Adipokine resistin predicts anti-inflammatory effect of glucocorticoids in asthma

<p>Abstract</p> <p>Background</p> <p>Adipokines are protein mediators secreted by adipose tissue. Recently, adipokines have also been involved in the regulation of inflammation and allergic responses, and suggested to affect the risk of asthma especially in obese female patients. We assessed if adipokines predict responsiveness to glucocorticoids and if plasma adipokine levels are associated with lung function or inflammatory activity also in non-obese (body mass index (BMI) ≤ 30 kg/m²) women with newly-diagnosed steroid-naïve asthma.</p> <p>Methods</p> <p>Lung function, exhaled NO, plasma levels of adipokines leptin, resistin, adiponectin and adipsin, and inflammatory markers were measured in 35 steroid-naïve female asthmatics and in healthy controls. The measurements were repeated in a subgroup of asthmatics after 8 weeks of treatment with inhaled fluticasone. Adipokine concentrations in plasma were adjusted for BMI.</p> <p>Results</p> <p>High baseline resistin concentrations were associated with a more pronounced decrease in serum levels of eosinophil cationic protein (ECP) (r = -0.745, p = 0.013), eosinophil protein X (EPX) (r = -0.733, p = 0.016) and myeloperoxidase (MPO) (r = -0.721, p = 0.019) during fluticasone treatment. In asthmatics, leptin correlated positively with asthma symptom score and negatively with lung function. However, no significant differences in plasma adipokine levels between non-obese asthmatics and healthy controls were found. The effects of resistin were also investigated in human macrophages in cell culture. Interestingly, resistin increased the production of proinflammatory factors IL-6 and TNF-α and that was inhibited by fluticasone.</p> <p>Conclusions</p> <p>High resistin levels predicted favourable anti-inflammatory effect of inhaled glucocorticoids suggesting that resistin may be a marker of steroid-sensitive phenotype in asthma. High leptin levels were associated with a more severe disease suggesting that the link between leptin and asthma is not restricted to obesity.</p

Adiponectin is associated with dynamic hyperinflation and a favourable response to inhaled glucocorticoids in patients with COPD

SummaryObjectivesAdipokines are protein mediators first described as products of adipose tissue regulating energy metabolism and appetite. Recently, adipokines have also been found to modulate inflammation and smooth muscle cell responses. Therefore we investigated the association of two adipokines, adiponectin and leptin, with the degree of emphysema, pulmonary function, symptoms and glucocorticoid responsiveness in patients with COPD.MethodsPlasma adiponectin and leptin levels, spirometry, body plethysmography and symptoms were measured in 43 male COPD patients with smoking history ≥ 20 pack-years, post bronchodilator FEV1/FVC < 0.7 and pulmonary emphysema on HRCT. The measurements were repeated in a subgroup of patients after 4 weeks' treatment with inhaled fluticasone.ResultsIn patients with COPD, plasma adiponectin levels correlated positively with airway resistance (Raw) (r = 0.362, p = 0.019) and functional residual capacity (FRC) (r = 0.355, p = 0.046). Furthermore, the baseline adiponectin concentration correlated negatively with the fluticasone induced changes in St George's Respiratory questionnaire (SGRQ) symptom score (r = −0.413, p = 0.040) and in FRC % pred (r = −0.428, p = 0.003), i.e. a higher baseline plasma adiponectin level was associated with more pronounced alleviation of symptoms and dynamic hyperinflation. Plasma leptin levels were not related to the measures of lung function, symptoms or glucocorticoid responsiveness.ConclusionsPlasma adiponectin levels were associated with peripheral airway obstruction and dynamic hyperinflation in patients with COPD. A higher adiponectin level predicted more favourable relief of symptoms and hyperinflation during glucocorticoid treatment. Adiponectin may have a role in the COPD pathogenesis; it may also be a biomarker of disease severity and treatment responses in this disease

Specialist Palliative Care Consultation for Patients with Nonmalignant Pulmonary Diseases : A Retrospective Study

publishedVersionPeer reviewe

Adipokines NUCB2/nesfatin-1 and visfatin as novel inflammatory factors in chronic obstructive pulmonary disease

