the blood and plasma levels of PGC1-α in subjects with OSA before and after treatment. However, the Mt/N ratio and protein levels of PGC1-α in the EBC of OSA subjects were higher than those in the control group and returned to normal levels after CPAP treatment. Conclusions: We successfully treated subjects with OSA by CPAP, which restored the Mt/N ratio and levels of PGC1-α in the EBC.

Dispersion and utilization of lipid droplets mediates respiratory syncytial virus-induced airway hyperresponsiveness.

Respiratory viral infections (RSV) can induce acute asthma attacks, thereby destroying lung function and accelerating the progression of the disease. However, medications in the stable phase of asthma are often not effective for acute attacks induced by viral infections. We aimed to clarify the possible mechanism of viral infection-induced asthma through fatty acid metabolism. The airway resistances, inflammatory injuries, and oxidative stress in the RSV-induced animal models were significantly higher than those in the control group at acute phase (7 days) and chronic phase (28 days). Moreover, the concentrations of the medium- and long-chain fatty acids in lung tissue at (28 days) were significantly increased, including 14:0 (myristic acid), 16:0 (palmitic acid, PA), 18:1 (oleic acid, OA), and 18:2 (linoleic acid, LA) using non-targeted metabonomics. Airway epithelial cells treated with RSV showed the reduced expression of FSP27, RAB8A, and PLIN5, which caused the fusion and growth of lipid droplet (LD), and increased expression of the LD dispersion gene perilipin 2. There was also a decrease in PPARγ expression and an increase in the fatty acid catabolism gene PPARα, causing lipid oxidation, free fatty acid releases, and an upsurge in IL-1, IL-2, IL-4, and IL-6 expression, which could be abrogated by GPR40 inhibitor. Treated mice or epithelial cells with C18 fatty acid exhibited inhibition of epithelial proliferation, increases of inflammation, and oxidative damage. RSV promoted lipid dispersion and utilization, causing enlarged oxidative injuries and an upsurge in the pro-inflammatory cytokines, leading to the progression of airway hyperresponsiveness (AHR).

Surfaxin attenuates PM2.5-induced airway inflammation via restoring surfactant proteins in rats exposed to cigarette smoke

Epidemiologic studies have shown that the fine particulate matter 2.5 (PM2.5) exaggerates chronic airway inflammation involving in acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Surfactant proteins (SPs) decreases significantly related to airflow limitation and airway inflammation. However, how to restore the reduction of SPs levels in airway inflammation exposed to PM2.5 has not been well understood. In the present study, the SPs including SPA, SPB, SPC and SPD levels in bronchoalveolar lavage fluid (BALF) were detected from patients with stable COPD. Rats were exposed to cigarette smoke and PM2.5. After given with Surfaxin, the expression of SPs, protein kinase C (PKC) and tight junction protein (ZO-1) in lung tissue and the levels of C-reactive protein (CRP) and fibrinogen (FIB) in plasma was observed. The results showed that SPA, SPB and SPD were significantly lower than those of the control group (p < 0.01). PM2.5 aggravated smoking-induced airway inflammation and oxidative stress demonstrated by pathological changes of lung tissue and increased levels of CRP and PKC in vivo. PM2.5 decreased the expression of all the SPs and ZO-1, which could be significantly restored by Surfaxin. These findings indicate that Surfaxin protects the alveolar epithelium from PM2.5 in airway inflammation through increasing SPs.

Acute responses of airway oxidative stress, inflammation, and hemodynamic markers to ambient PM2.5 and their trace metal contents among healthy adolescences: A panel study in highly polluted versus low polluted regions

Particulate air pollutants are known contributors to global cardiorespiratory mortality through several pathways. We examined the effects of varied exposure to PM2.5 and trace metals on biological markers of airway inflammation, oxidative stress, and hemodynamic function of young individuals living in two different exposure settings.We enrolled and followed a panel of 97 healthy nonsmoking participants aged 15–18 years living in a highly polluted metropolitan city of Tabriz (TBZ) and a much less polluted semi-urban town of Hadishahr (HDS). For five consecutive months, the subjects were examined by a physician, and fractional exhaled nitric oxide levels (FENO) were measured. Samples of exhaled breath condensation (EBC) were obtained for measuring interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and total nitric oxide (NOx). We measured daily outdoor PM2.5 mass concentration in a fixed station in each location for all this period. The PM-metal content was analyzed by ICP-MS. The linear mixed-effects regression models were applied for data analysis.The averages of PM2.5 mass and total metals in TBZ were nearly two and four times higher than in HDS, respectively. In TBZ, an increased IQR of PM2.5 mass during 0–5 days was -correlated with a significant rise in diastolic blood pressure, heart rate, TNF-α, FENO, and NOx and reduction of IL-6. Moreover, exposure to low PM2.5 concentration is significantly -correlated with an elevation in diastolic blood pressure in HDS. We also observed that exposure to metal constituents in the highly polluted region is correlated with increased TNF-α and IL-6 with 131.80% (95% CI: 56.01, 244.39) and 47.51% (95% CI: 33.01, 62.05) per IQR of Hg, respectively.This study suggests that exposure to ambient PM2.5 and their metal contents in highly polluted areas may incite significant changes in airway inflammation, oxidative stress, and hemodynamic parameters in healthy subjects.

Functional significance of 8-isoprostanes in sinonasal disease and asthma

BackgroundThe purpose of this study was to investigate how 8-isoprostanes, used as a marker of airway oxidative stress, were related to sinus disease and asthma. MethodsWe analyzed samples and data from two separate studies, one investigating sinonasal disease in asthma, the other investigating the effect of BMI on airway disease. We measured airway (nasal lavage) 8-isoprostanes and investigated the relationship with measures of sinus and asthma symptoms, asthma control and lung function. ResultsThe study of people with sinonasal disease and poorly controlled asthma included 48 obese, 31 overweight and 23 lean participants. In multivariate analysis, nasal lavage 8-isoprostane levels increased with increasing BMI (p < 0.01), and were higher in Caucasian than African American participants (p = 0.01). Sinus symptoms were inversely related to nasal 8-isoprostanes (p = 0.02) independent of BMI and Race. In the study investigating the effect of BMI on airway disease, we enrolled 13 controls with obesity and 21 people with obesity and asthma: 8-isoprostane levels were higher in obese controls than in obese people with asthma (p < 0.01), and levels were inversely related to sinus symptoms (p = 0.02) and asthma control (p < 0.01).Interpretation: 8-isoprostanes in nasal lavage are increased in obesity, and increased in Caucasians compared with African Americans. However, levels are higher in obese controls than obese people with asthma, and appear inversely related to symptoms of airway disease. Clinical implicationAirway 8-isoprostanes likely reflect complex oxidative signaling pathways, which are altered in obesity and those of different race, rather than being a simple marker of airway oxidative injury. Capsule summaryIncreased airway oxidative signaling (8-isoprostanes), may reflect normal physiology in the setting of obesity, as decreased levels are associated with disease activity in people with chronic sinonasal disease and asthma.