Showing papers in "Respiratory Research in 2018"

Idiopathic pulmonary fibrosis: pathogenesis and management.

Abstract: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease characterized by the aberrant accumulation of fibrotic tissue in the lungs parenchyma, associated with significant morbidity and poor prognosis. This review will present the substantial advances achieved in the understanding of IPF pathogenesis and in the therapeutic options that can be offered to patients, and will address the issues regarding diagnosis and management that are still open. Over the last two decades much has been clarified about the pathogenic pathways underlying the development and progression of the lung scarring in IPF. Sustained alveolar epithelial micro-injury and activation has been recognised as the trigger of several biological events of disordered repair occurring in genetically susceptible ageing individuals. Despite multidisciplinary team discussion has demonstrated to increase diagnostic accuracy, patients can still remain unclassified when the current diagnostic criteria are strictly applied, requiring the identification of a Usual Interstitial Pattern either on high-resolution computed tomography scan or lung biopsy. Outstanding achievements have been made in the management of these patients, as nintedanib and pirfenidone consistently proved to reduce the rate of progression of the fibrotic process. However, many uncertainties still lie in the correct use of these drugs, ranging from the initial choice of the drug, the appropriate timing for treatment and the benefit-risk ratio of a combined treatment regimen. Several novel compounds are being developed in the perspective of a more targeted therapeutic approach; in the meantime, the supportive care of these patients and their carers should be appropriately prioritized, and greater efforts should be made toward the prompt identification and management of relevant comorbidities. Building on the advances in the understanding of IPF pathobiology, the further investigation of the role of gene variants, epigenetic alterations and other molecular biomarkers reflecting disease activity and behaviour will hopefully enable earlier and more confident diagnosis, improve disease phenotyping and support the development of novel agents for personalized treatment of IPF.

Critical inhaler errors in asthma and COPD: a systematic review of impact on health outcomes

Abstract: Inhaled drug delivery is the cornerstone treatment for asthma and chronic obstructive pulmonary disease (COPD). However, use of inhaler devices can be challenging, potentially leading to critical errors in handling that can significantly reduce drug delivery to the lungs and effectiveness of treatment. A systematic review was conducted to define ‘critical’ errors and their impact on health outcomes and resource use between 2004 and 2016, using key search terms for inhaler errors in asthma and COPD (Search-1) and associated health-economic and patient burden (Search-2). Search-1 identified 62 manuscripts, 47 abstracts, and 5 conference proceedings (n = 114 total). Search-2 identified 9 studies. We observed 299 descriptions of critical error. Age, education status, previous inhaler instruction, comorbidities and socioeconomic status were associated with worse handling error frequency. A significant association was found between inhaler errors and poor disease outcomes (exacerbations), and greater health-economic burden. We have shown wide variations in how critical errors are defined, and the evidence shows an important association between inhaler errors and worsened health outcomes. Given the negative impact diminished disease outcomes impose on resource use, our findings highlight the importance of achieving optimal inhaler technique, and a need for a consensus on defining critical and non-critical errors.

The European IPF registry (eurIPFreg): baseline characteristics and survival of patients with idiopathic pulmonary fibrosis

Abstract: Since 2009, IPF patients across Europe are recruited into the eurIPFreg, providing epidemiological data and biomaterials for translational research. The registry data are based on patient and physician baseline and follow-up questionnaires, comprising 1700 parameters. The mid- to long-term objectives of the registry are to provide clues for a better understanding of IPF phenotype sub-clusters, triggering factors and aggravating conditions, regional and environmental characteristics, and of disease behavior and management. This paper describes baseline data of 525 IPF subjects recruited from 11/2009 until 10/2016. IPF patients had a mean age of 68.1 years, and seeked medical advice due to insidious dyspnea (90.1%), fatigue (69.2%), and dry coughing (53.2%). A surgical lung biopsy was performed in 32% in 2009, but in only 8% of the cases in 2016, possibly due to increased numbers of cryobiopsy. At the time of inclusion in the eurIPFreg, FVC was 68.4% ± 22.6% of predicted value, DLco ranged at 42.1% ± 17.8% of predicted value (mean value ± SD). Signs of pulmonary hypertension were found in 16.8%. Steroids, immunosuppressants and N-Acetylcysteine declined since 2009, and were replaced by antifibrotics, under which patients showed improved survival (p = 0.001). Our data provide important insights into baseline characteristics, diagnostic and management changes as well as outcome data in European IPF patients over time. The eurIPFreg and eurIPFbank are listed in ClinicalTrials.gov( NCT02951416 ).

Epithelial mesenchymal transition (EMT): a universal process in lung diseases with implications for cystic fibrosis pathophysiology

Abstract: Cystic Fibrosis (CF) is a genetic disorder that arises due to mutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene, which encodes for a protein responsible for ion transport out of epithelial cells. This leads to a disruption in transepithelial Cl-, Na + and HCO3− ion transport and the subsequent dehydration of the airway epithelium, resulting in infection, inflammation and development of fibrotic tissue. Unlike in CF, fibrosis in other lung diseases including asthma, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis has been well characterised. One of the driving forces behind fibrosis is Epithelial Mesenchymal Transition (EMT), a process where epithelial cells lose epithelial proteins including E-Cadherin, which is responsible for tight junctions. The cell moves to a more mesenchymal phenotype as it gains mesenchymal markers such as N-Cadherin (providing the cells with migration potential), Vimentin and Fibronectin (proteins excreted to help form the extracellular matrix), and the fibroblast proliferation transcription factors Snail, Slug and Twist. This review paper explores the EMT process in a range of lung diseases, details the common links that these have to cystic fibrosis, and explores how understanding EMT in cystic fibrosis may open up novel methods of treating patients with cystic fibrosis.