COPD (chronic obstructive pulmonary disease) is a common lung disease characterized by airflow limitation and systemic inflammation. Recently, adipose tissue mediated inflammation has gathered increasing interest in the pathogenesis of the disease. In this study, we investigated the role of novel adipocytokines nesfatin-1 and visfatin in COPD by measuring if they are associated with the inflammatory activity, lung function, or symptoms. Plasma levels of NUCB2/nesfatin-1 and visfatinweremeasured together with IL-6, IL-8, TNF-, andMMP-9, lung function, exhaled nitric oxide, and symptoms in 43 male patients with emphysematous COPD. The measurements were repeated in a subgroup of the patients after four weeks’ treatment with inhaled fluticasone. Both visfatin and NUCB2/nesfatin-1 correlated positively with plasma levels of IL-6 ( = 0.341, = 0.027 and rho = 0.401, = 0.008, resp.) and TNF- ( = 0.305, = 0.052 and rho = 0.329, = 0.033, resp.) and NUCB2/nesfatin-1 also with IL-8 (rho = 0.321, = 0.036) in patients with COPD. Further, the plasma levels of visfatin correlated negatively with pulmonary diffusing capacity ( = −0.369, = 0.016). Neither of the adipokines was affected by fluticasone treatment and they were not related to steroid-responsiveness.The present results introduce adipocytokines NUCB2/nesfatin-1 and visfatin as novel factors associated with systemic inflammation in COPD and suggest that visfatin may mediate impaired pulmonary diffusing capacity.Copyright © 2014 Sirpa Leivo-Korpela et al. This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Adipokiinit tulehduksellisissa keuhkosairauksissa

