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Chronic obstructive pulmonary disease (COPD) management remains challenging due to the high heterogeneity of clinical symptoms and the complex pathophysiological basis of the disease. Airflow limitation, diagnosed by spirometry, remains the cornerstone of the diagnosis. However, the calculation of the forced expiratory volume in the first second (FEV1) alone, has limitations in uncovering the underlying complexity of the disease. Incorporating additional pulmonary function tests (PFTs) in the everyday clinical evaluation of COPD patients, like resting volume, capacity and airway resistance measurements, diffusion capacity measurements, forced oscillation technique, field and cardiopulmonary exercise testing and muscle strength evaluation, may prove essential in tailoring medical management to meet the needs of such a heterogeneous patient population. We aimed to provide a comprehensive overview of the available PFTs, which can be incorporated into the primary care physician’s practice to enhance the efficiency of COPD management.

Introduction Resistive breathing (RB), the pathophysiologic hallmark of chronic obstructive pulmonary disease (COPD), especially during exacerbations, is associated with significant inflammation and mechanical stress on the lung. Mechanical forces are implicated in the progression of emphysema that is a major pathologic feature of COPD. We hypothesized that resistive breathing exacerbates emphysema. Methods C57BL/6 mice were exposed to 0.75 units of pancreatic porcine elastase intratracheally to develop emphysema. Resistive breathing was applied by suturing a nylon band around the trachea to reduce surface area to half for the last 24 or 72 hours of a 21-day time period after elastase treatment in total. Following RB (24 or 72 hours), lung mechanics were measured and bronchoalveolar lavage (BAL) was performed. Emphysema was quantified by the mean linear intercept (Lm) and the destructive index (DI) in lung tissue sections. Results Following 21 days of intratracheal elastase exposure, Lm and DI increased in lung tissue sections [Lm (μm), control 39.09±0.76, elastase 62.05±2.19, p=0.003 and DI, ctr 30.95±2.75, elastase 73.12±1.75, p

Globally, chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality, having a significant socioeconomic effect. Several molecular mechanisms have been related to COPD including chronic inflammation, telomere shortening, and epigenetic modifications. Nowadays, there is an increasing need for novel therapeutic approaches for the management of COPD. These treatment strategies should be based on finding the source of acute exacerbation of COPD episodes and estimating the patient’s own risk. The use of biomarkers and the measurement of their levels in conjunction with COPD exacerbation risk and disease prognosis is considered an encouraging approach. Many types of COPD biomarkers have been identified which include blood protein biomarkers, cellular biomarkers, and protease enzymes. They have been isolated from different sources including peripheral blood, sputum, bronchoalveolar fluid, exhaled air, and genetic material. However, there is still not an exclusive biomarker that is used for the evaluation of COPD but rather a combination of them, and this is attributed to disease complexity. In this review, we summarize the clinical significance of COPD-related biomarkers, their association with disease outcomes, and COPD patients’ management. Finally, we depict the various samples that are used for identifying and measuring these biomarkers.

Proinflammatory cytokines like interleukin-1β (IL-1β) affect the control of breathing. Our aim is to determine the effect of the anti-inflammatory cytokine IL-10 οn the control of breathing. IL-10 knockout mice (IL-10−/−, n = 10) and wild-type mice (IL-10+/+, n = 10) were exposed to the following test gases: hyperoxic hypercapnia 7% CO2-93% O2, normoxic hypercapnia 7% CO2-21% O2, hypoxic hypercapnia 7% CO2-10% O2, and hypoxic normocapnia 3% CO2-10% O2. The ventilatory function was assessed using whole body plethysmography. Recombinant mouse IL-10 (rIL-10; 10 μg/kg) was administered intraperitoneally to wild-type mice ( n = 10) 30 min before the onset of gas challenge. IL-10 was administered in neonatal medullary slices (10–30 ng/ml, n = 8). We found that IL-10−/−mice exhibited consistently increased frequency and reduced tidal volume compared with IL-10+/+mice during room air breathing and in all test gases (by 23.62 to 33.2%, P < 0.05 and −36.23 to −41.69%, P < 0.05, respectively). In all inspired gases, the minute ventilation of IL-10−/−mice was lower than IL-10+/+(by −15.67 to −22.74%, P < 0.05). The rapid shallow breathing index was higher in IL-10−/−mice compared with IL-10+/+mice in all inspired gases (by 50.25 to 57.5%, P < 0.05). The intraperitoneal injection of rIL-10 caused reduction of the respiratory rate and augmentation of the tidal volume in room air and also in all inspired gases (by −12.22 to −29.53 and 32.18 to 45.11%, P < 0.05, respectively). IL-10 administration in neonatal rat ( n = 8) in vitro rhythmically active medullary slice preparations did not affect either rhythmicity or peak amplitude of hypoglossal nerve discharge. In conclusion, IL-10 may induce a slower and deeper pattern of breathing.

