Telemonitoring in Chronic Obstructive Pulmonary Disease (CHROMED). A Randomized Clinical Trial.

RATIONALE: Early detection of chronic obstructive pulmonary disease (COPD) exacerbations using telemonitoring of physiological variables might reduce the frequency of hospitalization. OBJECTIVES: To evaluate the efficacy of home monitoring of lung mechanics by the forced oscillation technique and cardiac parameters in older patients with COPD and comorbidities. METHODS: This multicenter, randomized clinical trial recruited 312 patients with Global Initiative for Chronic Obstructive Lung Disease grades II to IV COPD (median age, 71 yr [interquartile range, 66-76 yr]; 49.6% grade II, 50.4% grades III-IV), with a history of exacerbation in the previous year and at least one nonpulmonary comorbidity. Patients were randomized to usual care (n = 158) or telemonitoring (n = 154) and followed for 9 months. All telemonitoring patients self-assessed lung mechanics daily, and in a subgroup with congestive heart failure (n = 37) cardiac parameters were also monitored. An algorithm identified deterioration, triggering a telephone contact to determine appropriate interventions. MEASUREMENTS AND MAIN RESULTS: Primary outcomes were time to first hospitalization (TTFH) and change in the EuroQoL EQ-5D utility index score. Secondary outcomes included: rate of antibiotic/corticosteroid prescription; hospitalization; the COPD Assessment Tool, Patient Health Questionnaire-9, and Minnesota Living with Heart Failure questionnaire scores; quality-adjusted life years; and healthcare costs. Telemonitoring did not affect TTFH, EQ-5D utility index score, antibiotic prescriptions, hospitalization rate, or questionnaire scores. In an exploratory analysis, telemedicine was associated with fewer repeat hospitalizations (-54%; P = 0.017). CONCLUSIONS: In older patients with COPD and comorbidities, remote monitoring of lung function by forced oscillation technique and cardiac parameters did not change TTFH and EQ-5D. Clinical trial registered with www.clinicaltrials.gov (NCT 01960907).

Sarcoidosis and chronic hepatitis C: a case report.

Several case reports deal with the relationship between hepatitis C virus (HCV) infection and pulmonary or hepatic sarcoidosis. Most publications describe interferon α-induced sarcoidosis. However, HCV infection per se is also suggested to cause sarcoidosis. The present case report describes a case of biopsy-verified lung and liver sarcoidosis and HCV infection, and the outcome of antiviral therapy. In March 2009, a 25-year-old man presented with moderately elevated liver enzymes without any clinical symptoms. The patient was positive for HCV antibodies and HCV RNA of genotype 1b. Four months later the patient became dyspnoic and pulmonary sarcoidosis was diagnosed by lung biopsy and radiography. A short course of corticosteroid treatment relieved symptoms. Three months later, liver biopsy showed noncaseating granulomas consisting of epithelioid histiocytes and giant cells with a small amount of peripheral lymphocyte infiltration, without any signs of fibrosis. Chronic HCV infection with coexistence of pulmonary and hepatic sarcoidosis was diagnosed. Antiviral therapy with peginterferon α and ribavirin at standard doses was started, which lasted 48 wk, and sustained viral response was achieved. A second liver biopsy showed disappearance of granulomas and chest radiography revealed normalization of mediastinal and perihilar glands. The hypothesis that HCV infection per se may have triggered systemic sarcoidosis was proposed. Successful treatment of HCV infection led to continuous remission of pulmonary and hepatic sarcoidosis. Further studies are required to understand the relationship between systemic sarcoidosis and HCV infection.

Mucin5B expression by lung alveolar macrophages is increased in long-term smokers.

This study investigated the expression of MUC5B by AMs in the lungs of cigarette smokers and nonsmokers. We analyzed MUC5B expression by measuring the levels of apomucin and mRNA in human BALF cells from 50 subjects (20 nonsmokers, 17 patients with CB, and 13 patients with COPD). apoMUC5B was observed in BALF mononuclear cells in 60% of all subjects, but a significantly higher frequency of apoMUC5B(+) cells was found in subjects with CB (95% CI, 4.5-24.9) or COPD (95% CI, 6.2-39.6) than in nonsmokers (95% CI, 0.5-2.5). apoMUC5B(+) mononuclear cells showed strong expression of CD163, confirming their identity as AMs. MUC5B mRNA expression was detected by ISH in AMs of subjects investigated, and real-time qPCR analysis confirmed MUC5B mRNA expression. In conclusion, MUC5B is expressed in a subset of lung AMs and long-term cigarette smoking may increase the level of MUC5B produced by these cells.

Understanding drug uptake and binding within targeted disease micro-environments in patients: a new tool for translational medicine.