Lihavuushormoni adipokiinit keuhkosairauksissa Tulehdusreaktiolla on keskeinen merkitys astman ja keuhkoahtaumataudin sekä asbestialtistuksen aiheuttaman keuhkofibroosin synnyssä. Käytännön työhön tarvitaan uusia merkkiaineita, joita mittaamalla voitaisiin havaita taudin tulehduksellinen aktiivisuus ja tunnistaa taudinkuvaltaan, ennusteeltaan ja hoitovasteeltaan toisistaan eroavat astman ja keuhkoahtaumataudin eri alatyypit. Asbestialtistuneilla henkilöillä veren merkkiainemittaukset voisivat ennustaa tulehdus- ja fibroosiprosessin etenemistä keuhkoissa ja siten ohjata seurannan kohdistamista niihin potilaisiin, joilla on suurin riski sairastua parantumattomaan asbestoosiin. Lihavuushormonit eli adipokiinit ovat rasvakudoksen erittämiä välittäjäaineita. Ne on liitetty alun perin energia-aineenvaihduntaan, mutta sittemmin niiden on todettu säätelevän myös tulehdusvastetta ja immuunipuolustusta. Viime vuosina on todettu yhteys lihavuuden ja tulehduksellisten keuhkosairauksien välillä, samalla kun on havaittu, ettei tulehdus näissä sairauksissa rajoitu pelkästään keuhkoihin, vaan se kohdistuu koko elimistöön. Kuitenkin adipokiinien merkityksestä keuhkosairauksissa tiedetään vielä hyvin vähän. Väitöstutkimuksen tavoitteena oli selvittää adipokiinien yhteyttä astmaan ja keuhkoahtaumatautiin sekä adipokiinien soveltuvuutta steroidiherkän tautimuodon tunnistamiseen. Lisäksi tutkittiin, ovatko adipokiinit yhteydessä asbestin aiheuttaman tulehdusvasteen tai keuhkofibroosin vaikeusasteeseen. Tutkimuksessa määritettiin adipokiinien (adiponektiini, adipsiini, leptiini, nesfatiini-1, resistiini ja visfatiini) veripitoisuuksia astmapotilaiden, keuhkoahtaumatautipotilaiden sekä työssään kohtalaisesti tai voimakkaasti asbestille altistuneiden henkilöiden näytteistä. Astmaa sairastavilla potilailla veren suuren leptiinipitoisuuden todettiin liittyvän runsaampiin astmaoireisiin ja huonompaan keuhkojen toimintaan. Keuhkoahtaumataudissa suuri veren adiponektiinipitoisuus oli yhteydessä pienten hengitysteiden ahtautumiseen ja keuhkojen ilmatäyteisyyden lisääntymiseen, kun taas korkean visfatiinipitoisuuden todettiin liittyvän kaasujenvaihdunnan vaikeutumiseen. Lisäksi nesfatiini-1:n ja visfatiinin todettiin liittyvät koko elimistön tulehdusvasteeseen. Tulosten perusteella leptiinillä ja adiponektiinillä näyttäisi olevan itsenäinen, potilaan painosta riippumaton yhteys astman ja keuhkoahtaumataudin vaikeusasteeseen sekä lisäksi nesfatiini-1 ja visfatiini todettiin uusiksi tulehdustekijöiksi keuhkoahtaumatautiin liittyvässä yleistyneessä tulehduksessa. Tutkimuksessa havaittiin verenkierron suuren resistiinipitoisuuden astmapotilailla ja vastaavasti suuren adiponektiinipitoisuuden keuhkoahtaumatautia sairastavilla ennustavan hyvää vastetta hengitettävälle kortisonihoidolle. Saadut tulokset ehdottavat, että ahtauttavissa keuhkosairauksissa veren adipokiinimääritykset voisivat auttaa löytämään hengitettävästä kortisonihoidosta hyötyvät potilaat. Väitöstutkimuksessa osoitettiin ensimmäisen kerran adipokiinien yhteys asbestialtistuksen aiheuttamaan tulehdusprosessiin ja keuhkofibroosiin. Adipsiinipitoisuuden todettiin olevan yhteydessä veren tulehdustekijöihin, asbestin aiheuttamien keuhkopussin paksuuntumien eli pleuraplakkien laajuuteen, keuhkofibroosin vaikeusasteeseen ja alentuneeseen keuhkojen kaasujenvaihduntaan. Tämä väitöstutkimus tuotti uutta tietoa adipokiinien yhteydestä keuhkosairauksiin. Tulokset avaavat näkymiä adipokiinien käytettävyydestä tulehduksellisten keuhkosairauksien luokitteluun ja seurantaan sekä niiden merkityksestä uusina lääkevaikutuskohteina.Chronic inflammation is present in many lung diseases, not only in airway diseases, like asthma and chronic obstructive pulmonary disease (COPD), but also in interstitial lung disorders. Different cell types and cytokines are known to be involved in the complex inflammatory processes encountered in these disorders, but still many pieces are lacking in our understanding on the pathogenesis of these diseases. Asthma and COPD are heterogeneous syndromes with different inflammatory profiles, clinical phenotypes and treatment responses, and therefore the characterization and the management of these patients is challenging. The pathogenesis of asbestos-induced interstitial fibrosis i.e. asbestosis, is poorly understood, and furthermore there is no clinical tool which could monitor the current activity of the asbestos-induced immune response. Although inflammation is important in the pathogenesis of these diseases, their diagnosis and follow-up are not based on measurement of the inflammatory response itself but on revealing the secondary changes either by radiography or by measuring pulmonary function. Clinically useful biomarkers for the detection of the inflammatory process and its activity are therefore needed. Adipokines (also known as adipocytokines) are a group of hormone-like mediators secreted by adipose tissue. They were first described as regulators of energy metabolism, but later also recognized as being produced by inflammatory cells and to be involved in many immune and inflammatory processes in the human body. Recently, adipokines have been found to mediate inflammation responses also in the human lung and associations between some adipokines and obstructive airway diseases have been described, but there is practically no data on wheather adipokines are involved in interstitial lung diseases. The aim of the present study was to investigate if plasma adipokines would be associated with the airway and systemic inflammation and disease severity in asthma (I), COPD (III-IV) and pulmonary fibrosis in asbestos-exposed subjects (II). Another major aim was to examine if adipokines would be related to glucocorticoid-responsiveness in asthma and/or COPD. Steroid-naïve, newly diagnosed patients with asthma (n = 35) and patients with COPD (n = 43) were recruited at the Department of Respiratory Medicine (I, III-IV) and subjects with moderate to heavy occupational exposure to asbestos (n = 85) at the Department of Occupational Medicine (II) at Tampere University Hospital. It was found that the plasma leptin levels were associated with disease severity in non-obese, steroid-naïve asthmatics suggesting that the relationship between leptin and asthma is not restricted to obesity. In addition, high pre-treatment plasma resistin levels predicted a more favourable anti-inflammatory effect of inhaled glucocorticoids indicating that resistin may be a marker of the steroid-sensitive phenotype in asthma. Plasma levels of adiponectin were associated with peripheral airway obstruction and dynamic hyperinflation in COPD and also with favourable relief of symptoms and hyperinflation during glucocorticoid treatment. These findings support the experimental data that adiponectin can act as a pro-inflammatory mediator able to induce tissue matrix degradation and to evoke smooth muscle contraction in COPD. In addition, the present study introduced adipokines nesfatin-1 and visfatin as novel factors associated with systemic inflammation in emphysematous COPD. Plasma levels of adipsin were associated with the degree of interstitial fibrosis, with impairment of pulmonary diffusing capacity and with inflammatory activity in workers with a history of moderate to heavy exposure to asbestos. These findings suggest that adipsin may have a role in the pathogenesis of asbestos-induced lung injury. This study provides new information on the role of adipokines in non-obese patients with asthma and COPD and presents as an original finding the fact that adipsin is associated with asbestos-induced interstitial lung disease. In the light of these results in the future it would be interesting to determine whether the levels of resistin or adiponectin can be used clinically to identify steroid-sensitive phenotypes of asthma and COPD, respectively, or if adipsin could be used as a biomarker of ongoing disease activity in asbestos-exposed subjects