Macrophages: friend or foe in idiopathic pulmonary fibrosis?

Abstract: Idiopathic pulmonary fibrosis (IPF) is a prototype of lethal, chronic, progressive interstitial lung disease of unknown etiology. Over the past decade, macrophage has been recognized to play a significant role in IPF pathogenesis. Depending on the local microenvironments, macrophages can be polarized to either classically activated (M1) or alternatively activated (M2) phenotypes. In general, M1 macrophages are responsible for wound healing after alveolar epithelial injury, while M2 macrophages are designated to resolve wound healing processes or terminate inflammatory responses in the lung. IPF is a pathological consequence resulted from altered wound healing in response to persistent lung injury. In this review, we intend to summarize the current state of knowledge regarding the process of macrophage polarization and its mediators in the pathogenesis of pulmonary fibrosis. Our goal is to update the understanding of the mechanisms underlying the initiation and progression of IPF, and by which, we expect to provide help for developing effective therapeutic strategies in clinical settings.

Regulation of alveolar macrophage death in acute lung inflammation.

Abstract: Acute lung injury (ALI) and its severe form, known as acute respiratory distress syndrome (ARDS), are caused by direct pulmonary insults and indirect systemic inflammatory responses that result from conditions such as sepsis, trauma, and major surgery. The reciprocal influences between pulmonary and systemic inflammation augments the inflammatory process in the lung and promotes the development of ALI. Emerging evidence has revealed that alveolar macrophage (AM) death plays important roles in the progression of lung inflammation through its influence on other immune cell populations in the lung. Cell death and tissue inflammation form a positive feedback cycle, ultimately leading to exaggerated inflammation and development of disease. Pharmacological manipulation of AM death signals may serve as a logical therapeutic strategy for ALI/ARDS. This review will focus on recent advances in the regulation and underlying mechanisms of AM death as well as the influence of AM death on the development of ALI.

Is IgE or eosinophils the key player in allergic asthma pathogenesis? Are we asking the right question?

Abstract: Bronchial asthma (BA) is a chronic inflammatory disease with a marked heterogeneity in pathophysiology and etiology. The heterogeneity of BA may be related to the inducing mechanism(s) (allergic vs non-allergic), the histopathological background (eosinophilic vs non-eosinophilic), and the clinical manifestations, particularly in terms of severity and frequency of exacerbations. Asthma can be divided into at least two different endotypes based on the degree of Th2 inflammation (T2 ‘high’ and T2 ‘low’). For patients with severe uncontrolled asthma, monoclonal antibodies (mAbs) against immunoglobulin E (IgE) or interleukin (IL)-5 are now available as add-on treatments. Treatment decisions for individual patients should consider the biological background in terms of the “driving mechanisms” of inflammation as this should predict the patients’ likely responses to treatment. The question is not whether an anti-IgE or an anti-eosinophilic strategy is more effective, but rather what the mechanism is at the origin of the airway. While IgE is involved early in the inflammatory cascade and can be considered as a cause of allergic asthma, eosinophilia can be considered a consequence of the whole process. This article discusses the different roles of the IgE and IL-5/eosinophil pathways in the pathogenic mechanisms of airway inflammation occurring in allergic asthma, and the possible reasons to choose an anti-IgE mAb or anti-IL-5 treatment.

A circulating cell population showing both M1 and M2 monocyte/macrophage surface markers characterizes systemic sclerosis patients with lung involvement.

Abstract: Systemic sclerosis (SSc) is a disorder characterized by immune system alterations, vasculopathy and fibrosis. SSc-related interstitial lung disease (ILD) represents a common and early complication, being the leading cause of mortality. Monocytes/macrophages seem to have a key role in SSc-related ILD. Interestingly, the classically (M1) and alternatively (M2) activated monocyte/macrophage phenotype categorization is currently under revision. Our aim was to evaluate if circulating monocyte/macrophage phenotype could be used as biomarker for lung involvement in SSc. To this purpose we developed a wide phenotype characterization of circulating monocyte/macrophage subsets in SSc patients and we evaluated possible relations with lung involvement parameter values. A single centre cross-sectional study was performed in fifty-five consecutive SSc patients, during the year 2017. All clinical and instrumental tests requested for SSc follow up and in particular, lung computed tomography (CT) scan, pulmonary function tests (PFTs), Doppler echocardiography with systolic pulmonary artery pressure (sPAP) measurement, blood pro-hormone of brain natriuretic peptide (pro-BNP) evaluation, were performed in each patient in a maximum one-month period. Flow cytometry characterization of circulating cells belonging to the monocyte/macrophage lineage was performed using specific M1 (CD80, CD86, TLR2 and TLR4) and M2 surface markers (CD204, CD163 and CD206). Non-parametric tests were used for statistical analysis. A higher percentage of circulating CD204+CD163+CD206+TLR4+CD80+CD86+ and CD14+CD206+CD163+CD204+TLR4+CD80+CD86+ mixed M1/M2 monocyte/macrophage subsets, was identified to characterize patients affected by SSc-related ILD and higher systolic pulmonary artery pressure. Mixed M1/M2 monocyte/macrophage subset showed higher percentages in patients positive for anti-topoisomerase antibody, a known lung involvement predictor. The present study shows for the first time, through a wide flow cytometry surface marker analysis, that higher circulating mixed M1/M2 monocyte/macrophage cell percentages are associated with ILD, sPAP and anti-topoisomerase antibody positivity in SSc, opening the path for research on their possible role as pathogenic or biomarker elements for SSc lung involvement.

