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

Dietary ω-6 polyunsaturated fatty acid arachidonic acid increases inflammation, but inhibits ECM protein expression in COPD

© 2018 The Author(s). Background: The obesity paradox in COPD describes protective effects of obesity on lung pathology and inflammation. However, the underlying relationships between obesity, diet and disease outcomes in COPD are not fully understood. In this study we measured the response to dietary fatty acids upon markers of inflammation and remodelling in human lung cells from people with and without COPD. Methods: Pulmonary fibroblasts were challenged with ω-3 polyunsaturated fatty acids (PUFAs), ω-6 PUFAs, saturated fatty acids (SFAs) or the obesity-associated cytokine TNFα. After 48-72 h release of the pro-inflammatory cytokines interleukin (IL)-6 and CXCL8 was measured using ELISA and mRNA expression and deposition of the extracellular matrix (ECM) proteins fibronectin, type I collagen, tenascin and perlecan were measured using qPCR or ECM ELISA, respectively. Results: Challenge with the ω-6 PUFA arachidonic acid (AA), but not ω-3 PUFAs or SFAs, resulted in increased IL-6 and CXCL8 release from fibroblasts, however IL-6 and CXCL8 release was reduced in COPD (n = 19) compared to non-COPD (n = 36). AA-induced cytokine release was partially mediated by downstream mediators of cyclooxygenase (COX)-2 in both COPD and non-COPD. In comparison, TNFα-induced IL-6 and CXCL8 release was similar in COPD and non-COPD, indicating a specific interaction of AA in COPD. In patients with or without COPD, regression analysis revealed no relationship between BMI and cytokine release. In addition, AA, but not SFAs or ω-3 PUFAs reduced the basal deposition of fibronectin, type I collagen, tenascin and perlecan into the ECM in COPD fibroblasts. In non-COPD fibroblasts, AA-challenge decreased basal deposition of type I collagen and perlecan, but not fibronectin and tenascin. Conclusions: This study shows that AA has disease-specific effects on inflammation and ECM protein deposition. The impaired response to AA in COPD might in part explain why obesity appears to have less detrimental effects in COPD, compared to other lung diseases

Airway smooth muscle cells from severe asthma patients with fixed airflow obstruction are responsive to steroid and bronchodilator treatment in vitro

Asthma is characterised by recurrent symptoms associated with variable airflow obstruction and airway hyperresponsiveness, all of which are improved with combination inhaled corticosteroid (ICS)/long-acting β-agonist (LABA) treatment in mild-to-moderate asthma [1]. A proportion of patients however develop fixed airflow obstruction (FAO), despite optimised treatment. FAO is prevalent in up to 60% of patients with severe asthma and is associated with a more rapid decline in lung function and increased symptoms [2]. The underlying mechanisms of FAO in asthma are poorly understood; therefore, development of novel treatment strategies remains a challenge. Airway smooth muscle cells (ASMCs) are the major effector cells of bronchoconstriction in asthma and also contribute to the inflammatory process by secreting pro-inflammatory cytokines and chemokines. Therefore, ASMCs are a major target of both β2-agonist and ICS treatment [3]. Although several studies have suggested that steroid signalling [4] or β2-adrenoceptor (β2AR) signalling may be abnormally regulated in severe asthma [5], it remains unknown whether impaired airway smooth muscle corticosteroid and/or β2-agonist response may contribute to the development of FAO. The aim of this study was to investigate whether primary human ASMCs obtained from severe asthma patients with FAO differ in their response to β2-agonists and corticosteroids compared with asthma patients without FAO and healthy controls. We hypothesised that ASMCs from asthma patients with FAO are less responsive to corticosteroid and β2-agonist treatment than those from patients without FA

Controlled versus free breathing for multiple-breath nitrogen washout in asthma.

