Mathew Suji Eapen

Airway inflammation in chronic obstructive pulmonary disease (COPD): a true paradox

ABSTRACT Introduction: Chronic obstructive pulmonary disease (COPD) is primarily an airway condition, which mainly affects cigarette smokers and presents with shortness of breath that is progressive and poorly reversible. In COPD research, there has been a long held belief that airway disease progression is due to inflammation. Although this may be true in the airway lumen with innate immunity activated by the effect of smoke or secondary to infection, the accurate picture of inflammatory cells in the airway wall, where the pathophysiological COPD remodeling occurs, is uncertain and debatable. Areas covered: The current review provides a comprehensive literature survey of the changes in the main inflammatory cells in human COPD patients and focuses on contrarian views that affect the prevailing dogma on inflammation. The review also delves into the role of oxidative stress and inflammasomes in modulating the immune response in COPD. Further, the effects of inflammation in affecting the epithelium, fibroblasts, and airway remodeling are discussed. Expert commentary: Inflammation as a driving force for airway wall damage and remodelling in early COPD is at the very least ‘oversimplified’ and is likely to be misleading. This has serious implications for rational thinking about the illness, including pathogenesis and designing therapy.

Opposing Effects of Low Molecular Weight Heparins on the Release of Inflammatory Cytokines from Peripheral Blood Mononuclear Cells of Asthmatics

Background T-cell-mediated inflammatory cytokines, such as interleukin (IL)-4, IL-5, IL-13 and tumor necrosis factor-alpha (TNF-α), play an important role in the initiation and progression of inflammatory airways diseases. Low-molecular-weight heparins (LMWHs), widely used anticoagulants, possess anti-inflammatory properties making them potential treatment options for inflammatory diseases, including asthma. In the current study, we investigated the modulating effects of two LMWHs (enoxaparin and dalteparin) on the release of cytokines from stimulated peripheral blood mononuclear cells (PBMCs) of asthmatic subjects to identify the specific components responsible for the effects. Methods PBMCs from asthmatic subjects (consist of ~75% of T-cells) were isolated from blood taken from ten asthmatic subjects. The PBMCs were pre-treated in the presence or absence of different concentrations of LMWHs, and were then stimulated by phytohaemagglutinin for the release of IL-4, IL-5, IL-13 and TNF-α. LMWHs were completely or selectively desulfated and their anticoagulant effect, as well as the ability to modulate cytokine release, was determined. LMWHs were chromatographically fractionated and each fraction was tested for molecular weight determination along with an assessment of anticoagulant potency and effect on cytokine release. Results Enoxaparin inhibited cytokine release by more than 48%, whereas dalteparin increased their release by more than 25%. The observed anti-inflammatory effects of enoxaparin were independent of their anticoagulant activities. Smaller fractions, in particular dp4 (four saccharide units), were responsible for the inhibitory effect of enoxaparin. Whereas, the larger fractions, in particular dp22 (twenty two saccharide units), were associated with the stimulatory effect of dalteparin. Conclusion Enoxaparin and dalteparin demonstrated opposing effects on inflammatory markers. These observed effects could be due to the presence of structurally different components in the two LMWHs arising from different methods of depolymerisation. This study provides a platform for further studies investigating the usefulness of enoxaparin in various inflammatory diseases.

Platelet activating factor receptor: gateway for bacterial chronic airway infection in chronic obstructive pulmonary disease and potential therapeutic target

The authors established that cigarette smoke increases airway epithelial platelet activating factor receptor (PAFr) expression and that PAFr is markedly up-regulated in the lungs of chronic obstructive pulmonary disease (COPD) patients. Crucially, PAFr is used by the two key bacterial species involved in chronic infection and acute exacerbations in COPD, that is, Streptococcus pneumoniae and Haemophilus influenzae, as a receptor for lung epithelial colonization. The cognate adhesin of PAFr, phosphorylcholine (ChoP), in the cell wall of these bacterial species may be a key effector that underpins host colonization. In this review, the authors evaluate the respective roles of PAFr and ChoP in the natural history of COPD and discuss the potential of the airway epithelial PAFr–bacterial ChoP interaction as a selective anti-infective target in COPD therapeutics.

Abnormal M1/M2 macrophage phenotype profiles in the small airway wall and lumen in smokers and chronic obstructive pulmonary disease (COPD)

We explore potential dysregulation of macrophage phenotypes in COPD pathogenesis through integrated study of human small airway tissue, bronchoalveolar lavage (BAL) and an experimental murine model of COPD. We evaluated human airway tissue and BAL from healthy controls, normal lung function smokers (NLFS), and COPD subjects. Both small airways and BAL cells were immunohistochemically stained with anti-CD68 for total macrophages and with anti-CD163 for M2, and anti-iNOS for M1 macrophages. Multiplex ELISA measured BAL cytokines. Comparable cigarette smoke-induced experimental COPD mouse model was assessed for relevant mRNA profiles. We found an increase in pro-inflammatory M1s in the small airways of NLFS and COPD compared to controls with a reciprocal decrease in M2 macrophages, which remained unchanged among pathological groups. However, luminal macrophages showed a dominant M2 phenotype in both NLFS and COPD subjects. BAL cytokine skewed towards an M2 profile with increase in CCL22, IL-4, IL-13, and IL-10 in both NLFS and COPDs. The mouse-model of COPD showed similar increase in mRNA for M2 markers. Our finding suggests abnormal macrophage switching in both mucosal and luminal areas of COPD patients, that strongly associated with cytokine balance. There may be potential for beneficial therapeutic cytokine manipulation of macrophage phenotypes in COPD.

