Terttu Harju

Cold temperature and low humidity are associated with increased occurrence of respiratory tract infections.

OBJECTIVE The association between cold exposure and acute respiratory tract infections (RTIs) has remained unclear. The study examined whether the development of RTIs is potentiated by cold exposure and lowered humidity in a northern population. METHODS A population study where diagnosed RTI episodes, outdoor temperature and humidity among conscripts (n=892) were analysed. RESULTS Altogether 643 RTI episodes were diagnosed during the follow-up period. Five hundred and ninety-five episodes were upper (URTI) and 87 lower (LRTI) RTIs. The mean average daily temperature preceding any RTIs was -3.7+/-10.6; for URTI and LRTI they were -4.1+/-10.6 degrees C and -1.1+/-10.0 degrees C, respectively. Temperature was associated with common cold (p=0.017), pharyngitis (p=0.011) and LRTI (p=0.048). Absolute humidity was associated with URTI (p<0.001). A 1 degrees C decrease in temperature increased the estimated risk for URTI by 4.3% (p<0.0001), for common cold by 2.1% (p=0.004), for pharyngitis by 2.8% (p=0.019) and for LRTI by 2.1% (p=0.039). A decrease of 1g/m(-3) in absolute humidity increased the estimated risk for URTI by 10.0% (p<0.001) and for pharyngitis by 10.8% (p=0.023). The average outdoor temperature decreased during the preceding three days of the onset of any RTIs, URTI, LRTI or common cold. The temperature for the preceding 14 days also showed a linear decrease for any RTI, URTI or common cold. Absolute humidity decreased linearly during the preceding three days before the onset of common cold, and during the preceding 14 days for all RTIs, common cold and LRTI. CONCLUSIONS Cold temperature and low humidity were associated with increased occurrence of RTIs, and a decrease in temperature and humidity preceded the onset of the infections.

Pathogenic bacteria and viruses in induced sputum or pharyngeal secretions of adults with stable asthma

Background: Respiratory infections are well known triggers of asthma exacerbations, but their role in stable adult asthma remains unclear. Methods: 103 asthmatics and 30 control subjects were enrolled in the study. Sputum was induced by inhalation of 3% NaCl solution. Oropharyngeal swab specimens were obtained from the posterior wall of the oropharynx. Respiratory specimens were analysed by RT-PCR for rhinovirus, enterovirus and respiratory syncytial virus and by PCR for adenovirus, Chlamydia pneumoniae, Mycoplasma pneumoniae and Bordetella pertussis. Results: Sputum samples from two of the 30 healthy controls (6.7%), five of 53 patients with mild asthma (9.4%), and eight of 50 with moderate asthma (16.0%) were positive for rhinovirus. Rhinovirus positive asthmatic subjects had more asthma symptoms and lower forced expiratory volume in 1 second (FEV1) (79% predicted) than rhinovirus negative cases (93.5% predicted; p = 0.020). Chlamydia pneumoniae PCR was positive in 11 healthy controls (36.6%), 11 mild asthmatics (20.8%), and 11 moderate asthmatics (22%), and PCR positive asthmatics had lower FEV1/FVC than negative cases (78.2% v 80.8%, p = 0.023). Bordetella pertussis PCR was positive in 30 cases: five healthy controls (16.7%), 15 mild asthmatics (28.3%), and 10 moderate asthmatics (20%). Bordetella pertussis positive individuals had lower FEV1/FVC (77.1% v 80.7%, p = 0.012) and more asthma symptoms than B pertussis negative cases. Conclusions: Rhinovirus, C pneumoniae, and B pertussis are found in the sputum or pharyngeal swab specimens of asthmatic subjects without concurrent symptoms of infection or asthma exacerbation, as well as in some healthy controls. Positivity is associated with lower lung function and more frequent asthma symptoms.