The JAK2 pathway is activated in idiopathic pulmonary fibrosis.

Abstract: Idiopathic pulmonary fibrosis (IPF) is the most rapidly progressive and fatal fibrotic disorder, with no curative therapies. The signal transducer and activator of transcription 3 (STAT3) protein is activated in lung fibroblasts and alveolar type II cells (ATII), thereby contributing to lung fibrosis in IPF. Although activation of Janus kinase 2 (JAK2) has been implicated in proliferative disorders, its role in IPF is unknown. The aim of this study was to analyze JAK2 activation in IPF, and to determine whether JAK2/STAT3 inhibition is a potential therapeutic strategy for this disease. JAK2/p-JAK2 and STAT3/pSTAT3 expression was evaluated using quantitative real time-PCR, western blotting, and immunohistochemistry. Compared to human healthy lung tissue (n = 10) both proteins were upregulated in the lung tissue of IPF patients (n = 12). Stimulating primary ATII and lung fibroblasts with transforming growth factor beta 1 or interleukin (IL)-6/IL-13 activated JAK2 and STAT3, inducing epithelial to mesenchymal and fibroblast to myofibroblast transitions. Dual p-JAK2/p-STAT3 inhibition with JSI-124 or silencing of JAK2 and STAT3 genes suppressed ATII and the fibroblast to myofibroblast transition, with greater effects than the sum of those obtained using JAK2 or STAT3 inhibitors individually. Dual rather than single inhibition was also more effective for inhibiting fibroblast migration, preventing increases in fibroblast senescence and Bcl-2 expression, and ameliorating impaired autophagy. In rats administered JSI-124, a dual inhibitor of p-JAK2/p-STAT3, at a dose of 1 mg/kg/day, bleomycin-induced lung fibrosis was reduced and collagen deposition in the lung was inhibited, as were JAK2 and STAT3 activation and several markers of fibrosis, autophagy, senescence, and anti-apoptosis. JAK2 and STAT3 are activated in IPF, and their dual inhibition may be an attractive strategy for treating this disease.

Pollution and respiratory disease: can diet or supplements help? A review

Abstract: Pollution is known to cause and exacerbate a number of chronic respiratory diseases. The World Health Organisation has placed air pollution as the world’s largest environmental health risk factor. There has been recent publicity about the role for diet and anti-oxidants in mitigating the effects of pollution, and this review assesses the evidence for alterations in diet, including vitamin supplementation in abrogating the effects of pollution on asthma and other chronic respiratory diseases. We found evidence to suggest that carotenoids, vitamin D and vitamin E help protect against pollution damage which can trigger asthma, COPD and lung cancer initiation. Vitamin C, curcumin, choline and omega-3 fatty acids may also play a role. The Mediterranean diet appears to be of benefit in patients with airways disease and there appears to be a beneficial effect in smokers however there is no direct evidence regarding protecting against air pollution. More studies investigating the effects of nutrition on rapidly rising air pollution are urgently required. However it is very difficult to design such studies due to the confounding factors of diet, obesity, co-morbid illness, medication and environmental exposure.

Altered lung biology of healthy never smokers following acute inhalation of E-cigarettes.

Abstract: Little is known about health risks associated with electronic cigarette (EC) use although EC are rising in popularity and have been advocated as a means to quit smoking cigarettes. Ten never-smokers, without exposure history to tobacco products or EC, were assessed at baseline with questionnaire, chest X-ray, lung function, plasma levels of endothelial microparticles (EMP), and bronchoscopy to obtain small airway epithelium (SAE) and alveolar macrophages (AM). One week later, subjects inhaled 10 puffs of “Blu” brand EC, waited 30 min, then another 10 puff; n = 7 were randomized to EC with nicotine and n = 3 to EC without nicotine to assess biological responses in healthy, naive individuals. Two hr. post-EC exposure, subjects were again assessed as at baseline. No significant changes in clinical parameters were observed. Biological changes were observed compared to baseline, including altered transcriptomes of SAE and AM for all subjects and elevated plasma EMP levels following inhalation of EC with nicotine. This study provides in vivo human data demonstrating that acute inhalation of EC aerosols dysregulates normal human lung homeostasis in a limited cohort of healthy naive individuals. These observations have implications to new EC users, nonsmokers exposed to secondhand EC aerosols and cigarette smokers using EC to quit smoking. ClinicalTrials.gov NCT01776398 (registered 10/12/12), NCT02188511 (registered 7/2/14).

Upregulation of Mas-related G Protein coupled receptor X2 in asthmatic lung mast cells and its activation by the novel neuropeptide hemokinin-1.

Abstract: Hemokinin-1 (HK-1) is a novel neuropeptide produced by human bronchial cells and macrophages and causes contraction of human bronchi ex vivo. It is also generated by antigen/IgE-activated murine mast cells (MCs) and contributes to experimental chronic allergic airway inflammation via the activation of the neurokinin receptor-1 (NK-1R) expressed on murine MCs. We found elevated MC numbers in the lungs of individuals who died from asthma (asthma) when compared to lungs of individuals who died from other causes (non-asthma). Mas-related G Protein coupled receptor X2 (MRGPRX2) is a novel G-protein coupled receptor (GPCR) that is expressed predominantly on human MCs. We detected low level of MRGPRX2 in non-asthma lung MCs but its expression was significantly upregulated in asthma lung MCs. HK-1 caused degranulation in a human MC line (LAD2) and RBL-2H3 cells stably expressing MRGPRX2 and this response was resistant to inhibition by an NK-1R antagonist. However, knockdown of MRGPRX2 in LAD2 cells resulted in substantial inhibition of HK-1-induced degranulation. These findings suggest that while HK-1 contributes to the development of experimental asthma in mice via NK-1R on murine MCs the effect of this neuropeptide on human bronchoconstriction likely reflects the activation of MRGPRX2 on lung MCs. Thus, development of selective MRGPRX2 antagonists could serve as novel target for the modulation of asthma.

