228 results found
Koss CK, Wohnhaas CT, Baker JR, et al., 2021, IL36 is a critical upstream amplifier of neutrophilic lung inflammation in mice, Communications Biology, Vol: 4, Pages: 1-15, ISSN: 2399-3642
IL-36, which belongs to the IL-1 superfamily, is increasingly linked to neutrophilic inflammation. Here, we combined in vivo and in vitro approaches using primary mouse and human cells, as well as, acute and chronic mouse models of lung inflammation to provide mechanistic insight into the intercellular signaling pathways and mechanisms through which IL-36 promotes lung inflammation. IL-36 receptor deficient mice exposed to cigarette smoke or cigarette smoke and H1N1 influenza virus had attenuated lung inflammation compared with wild-type controls. We identified neutrophils as a source of IL-36 and show that IL-36 is a key upstream amplifier of lung inflammation by promoting activation of neutrophils, macrophages and fibroblasts through cooperation with GM-CSF and the viral mimic poly(I:C). Our data implicate IL-36, independent of other IL-1 family members, as a key upstream amplifier of neutrophilic lung inflammation, providing a rationale for targeting IL-36 to improve treatment of a variety of neutrophilic lung diseases.
Berge MVD, Genton C, Heuvelin E, et al., 2021, Success and continuous growth of the ERS clinical research collaborations, EUROPEAN RESPIRATORY JOURNAL, Vol: 58, ISSN: 0903-1936
Lightley J, Gorlitz F, Kumar S, et al., 2021, Robust deep learning optical autofocus system applied to automated multiwell plate single molecule localization microscopy, JOURNAL OF MICROSCOPY, ISSN: 0022-2720
Baker JR, Donnelly LE, 2021, Leukocyte function in COPD: clinical relevance and potential for drug therapy., The International Journal of Chronic Obstructive Pulmonary Disease, Vol: 16, Pages: 2227-2242, ISSN: 1176-9106
Chronic obstructive pulmonary disease (COPD) is a progressive lung condition affecting 10% of the global population over 45 years. Currently, there are no disease-modifying treatments, with current therapies treating only the symptoms of the disease. COPD is an inflammatory disease, with a high infiltration of leukocytes being found within the lung of COPD patients. These leukocytes, if not kept in check, damage the lung, leading to the pathophysiology associated with the disease. In this review, we focus on the main leukocytes found within the COPD lung, describing how the release of chemokines from the damaged epithelial lining recruits these cells into the lung. Once present, these cells become active and may be driven towards a more pro-inflammatory phenotype. These cells release their own subtypes of inflammatory mediators, growth factors and proteases which can all lead to airway remodeling, mucus hypersecretion and emphysema. Finally, we describe some of the current therapies and potential new targets that could be utilized to target aberrant leukocyte function in the COPD lung. Here, we focus on old therapies such as statins and corticosteroids, but also look at the emerging field of biologics describing those which have been tested in COPD already and potential new monoclonal antibodies which are under review.
Ramakrishnan S, Nicolau D, Langford B, et al., 2021, Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial, LANCET RESPIRATORY MEDICINE, Vol: 9, Pages: 763-772, ISSN: 2213-2600
Ritchie AI, Baker JR, Parekh TM, et al., 2021, Update in Chronic Obstructive Pulmonary Disease 2020, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 204, Pages: 14-22, ISSN: 1073-449X
Singh R, Belchamber K, Fenwick P, et al., 2021, Defective monocyte-derived macrophage phagocytosis is associated with exacerbation frequency in COPD, Respiratory Research, Vol: 22, Pages: 1-11, ISSN: 1465-9921
BackgroundLower airway bacterial colonisation (LABC) in COPD patients is associated with increased exacerbation frequency and faster lung function decline. Defective macrophage phagocytosis in COPD drives inflammation, but how defective macrophage function contributes to exacerbations is not clear. This study investigated the association between macrophage phagocytosis and exacerbation frequency, LABC and clinical parameters.MethodsMonocyte-derived macrophages (MDM) were generated from 92 stable COPD patients, and at the onset of exacerbation in 39 patients. Macrophages were exposed to fluorescently labelled Haemophilus influenzae or Streptococcus pneumoniae for 4 h, then phagocytosis measured by fluorimetry and cytokine release by ELISA. Sputum bacterial colonisation was measured by PCR.ResultsPhagocytosis of H. influenzae was negatively correlated with exacerbation frequency (r = 0.440, p < 0.01), and was significantly reduced in frequent vs. infrequent exacerbators (1.9 × 103 RFU vs. 2.5 × 103 RFU, p < 0.01). There was no correlation for S. pneumoniae. There was no association between phagocytosis of either bacteria with age, lung function, smoking history or treatment with inhaled corticosteroids, or long-acting bronchodilators. Phagocytosis was not altered during an exacerbation, or in the 2 weeks post-exacerbation. In response to phagocytosis, MDM from exacerbating patients showed increased release of CXCL-8 (p < 0.001) and TNFα (p < 0.01) compared to stable state.ConclusionImpaired COPD macrophage phagocytosis of H. influenzae, but not S. pneumoniae is associated with exacerbation frequency, resulting in pro-inflammatory macrophages that may contribute to disease progression. Targeting these frequent exacerbators with drugs that improve macrophage phagocytosis may prove beneficial.