The lack of comparability in indices of ventilation heterogeneity between free- and controlled-breathing MBNW protocols is confirmed in asthma https://bit.ly/3lmri4A

Dietary fatty acids amplify inflammatory responses to infection through p38 MAPK signaling

Copyright © 2019 by the American Thoracic Society. Obesity is an important risk factor for severe asthma exacerbations, which are mainly caused by respiratory infections. Dietary fatty acids, which are increased systemically in obese patients and are further increased after high-fat meals, affect the innate immune system and may contribute to dysfunctional immune responses to respiratory infection. In this study we investigated the effects of dietary fatty acids on immune responses to respiratory infection in pulmonary fibroblasts and a bronchial epithelial cell line (BEAS-2B). Cells were challenged with BSA-conjugated fatty acids (v-6 polyunsaturated fatty acids [PUFAs], v-3 PUFAs, or saturated fatty acids [SFAs]) 1/2 the viral mimic polyinosinic:polycytidylic acid (poly[I:C]) or bacterial compound lipoteichoic acid (LTA), and release of proinflammatory cytokines was measured. In both cell types, challenge with arachidonic acid (AA) (v-6 PUFA) and poly(I:C) or LTA led to substantially greater IL-6 and CXCL8 release than either challenge alone, demonstrating synergy. In epithelial cells, palmitic acid (SFA) combined with poly(I:C) also led to greater IL-6 release. The underlying signaling pathways of AA and poly(I:C)- or LTA-induced cytokine release were examined using specific signaling inhibitors and IB. Cytokine production in pulmonary fibroblasts was prostaglandin dependent, and synergistic upregulation occurred via p38 mitogen-activated protein kinase signaling, whereas cytokine production in bronchial epithelial cell lines was mainly mediated through JNK and p38 mitogen-activated protein kinase signaling. We confirmed these findings using rhinovirus infection, demonstrating that AA enhances rhinovirus-induced cytokine release. This study suggests that during respiratory infection, increased levels of dietary v-6 PUFAs and SFAs may lead to more severe airway inflammation and may contribute to and/or increase the severity of asthma exacerbations

Tropomyosin 2.1 collaborates with fibronectin to promote TGF-β1-induced contraction of human lung fibroblasts

Many lung diseases are characterized by fibrosis, leading to impaired tissue patency and reduced lung function. Development of fibrotic tissue depends on two-way interaction between the cells and the extra-cellular matrix (ECM). Concentration-dependent increased stiffening of the ECM is sensed by the cells, which in turn increases intracellular contraction and pulling on the matrix causing matrix reorganization and further stiffening. It is generally accepted that the inflammatory cytokine growth factor β1 (TGF-β1) is a major driver of lung fibrosis through the stimulation of ECM production. However, TGF-β1 also regulates the expression of members of the tropomyosin (Tm) family of actin associating proteins that mediate ECM reorganization through intracellular-generated forces. Thus, TGF-β1 may mediate the bi-directional signaling between cells and the ECM that promotes tissue fibrosis. Using combinations of cytokine stimulation, mRNA, protein profiling and cellular contractility assays with human lung fibroblasts, we show that concomitant induction of key Tm isoforms and ECM by TGF-β1, significantly accelerates fibrotic phenotypes. Knocking down Tpm2.1 reduces fibroblast-mediated collagen gel contraction. Collectively, the data suggest combined ECM secretion and actin cytoskeleton contractility primes the tissue for enhanced fibrosis. Our study suggests that Tms are at the nexus of inflammation and tissue stiffening. Small molecules targeting specific Tm isoforms have recently been designed; thus targeting Tpm2.1 may represent a novel therapeutic target in lung fibrosis

Menunggu hala tuju baharu khazanah

E-cigarettes induce greater inflammatory mediators from COPD lung cells; therefore, the risks of e-cigarette use in COPD might be greater than in people without COPD http://ow.ly/xmnN30nzDhX

BET proteins are associated with the induction of small airway fibrosis in COPD.