Short and long-term effects of pulmonary rehabilitation in interstitial lung diseases: a randomised controlled trial

Abstract: Few data are available on the long-term effect of pulmonary rehabilitation (PR) and on long PR programs in interstitial lung diseases (ILD). We aimed to evaluate the effects of PR on exercise capacity (6-Minute Walking Distance, 6MWD; Peak Work Rate, Wmax), quality of life (St George’s Respiratory Questionnaire, SGRQ), quadriceps force (QF) and objectively measured physical activity in ILD after the 6-month PR-program and after 1 year. 60 patients (64 ± 11 years; 62% males; 23% with IPF) were randomly assigned to receive a 6 month-PR program or usual medical care. Exercise capacity, quality of life and muscle force increased significantly after the program as compared to control (mean,95%CI[ll to ul]; 6MWD + 72,[36 to 108] m; Wmax 19, [8 to 29]%pred; SGRQ − 12,[− 19 to − 6] points; QF 10, [1 to 18] %pred). The gain was sustained after 1 year (6MWD 73,[28 to 118] m; Wmax 23, [10 to 35]%pred; SGRQ − 11,[− 18 to − 4] points; QF 9.5, [1 to 18] %pred). Physical activity did not change. PR improves exercise tolerance, health status and muscle force in ILD. The benefits are maintained at 1-year follow-up. The intervention did not change physical activity. Clinicaltrials.gov NCT00882817 .

Human alveolar macrophages predominately express combined classical M1 and M2 surface markers in steady state.

Abstract: Alveolar macrophages (AM) are critical to the homeostasis of the inflammatory environment in the lung. Differential expression of surface markers classifies macrophages to either classically (M1) or alternatively activated (M2). We investigated the phenotype of human alveolar macrophages (AM) in adults living in two different geographical locations: UK and Malawi. We show that the majority of AM express high levels of M1 and M2 markers simultaneously, with the M1/M2 phenotype being stable in individuals from different geographical locations. The combined M1/M2 features confer to AM a hybrid phenotype, which does not fit the classic macrophage classification. This hybrid phenotype may confer to alveolar macrophages an ability to quickly switch between M1 or M2 associated functions allowing for appropriate responses to stimuli and tissue environment.

Differential effects of Nintedanib and Pirfenidone on lung alveolar epithelial cell function in ex vivo murine and human lung tissue cultures of pulmonary fibrosis

Abstract: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease. Repetitive injury and reprogramming of the lung epithelium are thought to be critical drivers of disease progression, contributing to fibroblast activation, extracellular matrix remodeling, and subsequently loss of lung architecture and function. To date, Pirfenidone and Nintedanib are the only approved drugs known to decelerate disease progression, however, if and how these drugs affect lung epithelial cell function, remains largely unexplored. We treated murine and human 3D ex vivo lung tissue cultures (3D-LTCs; generated from precision cut lung slices (PCLS)) as well as primary murine alveolar epithelial type II (pmATII) cells with Pirfenidone or Nintedanib. Murine 3D-LTCs or pmATII cells were derived from the bleomycin model of fibrosis. Early fibrotic changes were induced in human 3D-LTCs by a mixture of profibrotic factors. Epithelial and mesenchymal cell function was determined by qPCR, Western blotting, Immunofluorescent staining, and ELISA. Low μM concentrations of Nintedanib (1 μM) and mM concentrations of Pirfenidone (2.5 mM) reduced fibrotic gene expression including Collagen 1a1 and Fibronectin in murine and human 3D-LTCs as well as pmATII cells. Notably, Nintedanib stabilized expression of distal lung epithelial cell markers, especially Surfactant Protein C in pmATII cells as well as in murine and human 3D-LTCs. Pirfenidone and Nintedanib exhibit distinct effects on murine and human epithelial cells, which might contribute to their anti-fibrotic action. Human 3D-LTCs represent a valuable tool to assess anti-fibrotic mechanisms of potential drugs for the treatment of IPF patients.

Prevalence of asthma, aspirin sensitivity and allergy in chronic rhinosinusitis: data from the UK National Chronic Rhinosinusitis Epidemiology Study

Abstract: Chronic rhinosinusitis (CRS) is a common disorder associated with other respiratory tract diseases such as asthma and inhalant allergy. However, the prevalence of these co-morbidities varies considerably in the existing medical literature and by phenotype of CRS studied. The study objective was to identify the prevalence of asthma, inhalant allergy and aspirin sensitivity in CRS patients referred to secondary care and establish any differences between CRS phenotypes. All participants were diagnosed in secondary care according to international guidelines and invited to complete a questionnaire including details of co-morbidities and allergies. Data were analysed for differences between controls and CRS participants and between phenotypes using chi-squared tests. The final analysis included 1470 study participants: 221 controls, 553 CRS without nasal polyps (CRSsNPs), 651 CRS with nasal polyps (CRSwNPs) and 45 allergic fungal rhinosinusitis (AFRS). The prevalence of asthma was 9.95, 21.16, 46.9 and 73.3% respectively. The prevalence of self-reported confirmed inhalant allergy was 13.1, 20.3, 31.0 and 33.3% respectively; house dust mite allergy was significantly higher in CRSwNPs (16%) compared to CRSsNPs (9%, p < 0.001). The prevalence of self- reported aspirin sensitivity was 2.26, 3.25, 9.61 and 40% respectively. The odds ratio for aspirin sensitivity amongst those with AFRS was 28.8 (CIs 9.9, 83.8) p < 0.001. The prevalence of asthma and allergy in CRS varies by phenoytype, with CRSwNPs and AFRS having a stronger association with both. Aspirin sensitivity has a highly significant association with AFRS. All of these comorbidities are significantly more prevalent than in non-CRS controls and strengthen the need for a more individualised approach to the combined airway.