Dimitrios Toumpanakis,1 Athanasia Chatzianastasiou,1 Vyronia Vassilakopoulou,1 Eleftheria Mizi,1 Maria Dettoraki,1 Fotis Perlikos,1 Georgia Giatra,1,2 Nikolaos Mikos,3 Stamatios Theocharis,4 Theodoros Vassilakopoulos1,2 1“Marianthi Simou” Applied Biomedical Research and Training Center, Evangelismos Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 2 3rd Department of Critical Care Medicine, Evgenideio Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 3Allergology Department, Laiko General Hospital, Athens, Greece; 4First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens, GreeceCorrespondence: Dimitrios Toumpanakis, Email dtoumpanakis@yahoo.grIntroduction: TRPV4 channels are calcium channels, activated by mechanical stress, that have been implicated in the pathogenesis of pulmonary inflammation. During resistive breathing (RB), increased mechanical stress is imposed on the lung, inducing lung injury. The role of TRPV4 channels in RB-induced lung injury is unknown.Materials and Methods: Spontaneously breathing adult male C57BL/6 mice were subjected to RB by tracheal banding. Following anaesthesia, mice were placed under a surgical microscope, the surface area of the trachea was measured and a nylon band was sutured around the trachea to reduce area to half. The specific TRPV4 inhibitor, HC-067047 (10 mg/kg ip), was administered either prior to RB and at 12 hrs following initiation of RB (preventive) or only at 12 hrs after the initiation of RB (therapeutic protocol). Lung injury was assessed at 24 hrs of RB, by measuring lung mechanics, total protein, BAL total and differential cell count, KC and IL-6 levels in BAL fluid, surfactant Protein (Sp)D in plasma and a lung injury score by histology.Results: RB decreased static compliance (Cst), increased total protein in BAL (p < 0.001), total cell count due to increased number of both macrophages and neutrophils, increased KC and IL-6 in BAL (p < 0.001 and p = 0.01, respectively) and plasma SpD (p < 0.0001). Increased lung injury score was detected. Both preventive and therapeutic HC-067047 administration restored Cst and inhibited the increase in total protein, KC and IL-6 levels in BAL fluid, compared to RB. Preventive TRPV4 inhibition ameliorated the increase in BAL cellularity, while therapeutic TRPV4 inhibition exerted a partial effect. TRPV4 inhibition blunted the increase in plasma SpD (p < 0.001) after RB and the increase in lung injury score was also inhibited.Conclusion: TRPV4 inhibition exerts protective effects against RB-induced lung injury.Keywords: resistive breathing, TRPV4, lung permeability, pulmonary inflammation

Objective There is controversy regarding the significance of radiological consolidation in the context of COPD exacerbation (eCOPD). While some studies into eCOPD exclude these cases, consolidation is a common feature of eCOPD admissions in real practice. This study aims to address the question of whether consolidation in eCOPD is a distinct clinical phenotype with implications for management decisions and outcomes. Patients and Methods The European COPD Audit was carried out in 384 hospitals from 13 European countries between 2010 and 2011 to analyze guideline adherence in eCOPD. In this analysis, admissions were split according to the presence or not of consolidation on the admission chest radiograph. Groups were compared in terms of clinical and epidemiological features, existing treatment, clinical care utilized and mortality. Results 14,111 cases were included comprising 2,714 (19.2%) with consolidation and 11,397 (80.8%) without. The risk of radiographic consolidation increased with age, female gender, cardiovascular diseases, having had two or more admissions in the previous year, and sputum color change. Previous treatment with inhaled steroids was not associated. Patients with radiographic consolidation were significantly more likely to receive antibiotics, oxygen and non-invasive ventilation during the admission and had a lower survival from admission to 90-day follow-up. Conclusions Patients admitted for COPD exacerbation who have radiological consolidation have a more severe illness course, are treated more intensively by clinicians and have a poorer prognosis. We recommend that these patients be considered a distinct subset in COPD exacerbation.