Perez E, Baker JR, Di Giandomenico S, et al., 2020, Hepcidin Is Essential for Alveolar Macrophage Function and Is Disrupted by Smoke in a Murine Chronic Obstructive Pulmonary Disease Model, JOURNAL OF IMMUNOLOGY, Vol: 205, Pages: 2489-+, ISSN: 0022-1767
Baker JR, Fenwick PS, Donnelly L, et al., 2020, Altered iron metabolism and elevated cellular senescence in COPD small airway epithelial cells, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Wysoczanski R, Baker JR, Fenwick P, et al., 2020, Analysis of defective phagocytosis in COPD using super-resolution microscopy and automated bacterial quantification, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Devulder J, Baker JR, Donnelly LE, et al., 2020, LSC-2020-Extracellular vesicles produced by bronchial epithelial cells in response to oxidative stress contain micro-RNAs associated with senescence, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Delbrel E, Wrench C, Fenwick P, et al., 2020, Endoplasmic reticulum stress implication in senescence of small airway fibroblasts from COPD patients, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Alter P, Baker JR, Dauletbaev N, et al., 2020, Update in Chronic Obstructive Pulmonary Disease 2019, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 202, Pages: 348-355, ISSN: 1073-449X
Baker JR, Donnelly LE, Barnes PJ, 2020, Senotherapy A New Horizon for COPD Therapy, CHEST, Vol: 158, Pages: 562-570, ISSN: 0012-3692
Haw T, Balachandran L, Fricker M, et al., 2020, METFORMIN REDUCED CIGARETTE SMOKE-INDUCED SENESCENCE-ASSOCIATED beta-GALACTOSIDASE IN EXPERIMENTAL COPD, Publisher: WILEY, Pages: 30-30, ISSN: 1323-7799
Belchamber KBR, Donnelly LE, 2020, Targeting defective pulmonary innate immunity - A new therapeutic option?, PHARMACOLOGY & THERAPEUTICS, Vol: 209, ISSN: 0163-7258
Salvi SS, Brashier BB, Londhe J, et al., 2020, Phenotypic comparison between smoking and non-smoking chronic obstructive pulmonary disease, RESPIRATORY RESEARCH, Vol: 21
Baker J, Fenwick PS, Donnelly LE, et al., 2020, Elevated Levels of Cellular Senescence and Senescence-Associated Secretory Phenotype Markers in COPD Small Airway Epithelial Cells, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Wrench CL, Baker JR, Fenwick PS, et al., 2020, Alterations in Antioxidant Expression with Oxidative Stress in Small Airway Fibroblasts from COPD Patients, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Gorlitz F, Wysoczanski R, Kumar S, et al., 2020, Towards easier, faster super-resolved microscopy, Conference on Single Molecule Spectroscopy and Superresolution Imaging XIII, Publisher: SPIE-INT SOC OPTICAL ENGINEERING, ISSN: 0277-786X
Devulder J, Baker J, Donnelly L, et al., 2020, Extracellular Vesicles Produced by Bronchial Epithelial Cells in Response to Oxidative Stress Contain Micro-RNAs Associated with Cellular Senescence, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Belchamber K, Singh R, Batista C, et al., 2019, Defective bacterial phagocytosis is associated with dysfunctional mitochondria in COPD macrophages, European Respiratory Journal, Vol: 54, Pages: 1-14, ISSN: 0903-1936
Background: Increased reactive oxygen species (ROS) have been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). Objective: This study examined the effect of exogenous and endogenous oxidative stress on macrophage phagocytosis in patients with COPD. Methods: Monocyte-derived macrophages (MDM) were generated from non-smoker, smoker and COPD subjects, differentiated in either GM-CSF (G-Mϕ) or M-CSF (M-Mϕ). Alveolar macrophages were isolated from lung tissue or bronchoalveolar lavage. Macrophages were incubated +/- 200M H2O2 for 24 hours, then exposed to fluorescently-labelled H. influenzae or S. pneumoniae for 4 hours, after which phagocytosis, mitochondrial ROS (mROS), and mitochondrial membrane potential (m) were measured. Results: Phagocytosis of bacteria was significantly decreased in both G-Mϕ and M-Mϕ from COPD patients, compared to non-smoker controls. In non-smokers and smokers, bacterial phagocytosis did not alter mROS or m, however in COPD, phagocytosis increased early mROS and decreased m in both G-Mϕ and M-Mϕ. Exogenous oxidative stress reduced phagocytosis in non-smoker and COPD alveolar macrophages, and non-smoker MDM, associated with reduced mROS production. Conclusion: COPD macrophages show defective phagocytosis, which is associated with altered mitochondrial function and an inability to regulate mROS production. Targeting mitochondrial dysfunction may restore the phagocytic defect in COPD.