Therapeutic potential of products derived from mesenchymal stem/stromal cells in pulmonary disease

Abstract: Multipotent mesenchymal stem/stromal cells (MSCs) possess robust self-renewal characteristics and the ability to differentiate into tissue-specific cells. Their therapeutic potential appears promising as evident from their efficacy in several animal models of pulmonary disorders as well as early-phase clinical trials of acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD). Such therapeutic efficacy might be attributed to MSC-derived products (the “secretome”), namely conditioned media (CM) and extracellular vesicles (EVs), which have been shown to play pivotal roles in the regenerative function of MSCs. Importantly, the EVs secreted by MSCs can transfer a variety of bioactive factors to modulate the function of recipient cells via various mechanisms, including ligand-receptor interactions, direct membrane fusion, endocytosis, or phagocytosis. Herein, we review the current state-of-the-science of MSC-derived CM and EVs as potential therapeutic agents in lung diseases. We suggest that the MSC-derived secretome might be an appropriate therapeutic agent for treating aggressive pulmonary disorders because of biological and logistical advantages over live cell therapy. Nonetheless, further studies are warranted to elucidate the safety and efficacy of these components in combating pulmonary diseases.

Adverse events profile of oral corticosteroids among asthma patients in the UK: cohort study with a nested case-control analysis

Abstract: To evaluate the adverse events profile of oral prednisolone among adult asthma patients in the UK. Using data from the UK-based Clinical Practice Research Datalink, we conducted a series of cohort studies to quantify incidence rates and incidence rate ratios, and a series of nested case-control analyses to estimate crude and adjusted odds ratios, of 11 different potential corticosteroid-related adverse events (bone-related conditions, hypertension, peptic ulcer, severe infections, herpes zoster, diabetes mellitus type 2, cataract, glaucoma, chronic kidney disease, affective disorders, and cardiovascular events). Between 165,900 and 269,368 asthma patients were included in each of the 11 cohorts, of whom between 836 and 16,192 developed an outcome of interest. Incidence rates per 1000 person-years of potential corticosteroid-related adverse events in patients with new current use of oral prednisolone ranged from 1.4 (95% confidence interval [CI], 1.0–1.8) for peptic ulcer to 78.0 (95% CI, 74.8–81.2) for severe infections. After adjusting for confounding, current oral prednisolone use was most strongly associated with an increased risk of severe infection, compared with non-use of prednisolone; OR 2.16 (95% CI, 2.05–2.27). There were smaller elevated risks of peptic ulcer, affective disorders, and cataract at higher doses, and marginally increased risks of herpes zoster, cardiovascular events, diabetes mellitus type 2, and bone related conditions, compared with non-use of prednisolone. We did not observe an association between oral prednisolone use and glaucoma, chronic kidney disease, or hypertension. Oral prednisolone use is associated with infections, gastrointestinal, neuropsychiatric, ocular, cardiovascular, metabolic, and bone-related complications among adult asthma patients.

LncRNA H19 promotes the proliferation of pulmonary artery smooth muscle cells through AT 1 R via sponging let-7b in monocrotaline-induced pulmonary arterial hypertension

Abstract: Pulmonary arterial hypertension (PAH) is related to inflammation, and the lncRNA H19 is associated with inflammation. However, whether PDGF-BB-H19-let-7b-AT1R axis contributes to the pathogenesis of PAH has not been thoroughly elucidated to date. This study investigated the role of H19 in PAH and its related mechanism. In the present study, SD rats, C57/BL6 mice and H19−/− mice were injected with monocrotaline (MCT) to establish a PAH model. H19 was detected in the cytokine-stimulated pulmonary arterial smooth muscle cells (PASMCs), serum and lungs of rats/mice. H19 overexpression and knockdown experiments were also conducted. A dual luciferase reporter assay was used to explore whether let-7b is a sponge miRNA of H19, and AT1R is a novel target of let-7b. A CCK-8 assay and flow cytometry were used to analyse cell proliferation. The results showed that H19 was highly expressed in the serum and lungs of MCT-induced rats/mice, and H19 was upregulated by PDGF-BB in vitro. H19 upregulated AT1R expression via sponging miRNA let-7b following PDGF-BB stimulation. AT1R is a novel target of let-7b. Moreover, the overexpression of H19 and AT1R could facilitate PASMCs proliferation in vitro. H19 knockout protected mice from pulmonary artery remodeling and PAH following MCT treatment. Our study showed that H19 is highly expressed in MCT-induced rodent lungs and upregulated by PDGF-BB. The H19-let-7b-AT1R axis contributed to the pathogenesis of PAH by stimulating PASMCs proliferation. The H19 knockout had a protective role in the development of PAH. H19 may be a potential tar-get for the treatment of PAH.