RationaleIn COPD, small airway fibrosis occurs due to increased extracellular matrix (ECM) deposition in and around the airway smooth muscle (ASM) layer. Studies of immune cells and peripheral lung tissue have shown that epigenetic changes occur in COPD but it is unknown whether airway mesenchymal cells are reprogrammed.ObjectivesDetermine if COPD ASM cells have a unique epigenetic response to profibrotic cytokine transforming growth factor β1 (TGF-β1).MethodsPrimary human ASM cells from COPD and non-COPD smoking patients were stimulated with TGF-β1. Gene array analysis performed to identify differences in ECM expression. Airway accumulation of collagen 15α1 and tenascin-C proteins was assessed. Aforementioned ASM cells were stimulated with TGF-β1 ± epigenetic inhibitors with qPCR quantification of COL15A1 and TNC. Global histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity were assessed. chromatin immunoprecipitation (ChIP)-qPCR for histone H3 and H4 acetylation at COL15A1 and TNC promoters was carried out. Effects of bromoterminal and extraterminal domain (BET) inhibitor JQ1(+) on expression and acetylation of ECM target genes were assessed.Measurements and main resultsCOPD ASM show significantly higher COL15A1 and TNC expression in vitro and the same trend for higher levels of collagen 15α1 and tenascin-c deposited in COPD airways in vivo. Epigenetic screening indicated differential response to HDAC inhibition. ChIP-qPCR revealed histone H4 acetylation at COL15A1 and TNC promoters in COPD ASM only. ChIP-qPCR found JQ1(+) pretreatment significantly abrogated TGF-β1 induced histone H4 acetylation at COL15A1 and TNC.ConclusionsBET protein binding to acetylated histones is important in TGF-β1 induced expression of COL15A1 and TNC and maintenance of TGF-β1 induced histone H4 acetylation in cell progeny

The future of food security, environments and livelihoods in Western Africa: Four socio-economic scenarios

This working paper examines the development of regional socioeconomic scenarios for West Africa’s development, agriculture, food security and climate impacts. We present four globally consistent regional scenarios framed and outlined by regional experts who crafted narratives and determined key drivers of change. Stakeholders identified the type of actors driving change and the timeline of strategic planning as the most uncertain and most relevant factors of change affecting food security, livelihoods and environments in the region. The scenarios were linked to the IPCC community’s global Shared Socio-economic Pathways (SSPs) and quantified using two agricultural economic models, GLOBIOM and IMPACT, in interaction with drivers outlined by the SSPs and guided by semi-quantitative information from the stakeholders. The quantification of the scenarios has provided additional insights into the possible development of Western Africa in the context of a global economy as well as how the agricultural sector may be affected by climate change. The scenarios process highlights the need to combine socio-economic and climate scenarios, to base these scenarios in regional expertise, and ways to make scenarios useful for policy design. The objective of this working paper is to provide scenarios for future regional development for West Africa on the future of food security, environment, and rural livelihoods as well as offer details of the multi-stakeholder scenarios development process. Using both qualitative and quantitative scenarios we provide insights into the possible development of West Africa as well as a scalable framework for regional decision makers and the scientific community to use scenarios to build and test policies to make them more robust in the face of future uncertainty. In these scenarios, strong economic development increases food security and agricultural development. Increased crop and livestock productivity may lead to an expansion of agricultural areas within the region but productivity improvements may reduce the pressure on land elsewhere. In the context of a global economy, West Africa remains a large consumer and producer of a selection of commodities. However, the growth in population in combination with rising incomes may lead to increases in the region’s imports. For West Africa, climate change is likely to have negative effects on both crop yields and grassland productivity, and lack of investment in agriculture may exacerbate them. The aim of the regional scenarios is provide challenging contexts for policy makers to test and develop a range of national and regional policies. To date, the scenarios have been used in a number of policy design processes which include collaborations with ECOWAS priority setting, the National Plan for the Rural Sector for Burkina Faso (PNSR), and district and national level policy processes in Ghana