Hassibi S, Baker J, Donnelly L, et al., 2019, The RNA binding protein HuR regulates the senescence-associated secretory phenotype under conditions of oxidative stress, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Wrench C, Baker J, Fenwick P, et al., 2019, COPD Small Airway Fibroblasts show reduced proliferation rate and are arrested in G1 phase, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Anders KL, Belchamber KBR, Barnes PJ, et al., 2019, Differential phosphorylation patterns of macrophage cytoskeletal proteins in COPD following phagocytosis, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Morty RE, Donnelly LE, Stolz D, et al., 2019, The ERS fellowship portfolio: fostering excellence and diversity, EUROPEAN RESPIRATORY JOURNAL, Vol: 54, ISSN: 0903-1936
Barnes PJ, Baker J, Donnelly LE, 2019, Cellular senescence as a mechanism and target in chronic lung diseases, American Journal of Respiratory and Critical Care Medicine, Vol: 200, ISSN: 1073-449X
Cellular senescence is now considered an important driving mechanism for chronic lung diseases, particularly COPD and idiopathic pulmonary fibrosis. Cellular senescence is due to replicative and stress-related senescence with activation of p53 and p16INK4a respectively, leading to activation of p21CIP1 and cell cycle arrest. Senescent cells secrete multiple inflammatory proteins known as the senescence-associated secretory phenotype (SASP), leading to low grade chronic inflammation, which further drives senescence. Loss of key anti-aging molecules sirtuin-1 and sirtuin-6 may be important in acceleration of aging and arises from oxidative stress reducing phosphatase PTEN, thereby activating PI3K (phosphoinositide-3-kinase) and mTOR (mammalian target of rapamycin). MicroRNA-34a, which is regulated by PI3K-mTOR signaling, plays a pivotal role in reducing sirtuin-1/6 and its inhibition with an antagomir results in their restoration, reducing markers of senescence, reducing SASP and reversing cell cycle arrest in epithelial cells from peripheral airways of COPD patients. MiR-570 is also involved in reduction of sirtuin-1 and cellular senescence and is activated by p38 MAP kinase. These miRNAs may be released from cells in extracellular vesicles that are taken up by other cells, thereby spreading senescence locally within the lung but outside the lung through the circulation; this may account for comorbidities of COPD and other lung diseases. Understanding the mechanisms of cellular senescence may result in new treatments for chronic lung disease, either by inhibiting PI3K-mTOR signaling, by inhibiting specific miRNAs or by deletion of senescent cells with senolytic therapies, already shown to be effective in experimental lung fibrosis.
Throughout 2018, the publications of the AJRCCM and associated ATS journals have continued to focus on the individual and societal impact of asthma and the challenges involved in managing this prevalent, but heterogeneous, condition. Asthma remains the most common chronic respiratory condition with ongoing significant unmet need at all levels of severity. The cardinal features of asthma, i.e. that it affects a significant proportion of all age‐groups, but generates highly individual effects on health and socioeconomic factors, have hampered previous attempts to gauge its true cost at a population level. Nurmagambetov et al. approached this task by utilising data from the 2008‐2013 household component of the Medical Expenditure Panel Survey, examining a total sample size of more than 200,000 persons (more than 10,000 of whom had ‘treated asthma’). Application of a two‐part regression model indicated the cost of asthma in the USA in 2013 to be $81.9 billion, underlining the huge potential for improvements in asthma care to benefit individuals and populations in multiple aspects, including financially.