Potential Mechanisms of Microbial Pathogens in Idiopathic Interstitial Lung Disease

To the Editor: We read with great interest the review by Azadeh et al published in this issue of CHEST on the role of infections in idiopathic interstitial lung disease (ILD). Mechanisms enhancing infections in chronic respiratory diseases are poorly understood, and wider discussion of new insights into potential mechanisms contributing to bacterial and viral infection vulnerability would be valuable. A fundamental issue is how these pathogens initially adhere to the airway epithelium. We suggest that our recent work on microbial adhesion sites on the airway epithelium in COPD might aid the understanding of enhanced infectivity in ILD and would be an important area of investigation in this context.

Ventilatory efficiency slope as a predictor of suitability for surgery in chronic obstructive pulmonary disease patients with lung cancer

Lung cancer is one of the leading cancers with an estimated 1.8 million new cases in 2012 as per WHO estimates. Tobacco smoking is considered to be the key driver causing 70% or more of total lung cancer-related deaths worldwide (1). Lung cancer and chronic obstructive pulmonary disease (COPD) commonly coexist in smokers, and the presence of COPD increases the risk of developing lung cancer by 4–5 folds, even when the smoking history is controlled for (2). Lung cancer may consist of small cell carcinoma and non-small cell carcinomas encompassing squamous cell carcinoma, adenocarcinoma and large cell carcinoma (3). In a recent very comprehensive study by Shafiek and colleagues published in European Journal of Cardio-Thoracic Surgery , highlighted the lethal association between COPD and lung cancer and the risk of postoperative complications in these patients considered fit for surgery (4). This publication is a very timely reminder highlighting the importance of this association between COPD/lung cancer and warrants further experimental studies exploring the link between the two and complications associated. Unfortunately, the research effort directed into this has been disproportionately weak compared to its clinical and scientific importance, and indeed, COPD itself is the least researched of all common chronic conditions compared to its social significance (5,6). It is of interest and relevance in this context that up to 70% of lung cancer occurs in the context of mild-to-moderate (not severe) COPD (1,5,7-9).

Investigations into the physical and chemical stability of concentrated co-trimoxazole intravenous infusions

Objectives High dose of intravenous sulfamethoxazole and trimethoprim (co-trimoxazole) is often used in immunocompromised patients for the treatment of Pneumocystis jiroveci pneumonia. Current manufacturer’s dilution recommendation for intravenous co-trimoxazole (1:25 v/v) requires the administration of 2 L of additional fluid per day causing serious complications including pulmonary oedema. Intravenous administration of concentrated solution of co-trimoxazole may minimise the risk of fluid overload associated side effects. Therefore, the objective of the study was to investigate the physicochemical stability of concentrated intravenous co-trimoxazole solutions. Methods Four ampoules of intravenous co-trimoxazole were injected into an infusion bag containing either 480 (1:25 v/v), 380 (1:20 v/v), 280 (1:15 v/v) or 180 (1:10 v/v) mL of glucose 5% solution. Three bags for each dilution (total 12 bags) were prepared and stored at room temperature. An aliquot was withdrawn immediately (at 0 hour) and after 0.5, 1, 2 and 4 hours of storage for high-performance liquid-chromatography (HPLC) analysis, and additional samples were withdrawn every half an hour for microscopic examination. Each sample was analysed for the concentration of trimethoprim and sulfamethoxazole using a stability indicating HPLC method. Samples were assessed for pH, change in colour (visually) and for particle content (microscopically) immediately after preparation and on each time of analysis. Results Intravenous co-trimoxazole at 1:25, 1:20, 1:15 and 1:10 v/v retained more than 98% of the initial concentration of trimethoprim and sulfamethoxazole for 4 hours. There was no major change in pH at time zero and at various time points. Microscopically, no particles were detected for at least 4 hours and 2 hours when intravenous co-trimoxazole was diluted at 1:25 or 1:20 and 1:15 v/v, respectively. More than 1200 particles/mL were detected after 2.5 hours of storage when intravenous co-trimoxazole was diluted at 1:15 v/v. Conclusions Intravenous co-trimoxazole is stable over a period of 4 hours when diluted with 380 mL of glucose 5% solution (1:20 v/v) and for 2 hours when diluted with 280 mL glucose 5% solution (1:15 v/v).

Understanding novel mechanisms of microbial pathogenesis in chronic lung disease: implications for new therapeutic targets

Airway infections are considered as one of the vital factors driving the pathophysiology of chronic lung disease with significant influences on disease trajectory. Opportunistic lung microbes in diseased conditions induce excessive exacerbations and contribute to airflow limitation. Though there has been considerable amount of information that ascertains their links with airway inflammation, the intricate interaction in clinical conditions are poorly understood and requires further deciphering. Current therapeutic interventions for such pathologies are few and lack the ability to modulate underlying dysfunctional immunity as well as suppress the excessive infectious conditions. Thus, in this Commentary we provide a focused outlook on the mechanisms involved in microbial infestation in lung diseases and provides important information on new therapeutic interventions including the potential role of Resolvins and their derivatives as alternative therapeutic agents in combating such multifaceted pathological mechanisms.