Roles of mitochondrial ROS and NLRP3 inflammasome in multiple ozone-induced lung inflammation and emphysema

Abstract: Mitochondrial damage leading to oxidant stress may play an important role in the pathogenesis of airflow obstruction and emphysema. NLPR3 inflammasome can be activated by mitochondrial ROS (mtROS) and other stimuli. We examined the importance of mtROS and NLRP3 inflammasome and their interactions in multiple ozone-induced lung inflammation and emphysema. C57/BL6 mice were exposed to ozone (2.5 ppm, 3 h) or filtered air twice a week over 6 weeks. MitoTEMPO (20 mg/kg), an inhibitor of mtROS, and VX765 (100 mg/kg), an inhibitor of caspase-1 activity, were administered by intraperitoneal or intragastric injection respectively 1 h prior to each ozone exposure for 6 weeks. Ozone-exposed mice had increased bronchoalveolar lavage (BAL) total cells and levels of IL-1β, KC and IL-6, augmented lung tissue inflammation scores, enhanced oxidative stress with higher serum 8-OHdG concentrations, emphysema with greater mean linear intercept (Lm), airway remodeling with increased airway smooth muscle mass and airflow limitation as indicated by a reduction in the ratio of forced expiratory volume at 25 and 50 milliseconds to forced vital capacity (FEV25/FVC, FEV50/FVC). Both MitoTEMPO and VX765 reduced lung inflammation scores, cytokine levels, oxidative stress and increased mitochondrial fission proteins. VX765 also attenuated emphysema, airway remodeling and airflow limitation. MitoTEMPO inhibited the increased expression of mitochondrial complex II and IV and of NLPR3 while VX765 inhibited the expression and activity of NLRP3 and caspase-1 pathway in the lung. Both mtROS and NLRP3 inflammasome play a role in ozone-induced lung inflammation while only NLRP3 is involved in ozone-induced emphysema.

IL-1β mediates lung neutrophilia and IL-33 expression in a mouse model of viral-induced asthma exacerbation

Abstract: Viral-induced asthma exacerbations, which exhibit both Th1-type neutrophilia and Th2-type inflammation, associate with secretion of Interleukin (IL)-1β. IL-1β induces neutrophilic inflammation. It may also increase Th2-type cytokine expression. We hypothesised that IL-1β is causally involved in both Th1 and Th2 features of asthma exacerbations. This hypothesis is tested in our mouse model of viral stimulus-induced asthma exacerbation. Wild-type (WT) and IL-1β deficient (IL-1β−/−) mice received house dust mite (HDM) or saline intranasally during three weeks followed by intranasal dsRNA (PolyI:C molecule known for its rhinovirus infection mimic) for three consecutive days to provoke exacerbation. Bronchoalveolar lavage fluid was analysed for inflammatory cells and total protein. Lung tissues were stained for neutrophilic inflammation and IL-33. Tissue homogenates were analysed for mRNA expression of Muc5ac, CXCL1/KC, TNF-α, CCL5, IL-25, TSLP, IL-33, IL-1β, CCL11 and CCL2 using RT-qPCR. Expression of IL-1β, neutrophil chemoattractants, CXCL1 and CCL5, the Th2-upstream cytokine IL-33, and Muc5ac were induced at exacerbation in WT mice and were significantly inhibited in IL-1β−/− mice at exacerbation. Effects of HDM alone were not reduced in IL-1β-deficient mice. Without being involved in the baseline HDM-induced allergic asthma, IL-1β signalling was required to induce neutrophil chemotactic factors, IL-33, and Muc5ac expression at viral stimulus-induced exacerbation. We suggest that IL-1β has a role both in neutrophilic and Th2 inflammation at viral-induced asthma exacerbations.

Prevalence and management of severe asthma in primary care: an observational cohort study in Sweden (PACEHR).

Abstract: Severe and uncontrolled asthma is associated with increased risk of exacerbations and death. A substantial proportion of asthma patients have poor asthma control, and a concurrent COPD diagnosis often increases disease burden. The objective of the study was to describe the prevalence and managemant of severe asthma in a Swedish asthma popuoation. In this observational cohort study, primary care medical records data (2006–2013) from 36 primary health care centers were linked to data from national mandatory Swedish health registries. The studied population (>18 years) had a record of drug collection for obstructive pulmonary disease (ATC code R03) during 2011–2012, and a physician diagnosed asthma (ICD-10 code J45-J46) prior to drug collection. Severe asthma was classified as collection of high dose inhaled steroid (> 800 budesonide or equivalent per day) and leukotriene receptor antagonist and/or long-acting beta-agonist. Poor asthma control was defined as either collection of ≥600 doses of short-acting beta-agonists, and/or ≥1 exacerbation(s) during the year post index date. A total of 18,724 asthma patients (mean 49 years, 62.8% women) were included, of whom 17,934 (95.8%) had mild to moderate and 790 (4.2%) had severe asthma. Exacerbations were more prevalent in severe asthma (2.59 [2.41–2.79], Relative Risk [95% confidence interval]; p < 0.001). Poor asthma control was observed for 28.2% of the patients with mild to moderate asthma and for more than half (53.6%) of the patients with severe asthma (<0.001). Prior to index, one in five severe asthma patients had had a contact with secondary care and one third with primary care. A concurrent COPD diagnosis increased disease burden. Severe asthma was found in 4.2% of asthma patients in Sweden, more than half of them had poor asthma control, and most patients had no regular health care contacts.

Factors associated with bronchiectasis in patients with uncontrolled asthma; the NOPES score: a study in 398 patients.

