oa Editorial [Hot Topic: Current Drug Targets for the Critically Ill COPD Patient (Guest Editors: Demosthenes Makris and Epaminondas Zakynthinos)]

Chronic Obstructive Pulmonary Disease (COPD) is characterized by airflow limitation and abnormal inflammatory response of the lungs to exogenous stimuli such as particles and gasses, primarily cigarette smoke [1]. COPD management is based mainly on smoking cessation, bronchodilator therapy and antinflammatory treatment such as steroids, prompt treatment of exacerbations and support of ventilation by invasive or non invasive modalities. However, effective definitive treatment of the disease does not exist despite therapeutic advances. Management of advanced COPD may be challenging; patients with severe forms of the disease or, those patients who experience severe exacerbations, may present critical deterioration requiring management in the Intensive Care Unit (ICU) [2]. COPD is still associated with significant morbidity and mortality and the disease is expected to be the third leading cause of death by 2020 [1]. In this respect, understanding the pathophysiology of the disease and development of effective novel therapeutic strategies are mandatory. COPD is marked by an excessive accumulation of cytokines and inflammatory cells which is further amplified in the severe forms of the disease and during exacerbations. The role of macrophages and lymphocytes at stable disease and at exacerbations has been already pointed out [3, 4]. These phenomena might partially explain the increased and prolonged inflammation seen at COPD. In addition, previous studies [5] provided evidence for the role of immunomodulation in COPD studying the role of dendritic cells whose primary function is the activation of T lymphocytes and the induction of primary immune responses suggesting an immune component in the pathophysiology of the disease. Tsoumakidou et al. [6] reviewed mechanisms implicated in innate and adaptive immune responses which are critical components of the host defence against exogenous stimuli and therefore, essential for COPD pathogenesis. Furthermore, there is evidence that in COPD, mechanisms controlling apoptosis of epithelial and inflammatory cells in the lungs may be altered. This is supported by a number of studies that reported increased induction of apoptosis in the inflammatory milieu of the airway in COPD patients [7-9]. In this respect, the role of defects in the apoptotic processes, such as failed efferocytosis, may be a promising field for the establishment of new therapies that are directed towards COPD specific pathology [10]. Especially in COPD patients, apoptotic processes are accelerated in the lung areas with excessive oxidative stress [7]. In turn, increased oxidative stress in the lungs has been related to increased expression of pro-inflammatory mediators, downregulation of relevant anti-inflammatory genes, increased sequestration of neutrophils in the pulmonary microvasculature, inactivation of antiproteinases, epithelial injury and mucus hypersecretion [11]. The sources of the increased oxidative stress in COPD derive either from inhaled oxidants or/and from the increased amounts of reactive oxygen species, generated by inflammatory and structural cells involved in the pathophysiology of the disease and can be triggered at exacerbations by exogenous stimuli such as bacteria [12]. Loukides et al. [11] reviewed several mechanisms of oxidative stress which are potentially related to COPD pathogenesis and highlighted pathways with potential therapeutic implications in COPD. Special Issues in Critically ill COPD Patients The development of novel efficient therapies for critically ill COPD patients requires not only understanding of the underlying pathobiology but also management of specific problems that critically ill COPD patients may present. First, these patients present immune defect due to the nutritional depletion which is associated with critical illness [13]. Chronic COPD undernutrition and acute micronutrient deficiency in ICU may compromise cytokine response and affect immune cell trafficking. The combination of undernutrition and infection may further weaken the immune response, leading to altered immune cell populations and a generalized increase in inflammatory mediators [14]. Thus, the immune response to exogenous insult such as bacteria colonizing the airway lumen may be insufficient, resulting in serious infections. Consequently, airway colonization caused by multidrug resistant bacteria may be critical for subsequent airway and lung parenchymal infections and may affect inversely the outcome of critically ill COPD patients [2, 15]. Gram negative bacteria which often colonize or infect the airways, such as pseudomonas aeruginosa strains, may show high frequencies of mutations in the environment of increased oxidative stress - which characterizes COPD - and this might be involved in the development of resistance to antibiotics [16-18]. In this respect, thorough understanding of pathogenetic mechanisms for airway colonization and of the mechanisms underlying bacterial (especially ps. areoginosa) resistance is a priority for effective management of severe COPD patients [15, 16]. Another important problem in critically ill COPD patients is muscle function impairment. This might be due to undernutrition and muscle wasting but also due to the fact that respiratory muscles are subject to the same systemic inflammatory, oxidative and metabolic insults as limb muscles, both in stable COPD and during acute exacerbations. Thus, critically ill COPD patients may often require mechanical support of breathing. This may entrap patients into a viscous circle since the use of mechanical ventilation may induce further respiratory muscle wasting and lung function deterioration. Notably, it has been reported that mechanical ventilation may affect inflammatory pathways known to be activated on stretch, in several experimental conditions of ventilation [19]. In this issue, Klimathianaki et al. [20] review muscular and cellular adaptive responses to the increased ventilatory load that characterizes COPD. Apart from the pathologic changes in airways and parenchyma, pulmonary circulation can be also affected in COPD and pulmonary hypertension is not rare in COPD. Several growth factors, including vascular endothelial and fibroblast factor are strongly expressed in pulmonary vascular endothelium of patients with pulmonary hypertension secondary to hypoxic conditions; Endothelin-1 levels were found increased in exacerbations implying a role in the pulmonary hypertension secondary to COPD. Thus, pathways of vascular remodelling and of pulmonary hypertension are potential drug targets which might be useful in COPD patients with severe PH, such as “out of proportion PH” where management is challenging for physicians [21]. This special issue of the Current Drug Targets reviews recent advances in COPD pathobiology (cell immune response, oxidative stress and apoptosis) [6, 10, 11] and focuses on problems related to severe disease such as respiratory muscle dysfunction [20], nutrional depletion [14], pulmonary hypertension [21] and airway colonization by bacteria resistant to antibiotics [15, 16] which could be targets for novel therapies in the future.