Modulation of glutaredoxin in the lung and sputum of cigarette smokers and chronic obstructive pulmonary disease

BackgroundOne typical feature in chronic obstructive pulmonary disease (COPD) is the disturbance of the oxidant/antioxidant balance. Glutaredoxins (Grx) are thiol disulfide oxido-reductases with antioxidant capacity and catalytic functions closely associated with glutathione, the major small molecular weight antioxidant of human lung. However, the role of Grxs in smoking related diseases is unclear.MethodsImmunohistochemical and Western blot analyses were conducted with lung specimens (n = 45 and n = 32, respectively) and induced sputum (n = 50) of healthy non-smokers and smokers without COPD and at different stages of COPD.ResultsGrx1 was expressed mainly in alveolar macrophages. The percentage of Grx1 positive macrophages was significantly lower in GOLD stage IV COPD than in healthy smokers (p = 0.021) and the level of Grx1 in total lung homogenate decreased both in stage I–II (p = 0.045) and stage IV COPD (p = 0.022). The percentage of Grx1 positive macrophages correlated with the lung function parameters (FEV1, r = 0.45, p = 0.008; FEV1%, r = 0.46, p = 0.007, FEV/FVC%, r = 0.55, p = 0.001). Grx1 could also be detected in sputum supernatants, the levels being increased in the supernatants from acute exacerbations of COPD compared to non-smokers (p = 0.013) and smokers (p = 0.051).ConclusionThe present cross-sectional study showed that Grx1 was expressed mainly in alveolar macrophages, the levels being decreased in COPD patients. In addition, the results also demonstrated the presence of Grx1 in extracellular fluids including sputum supernatants. Overall, the present study suggests that Grx1 is a potential redox modulatory protein regulating the intracellular as well as extracellular homeostasis of glutathionylated proteins and GSH in human lung.

Diagnosis and Pharmacotherapy of Stable Chronic Obstructive Pulmonary Disease: The Finnish Guidelines

The Finnish Medical Society Duodecim initiated and managed the update of the Finnish national guideline for chronic obstructive pulmonary disease (COPD). The Finnish COPD guideline was revised to acknowledge the progress in diagnosis and management of COPD. This Finnish COPD guideline in English language is a part of the original guideline and focuses on the diagnosis, assessment and pharmacotherapy of stable COPD. It is intended to be used mainly in primary health care but not forgetting respiratory specialists and other healthcare workers. The new recommendations and statements are based on the best evidence available from the medical literature, other published national guidelines and the GOLD (Global Initiative for Chronic Obstructive Lung Disease) report. This guideline introduces the diagnostic approach, differential diagnostics towards asthma, assessment and treatment strategy to control symptoms and to prevent exacerbations. The pharmacotherapy is based on the symptoms and a clinical phenotype of the individual patient. The guideline defines three clinically relevant phenotypes including the low and high exacerbation risk phenotypes and the neglected asthma–COPD overlap syndrome (ACOS). These clinical phenotypes can help clinicians to identify patients that respond to specific pharmacological interventions. For the low exacerbation risk phenotype, pharmacotherapy with short-acting β2-agonists (salbutamol, terbutaline) or anticholinergics (ipratropium) or their combination (fenoterol–ipratropium) is recommended in patients with less symptoms. If short-acting bronchodilators are not enough to control symptoms, a long-acting β2-agonist (formoterol, indacaterol, olodaterol or salmeterol) or a long-acting anticholinergic (muscarinic receptor antagonists; aclidinium, glycopyrronium, tiotropium, umeclidinium) or their combination is recommended. For the high exacerbation risk phenotype, pharmacotherapy with a long-acting anticholinergic or a fixed combination of an inhaled glucocorticoid and a long-acting β2-agonist (budesonide–formoterol, beclomethasone dipropionate–formoterol, fluticasone propionate–salmeterol or fluticasone furoate–vilanterol) is recommended as a first choice. Other treatment options for this phenotype include combination of long-acting bronchodilators given from separate inhalers or as a fixed combination (glycopyrronium–indacaterol or umeclidinium–vilanterol) or a triple combination of an inhaled glucocorticoid, a long-acting β2-agonist and a long-acting anticholinergic. If the patient has severe-to-very severe COPD (FEV1 < 50% predicted), chronic bronchitis and frequent exacerbations despite long-acting bronchodilators, the pharmacotherapy may include also roflumilast. ACOS is a phenotype of COPD in which there are features that comply with both asthma and COPD. Patients belonging to this phenotype have usually been excluded from studies evaluating the effects of drugs both in asthma and in COPD. Thus, evidence-based recommendation of treatment cannot be given. The treatment should cover both diseases. Generally, the therapy should include at least inhaled glucocorticoids (beclomethasone dipropionate, budesonide, ciclesonide, fluticasone furoate, fluticasone propionate or mometasone) combined with a long-acting bronchodilator (β2-agonist or anticholinergic or both).