Georgios Hillas,1 Fotis Perlikos,1 Nikolaos Tzanakis2 1Department of Critical Care and Pulmonary Services, University of Athens Medical School, Evangelismos Hospital, Athens, 2Department of Thoracic Medicine, University Hospital of Heraklion, Medical School, University of Crete, Crete, Greece Abstract: Chronic obstructive pulmonary disease (COPD) is one of the top five major causes of morbidity and mortality worldwide. Despite worldwide health care efforts, costs, and medical research, COPD figures demonstrate a continuously increasing tendency in mortality. This is contrary to other top causes of death, such as neoplasm, accidents, and cardiovascular disease. A major factor affecting COPD-related mortality is the acute exacerbation of COPD (AECOPD). Exacerbations and comorbidities contribute to the overall severity in individual patients. Despite the underestimation by the physicians and the patients themselves, AECOPD is a really devastating event during the course of the disease, similar to acute myocardial infarction in patients suffering from coronary heart disease. In this review, we focus on the evidence that supports the claim that AECOPD is the “stroke of the lungs”. AECOPD can be viewed as: a Semicolon or disease’s full-stop period, Triggering a catastrophic cascade, usually a Relapsing and Overwhelming event, acting as a Killer, needing Emergent treatment. Keywords: COPD, acute exacerbation, stroke&nbsp

The purpose of this study was the development of new quantitative methodologies for the general (total) COL11A1 gene and the C transcript (RT-qPCR methods for A and E transcripts have already been developed by our group previously), the quantification of all COL11A1 transcripts and the investigation for the first time of their potential association with histopathological prognostic factors in lung cancer.Real-time RT-qPCR methodologies with dual hybridization probes were developed on the Light Cycler 1.5 platform (Roche,Germany). All COL11A1 transcripts were measured in 27 cDNA lung tissue specimens in a blinded fashion (8 control and 19 non-small cell lung cancer (NSCLC) tissues with known histopathological data). Statistical analysis was performed with the IBM SPSS program.The novel real-time RT-qPCR methodologies were appropriately validated. All 19 NSCLC samples were positive for the general COL11A1 transcript (range 11.2-1198.0 copies/μg total RNA, while 5 out of 8 control samples were negative: mean values were also statistically significantly different (p0.001). In 4 tumor samples (21%), no specific COL11A1 transcript was detected. Transcript C was detected in only 3 tumor samples. Regarding transcripts A and E, 13 out of 19 tumor samples were positive for either one (68%) and 11 for both (58%).No other statistically significant association of the specific transcripts with histopathological data was observed, most probably due to the limited number of samples. As the number of general COL11A1 transcripts/µg exceeds the sum of A+E+C transcripts in all samples, there is opportunity for discovery and identification of other transcripts as well.

Inspiratory resistive breathing (IRB), a hallmark of obstructive airway diseases, is associated with strenuous contractions of the inspiratory muscles and increased negative intrathoracic pressures that act as an injurious stimulus to the lung. We have shown that IRB induces pulmonary inflammation in healthy animals. p38 kinase is activated in the lung under stress. We hypothesized that p38 is activated during IRB and contributes to IRB-induced pulmonary inflammation. Anesthetized, tracheostomized rats breathed spontaneously through a two-way valve. Resistance was connected to the inspiratory port to provoke a peak tidal inspiratory pressure 50% of maximum. Following 3 and 6 h of IRB, respiratory system mechanics were measured and bronchoalveolar lavage (BAL) was performed. Phosphorylated p38, TNF-α, and MIP-2α were detected in lung tissue. Lung injury was estimated histologically. SB203580 (p38 inhibitor) was administered prior to IRB (1 mg kg−1). Six hours of IRB increased phosphorylated p38 in the lung, compared with quietly breathing controls (p = 0.001). Six hours of IRB increased the numbers of macrophages and neutrophils (p = 0.01 and p = 0.005) in BAL fluid. BAL protein levels and lung elasticity increased after both 3 and 6 h IRB. TNF-α and MIP-2α increased after 6 h of IRB (p = 0.01 and p

Asthma is a chronic inflammatory airways disorder mainly characterized by heterogeneity. A phenotype is defined as a group of patients that present similar clinically observable characteristics, without establishing a direct etiologic relationship with a distinct pathophysiologic mechanism. An endotype, on the other hand, describes a subgroup that shares the same pathophysiologic processes that lead to the development, the progression and the presentation of a disease. A biomarker has been defined as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacologic responses to a therapeutic intervention. Several inflammatory phenotypes have been identified by the use of biomarkers. Most of them are based on the predominant type of cells in different biological fluids with sputum to be remained the most representative one. Eosinophilia represents the major characteristic of what we called classic atopic asthma. This particular phenotype usually responds well to corticosteroids, except for a small subgroup of severe asthma where even in the presence of eosinophils the ICS seem to have a less responsive role. Neutrophilic phenotype driven by the presence of neutrophils shows inadequate response to corticosteroid treatment, even in mild asthma. The major approach in order to define an endotype is driven by three main parameters. The statistical clustering approach, use of advanced statistical mathematics to create distinct patient clusters, the specific targeted immune therapies and finally the application of omics' approach. Both phenotypes and endotypes are trying to clarify mechanisms and processes that driven the complexity of asthma. Both concepts could identify approaches which could establish new targeted to specific biomarkers treatment therapies/strategies.