Finney LJ, Belchamber KBR, Fenwick PS, et al., 2019, Human rhinovirus impairs the innate immune response to bacteria in alveolar macrophages in chronic obstructive pulmonary disease, American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 1496-1507, ISSN: 1073-449X
Rationale Human rhinovirus (HRV) is a common cause of COPD exacerbations. Secondary bacterial infection is associated with more severe symptoms and delayed recovery. Alveolar macrophages clear bacteria from the lung and maintain lung homeostasis through cytokine secretion. These processes are defective in COPD. The effect of HRV on macrophage function is unknown. Objectives To investigate the effect of HRV on phagocytosis and cytokine response to bacteria by alveolar macrophages and monocyte derived macrophages (MDM) in COPD and healthy controls. Methods Alveolar macrophages were obtained by bronchoscopy and MDM by adherence. Macrophages were exposed to HRV 16 (multiplicity of infection 5), polyI:C 30μg/ml, interferon (IFN)-β 10μg/ml, IFN-γ 10μg/ml or medium control for 24 hours. Phagocytosis of fluorescently-labelled Haemophilus influenzae or Streptococcus pneumoniae was assessed by fluorimetry. CXCL8, TNF and IL-10 release was measured by ELISA. Main Results HRV significantly impaired phagocytosis of H. influenzae by 23% in MDM (n=37) and 18% in alveolar macrophages (n=20) in COPD. HRV also significantly reduced phagocytosis of S. pneumoniae by 33% in COPD MDM. There was no effect in healthy controls. Phagocytosis of H. influenzae was impaired by polyI:C but not IFN-β or IFN-γ. HRV significantly reduced cytokine responses to H. influenzae. The IL-10 response to H. influenzae was significantly impaired by polyI:C, IFN-β and IFN-γ. Conclusions HRV impairs phagocytosis of bacteria in COPD which may lead to an outgrowth of bacteria. HRV also impairs cytokine responses to bacteria via the TLR3/IFN pathway which may prevent resolution of inflammation leading to prolonged exacerbations in COPD.
Dunne A, Kawamatawong T, Fenwick P, et al., 2019, Direct inhibitory rffect of the phosphodiesterase-4 inhibitor, roflumilast, on neutrophil migration in COPD, American Journal of Respiratory Cell and Molecular Biology, Vol: 60, Pages: 445-453, ISSN: 1044-1549
Neutrophilic inflammation is characteristic of COPD, yet there are no effective anti-inflammatory therapies. The phosphodiesterase (PDE)4 inhibitor, roflumilast is approved for use in COPD and suppresses sputum neutrophilia. The mechanism underlying this observation is unclear and therefore this study addressed whether roflumilast directly affected neutrophil migration. Blood-derived neutrophils were isolated from non-smokers, smokers and COPD patients and chemotaxis measured using Boyden chambers. Intracellular calcium ion concentration ([Ca2+]i) was measured by fluorimetry and shape change and CD11b expression by flow cytometry. Neutrophils from COPD patients showed enhanced chemotactic responses towards both CXCL1 and LTB4 compared with control cells. Chemotaxis was inhibited by both the active metabolite, roflumilast-N-oxide, and rolipram in a concentration-dependent manner with no difference in responsiveness between subjects. Roflumilast-N-oxide and rolipram were less efficacious against CXCL1 and LTB4-mediated [Ca2+]i suggesting that inhibition was not via this pathway. Both PDE4 inhibitors attenuated chemoattractant-mediated shape change and CD11b up-regulation suggesting common mechanisms. The stable cAMP analogue, 8-Br-cAMP, inhibited chemotaxis, as did the direct Epac1 activator 8-pCPT-2’-O-Me-cAMP but not the direct PKA activator, 6-Bnz-cAMP. These data suggest that roflumilast inhibits neutrophil chemotaxis directly via a cAMP-mediated mechanism requiring activation of Epac1, and that Epac1 activators could reduce COPD neutrophilic inflammation.
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