BACKGROUND: For many common global diseases, such as cancer, diabetes, neurodegenerative and cardiovascular diseases there is an unmet need for diagnosing early indications of disease that could enable medical intervention and early treatment. The treatment of these diseases will require detailed knowledge of targeted pathways involved in disease pathogenesis but also the mode of drug actions at the biological location on these targets. Translational medicine is a new area of research where expert from different disciplines involved in basic science and clinical disciplines meet and join forces. Mode-of-drug-action mechanisms elucidation is key in the characterization of drugs that can relate to both efficacy and safety. METHODS: Matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was used providing evidence into the fate (destinations and distributions) of administered drugs within tumor regions of lung compartments. RESULTS: We hereby present a pulmonary study in which we have isolated lung tissue after inhaled drug administration and then localized the drug within airway wall compartments. The histology also provides evidence of drug binding to smooth muscle cell microenvironments. We also identified lung tissue regions with tumor cell invasion in these COPD patients. CONCLUSIONS: The ultimate goal is to identify bridging comprehension that forms a knowledge base that can be used by society to develop a better treatment and medicine for patients. Our results demonstrated that robust imaging data could be generated confirming drug localization in pulmonary regions of COPD patients with tumor pathology. TRIAL REGISTRATION: Tallinn Medical Research Ethical Committee decision #1724, 18.06.2009.

Direct demonstration of tissue uptake of an inhaled drug: proof-of-principle study using matrix-assisted laser desorption ionization mass spectrometry imaging.

Drug therapy is often directed to specific organ and tissue compartments where the mode of action of the compound affects specifically targeted biological processes. However, the direct measurement of drug uptake in terms of a time kinetic and concentrations attained at the local sites has not been readily available as a clinical index for most drugs. A proof-of-principle study was conducted to test the utility of applying matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) to demonstrate the qualitative distribution pattern of a locally administered drug within tissue sites of targeted action. Here we have measured the occurrence of an inhaled bronchodilator, the muscarinic receptor antagonist ipratropium, within human bronchial biopsies obtained by fiber optic bronchoscopy shortly after dosing exposure. Cryo-preserved biopsy samples from five subjects being evaluated for airway obstruction or potential tumor development were prepared as thin frozen sections. Samples coated with a MALDI matrix were analyzed by a MALDI LTQ Orbitrap XL mass spectrometer at large (100 µm) and small (30 µm) raster sizes. Our results demonstrate that ipratropium is rapidly absorbed into the airway wall. Ipratropium parent ion (m/z 332.332) and daughter ions (m/z 166.2 and 290.2) were coincidently partitioned within submucosal spaces containing targeted airway smooth muscle in four out of five subjects. The signal intensity of ipratropium fragment ions provided estimates that local drug concentrations between 3 and 80 nM were achieved within the airway wall. To our knowledge, this is the first reported study in applying MALDI-MSI to demonstrate the localization of a drug administered at therapeutic levels. The study highlights the potential benefit of MALDI-MSI to provide important measurements of drug efficacy in clinical settings.

Lung dysfunction of chronic smokers with no signs of COPD.

Cigarette smoking causes airflow limitation with lung hyperinflation being the primary causes of COPD. Fifty chronic smokers (CSs) with no signs of GOLD-adjusted COPD with smoking habit at least ≥10 pack-years (p/yrs) were divided into CS-mild (n = 24) with smoking history from ≥10 to ≤20 p/yrs and CS-heavy groups (n = 26) with smoking history ≥21 p/yrs. Spirometry, plethysmography and diffusing capacity were measured and lung computed tomography (CT) was performed. Residual volume (RV) (L) and RV/TLC (total lung capacity) ratio were significantly increased in CS-heavy when compared to CS-mild (p = 0.001, p = 0.03). A significant reduction of forced expiratory volume in 1 second/forced vital capacity (FEV(1)/FVC) ratio and airway specific conductance was shown in CS-heavy (p = 0.02, p = 0.03). Lung emphysema signs at CTs were revealed in 17 CSs and ten of them had declined diffusing capacity below 70% of predicted. The percentage of emphysematous lesions inversely and significantly correlated with measured diffusing capacity (p = 0.0009, r = --0.72). Study groups' smoking intensity inversely correlated the declined airway specific conductance (p = 0.004, r = --0.39) and increase of the RV (L) (p = 0.0004, r = 0.46). Multiple regression analysis determined that smoking intensity regardless of the subjects' age was significant factor for decline of airway specific conductance and increase of RV (L). Here we conclude that lung function deviation and lung structural changes are present in CSs before the clinical signs of airway obstruction reveal. Body plethysmography and diffusing capacity measurement with routine spirometry can provide valuable information for detection of changes reflecting to the early onset of COPD in CSs.

Proteomics: is it an approach to understand the progression of chronic lung disorders?