Divergent expression of claudin -1, -3, -4, -5 and -7 in developing human lung

BackgroundClaudins are the main components of tight junctions, structures which are associated with cell polarity and permeability. The aim of this study was to analyze the expression of claudins 1, 3, 4, 5, and 7 in developing human lung tissues from 12 to 40 weeks of gestation.Methods47 cases were analyzed by immunohistochemisty for claudins 1, 3, 4, 5 and 7. 23 cases were also investigated by quantitative RT-PCR for claudin-1, -3 and -4.ResultsClaudin-1 was expressed in epithelium of bronchi and large bronchioles from week 12 onwards but it was not detected in epithelium of developing alveoli. Claudin-3, -4 and -7 were strongly expressed in bronchial epithelium from week 12 to week 40, and they were also expressed in alveoli from week 16 to week 40. Claudin-5 was expressed strongly during all periods in endothelial cells. It was expressed also in epithelium of bronchi from week 12 to week 40, and in alveoli during the canalicular period. RT-PCR analyses revealed detectable amounts of RNAs for claudins 1, 3 and 4 in all cases studied.ConclusionClaudin-1, -3, -4, -5, and -7 are expressed in developing human lung from week 12 to week 40 with distinct locations and in divergent quantities. The expression of claudin-1 was restricted to the bronchial epithelium, whereas claudin-3, -4 and -7 were positive also in alveolar epithelium as well as in the bronchial epithelium. All claudins studied are linked to the development of airways, whereas claudin-3, -4, -5 and -7, but not claudin-1, are involved in the development of acinus and the differentiation of alveolar epithelial cells.

Nuclear factor erythroid-derived 2-like 2 (Nrf2) and DJ1 are prognostic factors in lung cancer

Nuclear factor erythroid-derived 2-like 2 (Nrf2) controls the expression of several enzymes that are protective against oxidative stress. We investigated the expression of nuclear factor erythroid-derived 2-like 2, DJ1 (Nrf2 stabilizer), and sulfiredoxin in a large set of lung carcinomas. The cases were analyzed immunohistochemically with antibodies to nuclear factor erythroid-derived 2-like 2, DJ1, and sulfiredoxin with the results being compared with histologic and clinical data. Significant differences were observed in the expression of DJ1 and sulfiredoxin between various types of lung tumors, while expression of nuclear factor erythroid-derived 2-like 2 was more constant. Patients with tumors with cytoplasmic (P = .033) or nuclear (P = .003) DJ1 positivity exhibited worse survival. Separately in squamous cell carcinomas, there was a tendency toward worse survival with both cytoplasmic (P = .013) and nuclear (P = .071) DJ1 positivity. Patients with a strong nuclear factor erythroid-derived 2-like 2 expression in their tumors had worse survival (P = .006). In the Cox regression analysis, nuclear factor erythroid-derived 2-like 2 was an independent prognostic factor (P = .012) along with the T status (P = .008) and DJ1 cytoplasmic positivity (P = .028). Interestingly, smokers and ex-smokers had significantly more sulfiredoxin expression in their tumors (P < .001); and in patients receiving cytostatic drugs or radiation therapy, sulfiredoxin expression predicted a poor prognosis (P = .038). Nuclear factor erythroid-derived 2-like 2 and its stabilizing protein DJ1 affect the prognosis of patients with lung cancer by inducing an elevated stress response to oxidative damage. There were differences in the expression of sulfiredoxin and DJ1 between different lung tumor types, suggesting that the pathways involved in combating oxidative stress vary in different lung cancer types.

