Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous disease, both at the clinical and biological level. However, COPD is still diagnosed and treated according to simple ...clinical measures (level of airflow limitation, symptoms, and frequency of previous exacerbations). To address this clinical and biological complexity and to move towards precision medicine in COPD, we need to integrate (bioinformatics) and interpret (clinical science) the vast amount of high-throughput information that existing technology provides (systems biology and network medicine) so diagnosis, stratification, and treatment of patients with COPD can occur on the basis of their pathobiological mechanism (ie, endotypes). Therefore, this Series paper discusses a possible new taxonomy of COPD, the role of endotypes and associated biomarkers and phenotypes, the gaps (and opportunities) in existing knowledge of COPD pathobiology, how systems biology and network medicine can improve understanding of the disease and help to identify relevant endotypes and their specific biomarkers, and how endotypes and their biomarkers can improve the precision, effectiveness, and safety of the treatment of patients with COPD.
Nontypeable Haemophilus influenzae (NTHI) is an opportunistic gram-negative pathogen that causes respiratory infections and is associated with progression of respiratory diseases. Cigarette smoke is ...a main risk factor for development of respiratory infections and chronic respiratory diseases. Glucocorticoids, which are anti-inflammatory drugs, are still the most common therapy for these diseases. Alveolar macrophages are professional phagocytes that reside in the lung and are responsible for clearing infections by the action of their phagolysosomal machinery and promotion of local inflammation. In this study, we dissected the interaction between NTHI and alveolar macrophages and the effect of cigarette smoke on this interaction. We showed that alveolar macrophages clear NTHI infections by adhesion, phagocytosis, and phagolysosomal processing of the pathogen. Bacterial uptake requires host actin polymerization, the integrity of plasma membrane lipid rafts, and activation of the phosphatidylinositol 3-kinase (PI3K) signaling cascade. Parallel to bacterial clearance, macrophages secrete tumor necrosis factor alpha (TNF-α) upon NTHI infection. In contrast, exposure to cigarette smoke extract (CSE) impaired alveolar macrophage phagocytosis, although NTHI-induced TNF-α secretion was not abrogated. Mechanistically, our data showed that CSE reduced PI3K signaling activation triggered by NTHI. Treatment of CSE-exposed cells with the glucocorticoid dexamethasone reduced the amount of TNF-α secreted upon NTHI infection but did not compensate for CSE-dependent phagocytic impairment. The deleterious effect of cigarette smoke was observed in macrophage cell lines and in human alveolar macrophages obtained from smokers and from patients with chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is a complex, heterogeneous disease. The severity of airflow limitation, traditionally used to guide therapy in patients with COPD, does not describe this ...complexity properly. As a result, over the past few years there has been a great deal of interest in characterizing COPD more precisely and identifying homogeneous groups of patients who respond to specific therapeutic interventions (i.e., phenotypes). This review summarizes a presentation at the Transatlantic Airway Conference held in Lucerne on January 31, 2013 on this topic. It addresses the following questions: (1) What do we mean by "phenotypes"? (2) Why do we care about them? (3) Are phenotypes the best strategy to understand COPD heterogeneity? and (4) How can we progress in this field?
Aging is a natural process characterized by progressive functional impairment and reduced capacity to respond appropriately to environmental stimuli and injury. The incidence of two common chronic ...respiratory diseases (chronic obstructive pulmonary disease COPD and idiopathic pulmonary fibrosis IPF) increases with advanced age. It is plausible, therefore, that abnormal regulation of the mechanisms of normal aging may contribute to the pathobiology of both COPD and IPF. This review discusses the available evidence supporting a number of aging mechanisms, including oxidative stress, telomere length regulation, cellular and immunosenescence, as well as changes in a number of antiaging molecules and the extracellular matrix, which are abnormal in COPD and/or IPF. A better understanding of these abnormalities may help in the design of novel and better therapeutic interventions for these patients.
Chronic obstructive pulmonary disease (COPD) is a global health issue with high social and economic costs. Concomitant chronic cardiac disorders are frequent in patients with COPD, likely owing to ...shared risk factors (e.g., aging, cigarette smoke, inactivity, persistent low-grade pulmonary and systemic inflammation) and add to the overall morbidity and mortality of patients with COPD. The prevalence and incidence of cardiac comorbidities are higher in patients with COPD than in matched control subjects, although estimates of prevalence vary widely. Furthermore, cardiac diseases contribute to disease severity in patients with COPD, being a common cause of hospitalization and a frequent cause of death. The differential diagnosis may be challenging, especially in older and smoking subjects complaining of unspecific symptoms, such as dyspnea and fatigue. The therapeutic management of patients with cardiac and pulmonary comorbidities may be similarly challenging: bronchodilators may have cardiac side effects, and, vice versa, some cardiac medications should be used with caution in patients with lung disease. The aim of this review is to summarize the evidence of the relationship between COPD and the three most frequent and important cardiac comorbidities in patients with COPD: ischemic heart disease, heart failure, and atrial fibrillation. We have chosen a practical approach, first summarizing relevant epidemiological and clinical data, then discussing the diagnostic and screening procedures, and finally evaluating the impact of lung-heart comorbidities on the therapeutic management of patients with COPD and heart diseases.
Chronic obstructive pulmonary disease (COPD) is a complex disease at the clinical, cellular, and molecular levels. However, its diagnosis, assessment, and therapeutic management are based almost ...exclusively on the severity of airflow limitation. A better understanding of the multiple dimensions of COPD and its relationship to other diseases is very relevant and of high current interest. Recent theoretical (scale-free networks), technological (high-throughput technology, biocomputing), and analytical improvements (systems biology) provide tools capable of addressing the complexity of COPD. The information obtained from the integrated use of those techniques will be eventually incorporated into routine clinical practice. This review summarizes our current knowledge in this area and offers an insight into the elements needed to progress toward an integrated, multilevel view of COPD based on the novel scientific strategy of systems biology and its potential clinical derivative, P4 medicine (Personalized, Predictive, Preventive, and Participatory).
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