Lung ischemia-reperfusion injury after thoracoabdominal aortic occlusion represents a major complication, which increases morbidity and mortality. In the present study we hypothesized that lazaroid U-74389G intravenous administration protects from lung ischemia-reperfusion injury through lipid peroxidation inhibition.A total of 24 pigs were randomized in three groups. Group I (n = 8) underwent sham operation, group II (n = 8) underwent thoracoabdominal aortic occlusion for 45min and received placebo and group III (n = 8) received 3 doses of lazaroid (3 mg/kg) 60 and 30min before thoracoabdominal aortic occlusion and at 30min during thoracoabdominal aortic occlusion (duration 45min). Aortic occlusion was performed with aortic balloon-catheters under fluoroscopic guidance. All animals were sacrificed at the 7 t h postoperative day and lung specimens were harvested for molecular analysis.mRNA levels of leukotrienes LB4 (LTB4R2), LC4 (LTC4S) and nitric oxide synthase (NOS) isoforms including iNOS, nNOS and eNOS were determined with real-time RT-qPCR. Nitric oxide can either induce (iNOS) or inhibit (nNOS and eNOS) lipid peroxidation based on its specific isoform origin. Group III showed significantly reduced mRNA levels of LTB4R2 (-63.7%), LTC4S (-35.9%) and iNOS (-60.2%) when compared with group II (P 0.05, for all). The mRNA levels of nNOS was significantly increased (+37.4%), while eNOS was slightly increased (+2.1%) in group III when compared with group II (P 0.05 and P = 0.467 respectively).Lazaroid U-74389G may represent an effective pharmacologic intervention in reducing lung ischemia-reperfusion injury following thoracoabdominal aortic occlusion.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Age and smoking are common risk factors for COPD and other illnesses, often leading COPD patients to demonstrate multiple coexisting comorbidities. COPD exacerbations and comorbidities contribute to the overall severity in individual patients. Clinical trials investigating the treatment of COPD routinely exclude patients with multiple comorbidities or advanced age. Clinical practice guidelines for a specific disease do not usually address comorbidities in their recommendations. However, the management and the medical intervention in COPD patients with comorbidities need a holistic approach that is not clearly established worldwide. This holistic approach should include the specific burden of each comorbidity in the COPD severity classification scale. Further, the pharmacological and nonpharmacological management should also include optimal interventions and risk factor modifications simultaneously for all diseases. All health care specialists in COPD management need to work together with professionals specialized in the management of the other major chronic diseases in order to provide a multidisciplinary approach to COPD patients with multiple diseases. In this review, we focus on the major comorbidities that affect COPD patients. We present an overview of the problems faced, the reasons and risk factors for the most commonly encountered comorbidities, and the burden on health care costs. We also provide a rationale for approaching the therapeutic options of the COPD patient afflicted by comorbidity.

Chronic obstructive pulmonary disease (COPD) is a major health problem worldwide, with co-morbidities contributing to the overall severity and mortality of the disease. The incidence and prevalence of cardiovascular disease among COPD patients are high. Both disorders often co-exist, mainly due to smoking, but they also share common underlying risk factors, such as aging and low-grade systemic inflammation. The therapeutic approach is based on agents, whose pharmacological properties are completely opposed. Beta2-agonists remain the cornerstone of COPD treatment due to their limited cardiac adverse effects. On the other hand, beta-blockers are administered in COPD patients with cardiovascular disease, but despite their proven cardiac benefits, they remain underused. There is still a trend among physicians over underprescription of these drugs in patients with heart failure and COPD due to bronchoconstriction. Therefore, cardioselective beta-blockers are preferred, and recent meta-analyses have shown reduced rates in mortality and exacerbations in COPD patients treated with beta-blockers.