Abstract: Some studies have reported a high prevalence of bronchiectasis in patients with uncontrolled asthma, but the factors associated with this condition are unknown. The objective of this study was to determine the prevalence of bronchiectasis in uncontrolled moderate-to-severe asthma and to identify risk factors and their correlation with bronchiectasis in these patients. This is a prospective study of data from consecutive patients with uncontrolled moderate-to-severe asthma. Diagnosis of bronchiectasis was based on high-resolution computed tomography. A prognostic score was developed using a logistic regression model, which was used to determine the factors associated with bronchiectasis. A total of 398 patients (60% with severe asthma) were included. The prevalence of bronchiectasis was 28.4%. The presence of bronchiectasis was associated with a higher frequency of chronic expectoration (OR, 2.95; 95% CI, 1.49–5.84; p = 0.002), greater severity of asthma (OR, 2.43; 95% CI, 1.29–4.57; p = 0.006), at least one previous episode of pneumonia (OR, 2.42; 95% CI, 1.03–5.69; p = 0.044), and lower levels of FeNO (OR, 0.98; 95% CI, 0.97–0.99; p = 0.016). The NOPES score was developed on the basis of these variables (FeNO[cut off point 20.5 ppb], Pneumonia, Expectoration and asthma Severity), and it ranges from 0 to 4 points, where 0 means “no risk” and 4 corresponds to “high risk”. The NOPES score yielded an AUC-ROC of 70% for the diagnosis of bronchiectasis, with a specificity of 95%. Almost a third of the patients with uncontrolled moderate-to-severe asthma had bronchiectasis. Bronchiectasis was related to the severity of asthma, the presence of chronic expectoration, a previous history of pneumonia, and lower levels of FeNO. The NOPES score is an easy-to-use scoring system with a high prognostic value for bronchiectasis in patients with uncontrolled moderate-to-severe asthma.

Use and inhalation technique of inhaled medication in patients with asthma and COPD: data from a randomized controlled trial

Abstract: The burden of asthma and COPD among patients is high and people affected are frequently hospitalized due to exacerbations. There are numerous reasons for the lack of disease control in asthma and COPD patients. It is associated with non-adherence to guidelines on the part of the health care provider and with poor inhalation technique and/or non-adherence to the prescribed treatment plan by the patient. This study aims to present data on inhaler technique and its impact on quality of life (QoL) and symptom control in a typical population of patients with chronic lung disease from a randomized controlled trial on medication adherence. For this cross-sectional analysis, 165 asthma and COPD patients were analyzed. Correct application of inhaler devices was tested using pre-defined checklists for each inhaler type. QoL and symptom control were investigated using COPD Assessment Test (CAT) and Asthma Control Test (ACT). Spirometry was used to measure forced vital capacity (FVC) and forced expiratory volume in one second (FEV1). Overall, incorrect inhalation technique ranged from 0 to 53% depending on the type of inhaler. COPD patients with incorrect device application had a higher CAT sum score compared to those with a correct device application (P = .02). Moreover, COPD patients with incorrect device application were more likely to suffer from cough (P = .03) and were more breathless while walking uphill or a flight of stairs (P = .02). While there was no significance found in asthma patients, COPD patients who used their devices correctly had a significantly better mean FEV1% predicted at baseline compared to those who applied their devices incorrectly (P = .04). Correct inhalation of prescribed medication is associated with improved health status and lung function. These findings should encourage health professionals to provide instructions on correct inhalation technique and to regularly re-evaluate the patients’ inhalation technique. ClinicalTrials.gov: NCT0238672 , Registered 14 February 2014.

Intermittent hypoxia promotes melanoma lung metastasis via oxidative stress and inflammation responses in a mouse model of obstructive sleep apnea

Abstract: Recently, increased tumor incidence and cancer-related mortality have been reported among patients with obstructive sleep apnea (OSA). Intermittent hypoxia (IH), the hallmark feature of OSA, contributes to the metastasis of tumors. However, the molecular mechanisms by which tumor metastasis is accelerated by OSA-like IH remain to be elucidated. C57BL/6 J male mice were subjected to intravenous injection of B16F10 melanoma cells before receiving IH treatment. Then, the animals were randomly distributed into three groups (n = 8 each): normoxia (N) group, IH group, and antioxidant tempol group (IHT, exposed to IH after treatment with tempol). After the mice were sacrificed, the number and weight of lung metastatic colonies were assessed. The lung tissues with tumor metastasis were analyzed for markers of oxidative stress and inflammation and for HIF-1α using western blotting and real-time PCR (qRT-PCR). The level of reactive oxygen species (ROS) in B16F10 cell was also assessed after N, IH and IH with tempol treatments. Compared with normoxia, IH significantly increased the number and weight of mouse lung metastatic colonies. Treatment of B16F10 cells with IH significantly enhanced ROS generation. Lung tissues with tumor metastasis provided evidence of increased oxidative stress, as assessed by p22phox and SOD mRNA levels and the NRF2 protein level, as well as increased inflammation, as assessed by TNF-α and IL-6 mRNA levels and the NF-κB P65 protein level. HIF-1α protein levels were increased in response to IH treatment. Tempol, an important antioxidant, ameliorated IH-induced melanoma lung metastasis in mice and reduced oxidative stress and inflammation responses. These results support the hypothesis that oxidative stress and inflammation responses play an important role in the pathogenesis of OSA-like IH-induced melanoma lung metastasis in mice. Antioxidant intervention provides a novel strategy for the prevention and treatment of cancer in OSA populations.

Circulating microRNAs and prediction of asthma exacerbation in childhood asthma

Abstract: Circulating microRNAs have shown promise as non-invasive biomarkers and predictors of disease activity. Prior asthma studies using clinical, biochemical and genomic data have not shown excellent prediction of exacerbation. We hypothesized that a panel of circulating microRNAs in a pediatric asthma cohort combined with an exacerbation clinical score might predict exacerbation better than the latter alone. Serum samples from 153 children at randomization in the Childhood Asthma Management Program were profiled for 754 microRNAs. Data dichotomized for asthma exacerbation one year after randomization to inhaled corticosteroid treatment were used for binary logistic regression with miRNA expressions and exacerbation clinical score. 12 of 125 well-detected circulating microRNAs had significant odd ratios for exacerbation with miR-206 being most significant. Each doubling of expression of the 12 microRNA corresponded to a 25–67% increase in exacerbation risk. Stepwise logistic regression yielded a 3-microRNA model (miR-146b, miR-206 and miR-720) that, combined with the exacerbation clinical score, had excellent predictive power with a 0.81 AUROC. These 3 microRNAs were involved in NF-kβ and GSK3/AKT pathways. This combined circulating microRNA-clinical score model predicted exacerbation in asthmatic subjects on inhaled corticosteroids better than each constituent feature alone. ClinicalTrials.gov Identifier: NCT00000575 .