Tissue injury, mediated by pathologically elevated production and action of various serine- and matrix metalloproteinases (MMPs), is a hallmark of chronic inflammatory airway diseases (CIAD). CIAD includes such diseases as bronchial asthma, bronchiectasis, and chronic obstructive pulmonary disease. Tissue injury, as a consequence of chronic inflammation, can disturb the relevant repair mechanisms and also result in irreversible alteration of lung architecture. By use of proteomic methods, we analyzed proteinase cascades as an initiator of tissue destruction in CIAD. The present results revealed that elevated levels of MMP-8, -13, -14, and -2, mainly in active forms, can also be detected in CIAD BALFs. Enhanced levels of different active MMPs evidently reflect ongoing tissue-destructive inflammation and airway remodeling occurring in CIAD lung. An inverse correlation between BALF MMP-8 levels and activation degree and airflow obstruction in bronchial asthma tissue injury was shown for the first time. This strongly indicates that chronic peri-inflammatory tissue injury is a main cause of decline of lung functional capacity. Together, these data suggest that the serine and MMP proteinase network is an important feature in predicting clinical worsening of airway obstruction in CIAD. Activation of elevated MMPs seems to have a common profile for all studied CIAD, but different lung disorders react differently to ICS treatment.

Airway obstruction correlates with collagenase-2 (MMP-8) expression and activation in bronchial asthma.

Matrix metalloproteinases (MMPs) contribute to extracellular matrix and basement membrane degradation in asthma. The present study analyzed molecular forms and degree of activation and expression of MMP-8 in bronchoalveolar lavage fluid (BALF), BALF cells, and bronchial tissue specimens from 14 steroid-naive asthma patients, 13 uncontrolled severe asthma patients, 13 controlled asthma patients, and 14 healthy subjects by Western immunoblotting, immunohistochemistry, and in situ hybridization. Immunohistochemistry and in situ hybridization revealed a prominent MMP-8 immunoreactivity in submucosal inflammatory, glandular, and shed, but not in intact bronchial epithelial cells of asthma patients. In BALF cytospins, both MMP-8 protein and mRNA expression were observed in epithelial cells, macrophages, and polymorphonuclear leukocytes (PMNs). MMP-8 was present in BALFs asthma patients in complex, pro- and active PMN-type, and pro- and active non-PMN-type forms. BALF MMP-8 was significantly converted to active form only in BALFs from steroid-naive and uncontrolled severe asthma patients, but not in BALFs from well-controlled asthma patients or healthy controls. A significant inverse correlation between BALF MMP-8 levels and FEV1 (r = -0.283, p = 0.04), and BALF activated MMP-8 forms and FEV1 (r = -0.427, p = 0.001) was detected. Overall, these data suggest that MMP-8 and its activation has an important role in the airway destruction, healing, remodeling, and treatment response in asthma.

Chemically modified tetracycline (CMT-8) and estrogen promote wound healing in ovariectomized rats: effects on matrix metalloproteinase-2, membrane type 1 matrix metalloproteinase, and laminin-5 gamma2-chain.

Estrogen deficiency is associated with impaired cutaneous wound healing. Remodeling of the extracellular matrix in wound healing involves the action of matrix metalloproteinases on basement membrane zone components, especially laminin-5. We studied the effects of estrogen and a potent matrix metalloproteinase inhibitor, chemically modified non-antimicrobial tetracycline, CMT-8, on wound healing in ovariectomized rats. At the tissue level, laminin-5 gamma2-chain expression was decreased and the migration-inductive 80 kDa form of laminin-5 gamma2-chain was absent in ovariectomized rats when compared with sham and CMT-8- or estrogen-treated ovariectomized animals as detected by Western blotting. The highest levels of gelatinolytic activity (matrix metalloproteinase-2 and -9) were found in sham animals. Levels were reduced in ovariectomized rats and were lowest after treating ovariectomized rats with CMT-8 or estrogen as analyzed by functional activity assay and zymography. The total amount of membrane type 1-matrix metalloproteinase was unchanged in all groups. We conclude that CMT-8 and estrogen can promote wound healing in ovariectomized rats, not only by normalizing wound bed total collagen content and structure, but also by recovering the expression and processing of key molecules in wound healing, i.e., laminin-5 gamma2-chain. This study shows, for the first time, the role of estrogen and CMT-8 in laminin-5 gamma2-chain modulation in vivo.

Soluble membrane-type 1 matrix metalloproteinase (MT1-MMP) and gelatinase A (MMP-2) in induced sputum and bronchoalveolar lavage fluid of human bronchial asthma and bronchiectasis.

The aim of this study was to investigate the involvement of the MT1-MMP/MMP-2 cascade in induced sputum (IS) and bronchoalveolar lavage fluid (BALF) from bronchial asthma (BA) and bronchiectasis (BE) patients and healthy controls. The molecular forms and cellular origins of MT1-MMP and MMP-2 were determined by Western immunoblotting, immunohistochemistry and in situ hybridization. Elevated levels of soluble activated and autocatalyzed MT1-MMP species as well as activated forms of MMP-2 in IS and BALF samples from BA and BE patients were evidenced. The activation degrees of soluble MT1-MMP and MMP-2 were significantly correlated in BA and BE IS and BALF. Only low levels of both these MMPs were observed in healthy control IS and BALF. The co-expression of MMP-2 with MT1-MMP was evidenced by double immunostaining in bronchial epithelial cells, submucosal glandular cells, smooth muscle cells and monocyte/macrophages. The MT1-MMP/MMP-2 cascade is present and active in human inflammatory lung disease fluid and tissue samples. This cascade seemingly reflects the active destructive phases of these chronic lung diseases.