Lung cancer remains one of the most common and malignant cancers worldwide. It is most often diagnosed at late stages, when it has already presented local invasion and distal metastases. The basic stages of invasion and metastasis involve the detachment of tumor cells from the extracellular matrix, invasion of surrounding tissues and basal lamina, intravasation into the blood stream, survival and transport through the blood stream, migration, arrest and extravasation at a distal site and formation of a metastatic lesion. These steps require fundamental mechanisms such as angiogenesis, degradation of matrix barriers, disruption of cell-cell and cell-matrix adhesion and inducement of cellular motility. Genes that regulate functions like unlimited growth potential, survival, genomic instability, angiogenesis, epithelial to mesenchymal transition and apoptosis evasion, are involved in giving lung cancer tumors invasive and metastatic competence. Improving of understanding of the underlying molecular and cellular mechanisms remains an urgent and essential issue, in order to develop new more effective strategies in preventing and treating lung cancer.

Chronic obstructive pulmonary disease (COPD) is one of the top five major causes of morbidity and mortality worldwide. Despite worldwide health care efforts, costs, and medical research, COPD figures demonstrate a continuously increasing tendency in mortality. This is contrary to other top causes of death, such as neoplasm, accidents, and cardiovascular disease. A major factor affecting COPD-related mortality is the acute exacerbation of COPD (AECOPD). Exacerbations and comorbidities contribute to the overall severity in individual patients. Despite the underestimation by the physicians and the patients themselves, AECOPD is a really devastating event during the course of the disease, similar to acute myocardial infarction in patients suffering from coronary heart disease. In this review, we focus on the evidence that supports the claim that AECOPD is the “stroke of the lungs”. AECOPD can be viewed as: a Semicolon or disease’s full-stop period, Triggering a catastrophic cascade, usually a Relapsing and Overwhelming event, acting as a Killer, needing Emergent treatment.

Inspiratory resistive breathing (RB), encountered in obstructive lung diseases, induces lung injury. The soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway is down-regulated in chronic and acute animal models of RB, such as asthma, chronic obstructive pulmonary disease, and in endotoxin-induced acute lung injury. Our objectives were to: (1) characterize the effects of increased concurrent inspiratory and expiratory resistance in mice via tracheal banding; and (2) investigate the contribution of the sGC/cGMP pathway in RB-induced lung injury. Anesthetized C57BL/6 mice underwent RB achieved by restricting tracheal surface area to 50% (tracheal banding). RB for 24 hours resulted in increased bronchoalveolar lavage fluid cellularity and protein content, marked leukocyte infiltration in the lungs, and perturbed respiratory mechanics (increased tissue resistance and elasticity, shifted static pressure–volume curve right and downwards, decreased static compliance), consistent with the presence of acute lung injury. RB down-regulated sGC expression in the lung. All manifestations of lung injury caused by RB were exacerbated by the administration of the sGC inhibitor, 1H-[1,2,4]oxodiazolo[4,3-]quinoxalin-l-one, or when RB was performed using sGCα1 knockout mice. Conversely, restoration of sGC signaling by prior administration of the sGC activator BAY 58-2667 (Bayer, Leverkusen, Germany) prevented RB-induced lung injury. Strikingly, direct pharmacological activation of sGC with BAY 58-2667 24 hours after RB reversed, within 6 hours, the established lung injury. These findings raise the possibility that pharmacological targeting of the sGC–cGMP axis could be used to ameliorate lung dysfunction in obstructive lung diseases.

Background & Objectives: During exacerbations of chronic obstructive pulmonary disease (COPD), increased airway inflammation and the accompanying bronchoconstriction lead to significant airway narrowing, i.e. resistive breathing (RB).To isolate the effects of mechanical stressor (i.e. RB) from the accompanying lung inflammation we developed an experimental model of RBthat exhibits both increased inspiratory and expiratory airway resistance, via tracheal banding . Since hydrogen sulphide (H 2 S) plays an important role in vasodilation and inflammation we hypothesized that the administration of a H 2 S fast releasing donor, Na 2 S, will attenuate the lung inflammation. Methods: C57BL/6 mice were studied: 1. Sham operated (controls) 2. Tracheal banded (TB) mice (tracheal surface area restricted to 50% of initial) 3. Sham operated mice treated with injected Na 2 S (10mg/kg) 4. Mice treated with injected Na 2 S 20 min prior to tracheal banding. Results: The proteinexpression of the three H 2 S synthesizing enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulphurtransferase (3MST), was the same between the TB and sham operated group in the lung. However, the lung mRNA level of CBS was decreased by 57% in TB mice (p=0.009). Finally interleukin IL-6 and IL-1β, were attenuated by 50% (p=0.004)and 45% (p=0.02)in the group of TB mice treated with Na 2 S compared to the TB mice, whereas the expression of TNF-α was the same among the groups. Conclusions: H 2 S ameliorates lung inflammation caused by airway narrowing. Our model of TB might offer new insights by which resistive breathing can enhance inflammation in obstructive lung disease.