Evaluation of oxidative stress biomarkers in idiopathic pulmonary fibrosis and therapeutic applications: a systematic review

Abstract: Idiopathic pulmonary fibrosis (IPF), a fatal lung disease of unknown origin, is characterized by chronic and progressive fibrosing interstitial pneumonia which progressively impairs lung function. Oxidative stress is one of the main pathogenic pathways in IPF. The aim of this systematic review was to describe the type of markers of oxidative stress identified in different biological specimens and the effects of antioxidant therapies in patients with IPF. We conducted a systematic search of publications listed in electronic databases (Pubmed, Web of Science, Scopus and Google Scholar) from inception to October 2017. Two investigators independently reviewed all identified articles to determine eligibility. After a substantial proportion of the initially identified articles (n = 554) was excluded because they were duplicates, abstracts, irrelevant, or did not meet the selection criteria, we identified 30 studies. In each study, we critically appraised the type, site (systemic vs. local, e.g. breath, sputum, expired breath condensate, epithelial lining fluid, bronchoalveolar lavage, and lung tissue specimens), and method used for measuring the identified oxidative stress biomarkers. Furthermore, the current knowledge on antioxidant therapies in IPF was summarized. A number of markers of oxidative stress, with individual advantages and limitations, have been described in patients with IPF. Nevertheless, trials of antioxidant treatments have been unable to demonstrate consistent benefits, barring recent pharmacogenomics data suggesting different results in specific genotype subgroups of patients with IPF.

The prostaglandin D 2 receptor 2 pathway in asthma: a key player in airway inflammation

Abstract: Asthma is characterised by chronic airway inflammation, airway obstruction and hyper-responsiveness. The inflammatory cascade in asthma comprises a complex interplay of genetic factors, the airway epithelium, and dysregulation of the immune response. Prostaglandin D2 (PGD2) is a lipid mediator, predominantly released from mast cells, but also by other immune cells such as TH2 cells and dendritic cells, which plays a significant role in the pathophysiology of asthma. PGD2 mainly exerts its biological functions via two G-protein-coupled receptors, the PGD2 receptor 1 (DP1) and 2 (DP2). The DP2 receptor is mainly expressed by the key cells involved in type 2 immune responses, including TH2 cells, type 2 innate lymphoid cells and eosinophils. The DP2 receptor pathway is a novel and important therapeutic target for asthma, because increased PGD2 production induces significant inflammatory cell chemotaxis and degranulation via its interaction with the DP2 receptor. This interaction has serious consequences in the pulmonary milieu, including the release of pro-inflammatory cytokines and harmful cationic proteases, leading to tissue remodelling, mucus production, structural damage, and compromised lung function. This review will discuss the importance of the DP2 receptor pathway and the current understanding of its role in asthma.

Efficacy and safety of nintedanib in advanced idiopathic pulmonary fibrosis.

Abstract: Phase 3 trials have shown that nintedanib reduces the decline in forced vital capacity (FVC) in patients with mild-to-moderate idiopathic pulmonary fibrosis (IPF) with acceptable safety profiles; however, its effects on advanced IPF are unclear. We investigated the efficacy and safety of nintedanib in patients with advanced IPF. Prospective data were obtained from 108 IPF patients administered at least one dose of nintedanib. Of these patients, 47.2% had advanced IPF (FVC < 50% predicted, or diffusing capacity < 30% predicted). The median treatment duration was 42.2 weeks. Nintedanib significantly reduced the decline rate in both FVC (− 0.55% [before] vs. -0.32% [after] predicted/month, p = 0.020) and total lung capacity (TLC) (− 0.35% vs. -0.06% predicted/month, p < 0.001) in all patients. A significant improvement in FVC decline rate after treatment was also observed in the advanced group (− 0.77% vs. -0.22% predicted/month, p = 0.003), but not in the non-advanced group (− 0.41% vs. -0.33% predicted/month, p = 0.564). Adverse events occurred in 97.2% of the cohort, including diarrhoea (50.0%) and anorexia (45.4%). Following adjustment for treatment duration, no inter-group difference in odds ratio was observed for the occurrence of adverse events. However, the advanced group showed a higher frequency of treatment interruption (68.0% vs. 40.0%), mainly as a result of disease progression (47.1% vs. 36.4%). The efficacy and safety profiles of nintedanib in the advanced group were comparable to those in the non-advanced group except for a higher frequency of discontinuation, which may be due to the advanced status itself.

Airway disease phenotypes in animal models of cystic fibrosis

Abstract: In humans, cystic fibrosis (CF) lung disease is characterised by chronic infection, inflammation, airway remodelling, and mucus obstruction. A lack of pulmonary manifestations in CF mouse models has hindered investigations of airway disease pathogenesis, as well as the development and testing of potential therapeutics. However, recently generated CF animal models including rat, ferret and pig models demonstrate a range of well characterised lung disease phenotypes with varying degrees of severity. This review discusses the airway phenotypes of currently available CF animal models and presents potential applications of each model in airway-related CF research.