Chronic obstructive pulmonary disease (COPD) is a disease characterised by persistent airflow limitation that is not fully reversible and is currently the fourth leading cause of death globally. It ...is now well established that cardiovascular-related comorbidities contribute to morbidity and mortality in COPD, with approximately 50% of deaths in COPD patients attributed to a cardiovascular event (e.g. myocardial infarction). Cardiovascular disease (CVD) and COPD share various risk factors including hypertension, sedentarism, smoking and poor diet but the underlying mechanisms have not been fully established. However, there is emerging and compelling experimental and clinical evidence to show that increased oxidative stress causes pulmonary inflammation and that the spill over of pro-inflammatory mediators from the lungs into the systemic circulation drives a persistent systemic inflammatory response that alters blood vessel structure, through vascular remodelling and arterial stiffness resulting in atherosclerosis. In addition, regulation of endothelial-derived vasoactive substances (e.g. nitric oxide (NO)), which control blood vessel tone are altered by oxidative damage of vascular endothelial cells, thus promoting vascular dysfunction, a key driver of CVD. In this review, the detrimental role of oxidative stress in COPD and comorbid CVD are discussed and we propose that targeting oxidant-dependent mechanisms represents a novel strategy in the treatment of COPD-associated CVD.
Influenza A viral infections claim millions of lives worldwide and continue to impose a major burden on healthcare systems. Current pharmacological strategies to control influenza A virus-induced ...lung disease are problematic owing to antiviral resistance and the requirement for strain-specific vaccination. The production of reactive oxygen species (ROS), particularly superoxide, is an important host defence mechanism for killing invading pathogens. However, excessive superoxide may be detrimental following influenza A virus infection. Indeed, suppression of superoxide production by targeting the primary enzymatic source of superoxide in mammalian inflammatory cells, NADPH oxidase 2 (Nox2), markedly alleviates influenza A virus-induced lung injury and virus replication, irrespective of the infecting strain. Therefore, we propose that Nox2 oxidase inhibitors, in combination with current therapeutics (i.e. antivirals and vaccines), could be useful for suppression of influenza A virus-induced lung disease.
Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and loss of lung function, and is currently the third largest cause of death in the world. It is now ...well established that cardiovascular-related comorbidities such as stroke contribute to morbidity and mortality in COPD. The mechanisms linking COPD and stroke remain to be fully defined but are likely to be interconnected. The association between COPD and stroke may be largely dependent on shared risk factors such as aging and smoking, or the association of COPD with traditional stroke risk factors. In addition, we propose that COPD-related systemic inflammation and oxidative stress may play important roles by promoting cerebral vascular dysfunction and platelet hyperactivity. In this review, we briefly discuss the pathogenesis of COPD, acute exacerbations of COPD (AECOPD) and cardiovascular comorbidities associated with COPD, in particular stroke. We also highlight and discuss the potential mechanisms underpinning the link between COPD and stroke, with a particular focus on the roles of systemic inflammation and oxidative stress.
Cigarette smoking has reached epidemic proportions within many regions of the world and remains the highest risk factor for chronic obstructive pulmonary disease (COPD) and lung cancer. Squamous cell ...lung cancer is commonly detected in heavy smokers, where the risk of developing lung cancer is not solely defined by tobacco consumption. Although therapies that target common driver mutations in adenocarcinomas are showing some promise, they are proving ineffective in smoking‐related squamous cell lung cancer. Since COPD is characterized by an excessive inflammatory and oxidative stress response, this review details how aberrant innate, adaptive and systemic inflammatory processes can contribute to lung cancer susceptibility in COPD. Activated leukocytes release increasing levels of proteases and free radicals as COPD progresses and tertiary lymphoid aggregates accumulate with increasing severity. Reactive oxygen species promote formation of reactive carbonyls that are not only tumourigenic through initiating DNA damage, but can directly alter the function of regulatory proteins involved in host immunity and tumour suppressor functions. Systemic inflammation is also markedly increased during infective exacerbations in COPD and the interplay between tumour‐promoting serum amyloid A (SAA) and IL‐17A is discussed. SAA is also an endogenous allosteric modifier of FPR2 expressed on immune and epithelial cells, and the therapeutic potential of targeting this receptor is proposed as a novel strategy for COPD–lung cancer overlap.
Linked Articles
This article is part of a themed section on Inflammation: maladies, models, mechanisms and molecules. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2016.173.issue-4
Chronic obstructive pulmonary disease (COPD) is a leading cause of disability and death world-wide, where chronic inflammation accelerates lung function decline. Pathological inflammation is worsened ...by chronic bacterial lung infections and susceptibility to recurrent acute exacerbations of COPD (AECOPD), typically caused by viral and/or bacterial respiratory pathogens. Despite ongoing efforts to reduce AECOPD rates with inhaled corticosteroids, COPD patients remain at heightened risk of developing serious lung infections/AECOPD, frequently leading to hospitalization and infection-dependent delirium. Here, we review emerging mechanisms into why COPD patients are susceptible to chronic bacterial infections and highlight dysregulated inflammation and production of reactive oxygen species (ROS) as central causes. This underlying chronic infection leaves COPD patients particularly vulnerable to acute viral infections, which further destabilize host immunity to bacteria. The pathogeneses of bacterial and viral exacerbations are significant as clinical symptoms are more severe and there is a marked increase in neutrophilic inflammation and tissue damage. AECOPD triggered by a bacterial and viral co-infection increases circulating levels of the systemic inflammatory marker, serum amyloid A (SAA). SAA is a functional agonist for formyl peptide receptor 2 (FPR2/ALX), where it promotes chemotaxis and survival of neutrophils. Excessive levels of SAA can antagonize the protective actions of FPR2/ALX that involve engagement of specialized pro-resolving mediators, such as resolvin-D1. We propose that the anti-microbial and anti-inflammatory actions of specialized pro-resolving mediators, such as resolvin-D1 should be harnessed for the treatment of AECOPD that are complicated by the co-pathogenesis of viruses and bacteria.
Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death globally and is characterized by airflow limitation that is progressive and not fully reversible. Cigarette ...smoking is the major cause of COPD. Fifty percent of deaths in the COPD population are due to a cardiovascular event and it is now recognised that COPD is a risk factor for stroke. Whether COPD increases stroke severity has not been explored. The aim of this study was to investigate whether functional and histological endpoints of stroke outcomes in mice after transient middle cerebral artery occlusion (tMCAo) were more severe in mice exposed to cigarette smoke (CS). 7-week-old male C57BL/6 mice were exposed to room air or CS generated from 9 cigarettes/day, 5 days/week for 2, 8 and 12 weeks. Following air or CS exposure, mice underwent tMCAO surgery with an ischaemic period of 30-40 min or sham surgery. Mice were euthanised 24 h following the induction of ischaemia and bronchoalveolar lavage fluid (BALF), lungs and brains collected. Mice exposed to CS for 2 weeks and subjected to a stroke had similar BALF macrophages to air-exposed and stroke mice. However, CS plus stroke mice had significantly more BALF total cells, neutrophils and lymphocytes than air plus stroke mice. Mice exposed to CS for 8 and 12 weeks had significantly greater BALF total cells, macrophages, neutrophils and lymphocytes than air-exposed mice, but stroke did not affect CS-induced BALF cellularity. Prior CS exposure did not worsen stroke-induced neurological deficit scores, reduced foregrip strength, infarct and oedema volumes. Collectively, we found that although CS exposure caused significant BALF inflammation, it did not worsen acute post-stroke outcomes in mice. This data suggests that while patients with COPD are at increased risk of stroke, it may not translate to COPD patients having more severe stroke outcomes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are highly prevalent worldwide. One of the major factors that limits the efficacy of current medication in these ...patients are viral infections, leading to exacerbations of symptoms and decreased quality of life. Current pharmacological strategies targeting virus-induced lung disease are problematic due to antiviral resistance and the requirement for strain-specific vaccination. Thus, new therapeutic strategies are urgently required. In this Opinion article, we provide state-of-the-art evidence from humans and preclinical animal models implicating the interleukin (IL)-33/IL-13 axis in virus-induced lung disease. Thus, targeting the IL-33/IL-13 axis may be a feasible way to overcome the limitations of current therapy used to treat virus-induced exacerbations of lung disease.
Formyl peptide receptor 2/lipoxin A
(LXA
) receptor (Fpr2/ALX) co-ordinates the transition from inflammation to resolution during acute infection by binding to distinct ligands including serum ...amyloid A (SAA) and Resolvin D1 (RvD1). Here, we evaluated the proresolving actions of aspirin-triggered RvD1 (AT-RvD1) in an acute coinfection pneumonia model. Coinfection with
and influenza A virus (IAV) markedly increased pneumococcal lung load and neutrophilic inflammation during the resolution phase. Fpr2/ALX transcript levels were increased in the lungs of coinfected mice, and immunohistochemistry identified prominent Fpr2/ALX immunoreactivity in bronchial epithelial cells and macrophages. Levels of circulating and lung SAA were also highly increased in coinfected mice. Therapeutic treatment with exogenous AT-RvD1 during the acute phase of infection (day 4-6 post-pneumococcal inoculation) significantly reduced the pneumococcal load. AT-RvD1 also significantly reduced neutrophil elastase (NE) activity and restored total antimicrobial activity in bronchoalveolar lavage (BAL) fluid (BALF) of coinfected mice. Pneumonia severity, as measured by quantitating parenchymal inflammation or alveolitis was significantly reduced with AT-RvD1 treatment, which also reduced the number of infiltrating lung neutrophils and monocytes/macrophages as assessed by flow cytometry. The reduction in distal lung inflammation in AT-RvD1-treated mice was not associated with a significant reduction in inflammatory and chemokine mediators. In summary, we demonstrate that in the coinfection setting, SAA levels were persistently increased and exogenous AT-RvD1 facilitated more rapid clearance of pneumococci in the lungs, while concurrently reducing the severity of pneumonia by limiting excessive leukocyte chemotaxis from the infected bronchioles to distal areas of the lungs.
Vlahos discusses the study by Wrennall et al which examined the therapeutic potential of a novel alpha6 peptidomimetic for asthma. There are potential limitations to the study that bear some ...discussion. First, the researchers have shown that alpha6 neither interacts with nor penetrates the epithelial barrier, suggesting that alpha6 imparts its anti-inflammatory effects solely through interactions with immune cells already recruited to the airway lumen. The study has shown that administration of a SPLUNC1 alpha6 peptidomimetic reduces HDM-induced airway inflammation in mice and that the alpha6 peptide may serve as a novel therapeutic for asthma treatment where conventional treatments do not work or where nonsteroidal alternatives are needed.
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