Pneumococcal carriage is more common in asthmatic than in non-asthmatic young men.

Introduction:  The aim was to investigate the prevalence of oropharyngeal carriage of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Neisseria meningitidis and beta‐haemolytic streptococci among asthmatic and non‐asthmatic young Finnish men and to identify putative risk factors.

Snail promotes an invasive phenotype in lung carcinoma

BackgroundSnail is a transcriptional factor which is known to influence the epitheliomesenchymal transition (EMT) by regulating adhesion proteins such as E-cadherin and claudins as well as matrix metalloproteases (MMP).MethodsTo evaluate the functional importance of snail, a transciptional factor involved in EMT in lung tumors, we investigated its expression in a large set of lung carcinomas by immunohistochemistry. Expression of snail and effects of snail knockdown was studied in cell lines.ResultsNuclear snail expression was seen in 21% of cases this being strongest in small cell lung carcinomas (SCLC). There was significantly greater snail expression in SCLC compared to squamous cell or adenocarcinoma. Positive snail expression was associated with poor survival in the whole material and separately in squamous cell and adenocarcinomas. In Cox regression analysis, snail expression showed an independent prognostic value in all of these groups. In several cell lines knockdown of snail reduced invasion in both matrigel assay and in the myoma tissue model for invasion. The influence of snail knockdown on claudin expression was cell type specific. Snail knockdown in these cell lines modified the expression of MMP2 and MMP9 but did not influence the activation of these MMPs to any significant degree.ConclusionsThe results show that snail plays an important role in the invasive characteristics of lung carcinoma influencing the survival of the patients. Snail knockdown might thus be one option for targeted molecular therapy in lung cancer. Snail knockdown influenced the expression of claudins individually in a cell-line dependent manner but did not influence MMP expressions or activations to any significant degree.

Pneumococcal carriage is more common in asthmatic than in non-asthmatic young men

Introduction:  The aim was to investigate the prevalence of oropharyngeal carriage of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Neisseria meningitidis and beta‐haemolytic streptococci among asthmatic and non‐asthmatic young Finnish men and to identify putative risk factors.

Glutathione S-transferase omega in the lung and sputum supernatants of COPD patients

BackgroundThe major contribution to oxidant related lung damage in COPD is from the oxidant/antioxidant imbalance and possibly impaired antioxidant defence. Glutathione (GSH) is one of the most important antioxidants in human lung and lung secretions, but the mechanisms participating in its homeostasis are partly unclear. Glutathione-S-transferase omega (GSTO) is a recently characterized cysteine containing enzyme with the capability to bind and release GSH in vitro. GSTO has not been investigated in human lung or lung diseases.MethodsGSTO1-1 was investigated by immunohistochemistry and Western blot analysis in 72 lung tissue specimens and 40 sputum specimens from non-smokers, smokers and COPD, in bronchoalveolar lavage fluid and in plasma from healthy non-smokers and smokers. It was also examined in human monocytes and bronchial epithelial cells and their culture mediums in vitro.ResultsGSTO1-1 was mainly expressed in alveolar macrophages, but it was also found in airway and alveolar epithelium and in extracellular fluids including sputum supernatants, bronchoalveolar lavage fluid, plasma and cell culture mediums. The levels of GSTO1-1 were significantly lower in the sputum supernatants (p = 0.023) and lung homogenates (p = 0.003) of COPD patients than in non-smokers.ConclusionGSTO1-1 is abundant in the alveolar macrophages, but it is also present in extracellular fluids and in airway secretions, the levels being decreased in COPD. The clinical significance of GSTO1-1 and its role in regulating GSH homeostasis in airway secretions, however, needs further investigations.