Adipokiinit tulehduksellisissa keuhkosairauksissa

Lihavuushormoni adipokiinit keuhkosairauksissa Tulehdusreaktiolla on keskeinen merkitys astman ja keuhkoahtaumataudin sekä asbestialtistuksen aiheuttaman keuhkofibroosin synnyssä. Käytännön työhön tarvitaan uusia merkkiaineita, joita mittaamalla voitaisiin havaita taudin tulehduksellinen aktiivisuus ja tunnistaa taudinkuvaltaan, ennusteeltaan ja hoitovasteeltaan toisistaan eroavat astman ja keuhkoahtaumataudin eri alatyypit. Asbestialtistuneilla henkilöillä veren merkkiainemittaukset voisivat ennustaa tulehdus- ja fibroosiprosessin etenemistä keuhkoissa ja siten ohjata seurannan kohdistamista niihin potilaisiin, joilla on suurin riski sairastua parantumattomaan asbestoosiin. Lihavuushormonit eli adipokiinit ovat rasvakudoksen erittämiä välittäjäaineita. Ne on liitetty alun perin energia-aineenvaihduntaan, mutta sittemmin niiden on todettu säätelevän myös tulehdusvastetta ja immuunipuolustusta. Viime vuosina on todettu yhteys lihavuuden ja tulehduksellisten keuhkosairauksien välillä, samalla kun on havaittu, ettei tulehdus näissä sairauksissa rajoitu pelkästään keuhkoihin, vaan se kohdistuu koko elimistöön. Kuitenkin adipokiinien merkityksestä keuhkosairauksissa tiedetään vielä hyvin vähän. Väitöstutkimuksen tavoitteena oli selvittää adipokiinien yhteyttä astmaan ja keuhkoahtaumatautiin sekä adipokiinien soveltuvuutta steroidiherkän tautimuodon tunnistamiseen. Lisäksi tutkittiin, ovatko adipokiinit yhteydessä asbestin aiheuttaman tulehdusvasteen tai keuhkofibroosin vaikeusasteeseen. Tutkimuksessa määritettiin adipokiinien (adiponektiini, adipsiini, leptiini, nesfatiini-1, resistiini ja visfatiini) veripitoisuuksia astmapotilaiden, keuhkoahtaumatautipotilaiden sekä työssään kohtalaisesti tai voimakkaasti asbestille altistuneiden henkilöiden näytteistä. Astmaa sairastavilla potilailla veren suuren leptiinipitoisuuden todettiin liittyvän runsaampiin astmaoireisiin ja huonompaan keuhkojen toimintaan. Keuhkoahtaumataudissa suuri veren adiponektiinipitoisuus oli yhteydessä pienten hengitysteiden ahtautumiseen ja keuhkojen ilmatäyteisyyden lisääntymiseen, kun taas korkean visfatiinipitoisuuden todettiin liittyvän kaasujenvaihdunnan vaikeutumiseen. Lisäksi nesfatiini-1:n ja visfatiinin todettiin liittyvät koko elimistön tulehdusvasteeseen. Tulosten perusteella leptiinillä ja adiponektiinillä näyttäisi olevan itsenäinen, potilaan painosta riippumaton yhteys astman ja keuhkoahtaumataudin vaikeusasteeseen sekä lisäksi nesfatiini-1 ja visfatiini todettiin uusiksi tulehdustekijöiksi keuhkoahtaumatautiin liittyvässä yleistyneessä tulehduksessa. Tutkimuksessa havaittiin verenkierron suuren resistiinipitoisuuden astmapotilailla ja vastaavasti suuren adiponektiinipitoisuuden keuhkoahtaumatautia sairastavilla ennustavan hyvää vastetta hengitettävälle kortisonihoidolle. Saadut tulokset ehdottavat, että ahtauttavissa keuhkosairauksissa veren adipokiinimääritykset voisivat auttaa löytämään hengitettävästä kortisonihoidosta hyötyvät potilaat. Väitöstutkimuksessa osoitettiin ensimmäisen kerran adipokiinien yhteys asbestialtistuksen aiheuttamaan tulehdusprosessiin ja keuhkofibroosiin. Adipsiinipitoisuuden todettiin olevan yhteydessä veren tulehdustekijöihin, asbestin aiheuttamien keuhkopussin paksuuntumien eli pleuraplakkien laajuuteen, keuhkofibroosin vaikeusasteeseen ja alentuneeseen keuhkojen kaasujenvaihduntaan. Tämä väitöstutkimus tuotti uutta tietoa adipokiinien yhteydestä keuhkosairauksiin. Tulokset avaavat näkymiä adipokiinien käytettävyydestä tulehduksellisten keuhkosairauksien luokitteluun ja seurantaan sekä niiden merkityksestä uusina lääkevaikutuskohteina.Chronic inflammation is present in many lung diseases, not only in airway diseases, like asthma and chronic obstructive pulmonary disease (COPD), but also in interstitial lung disorders. Different cell types and cytokines are known to be involved in the complex inflammatory processes encountered in these disorders, but still many pieces are lacking in our understanding on the pathogenesis of these diseases. Asthma and COPD are heterogeneous syndromes with different inflammatory profiles, clinical phenotypes and treatment responses, and therefore the characterization and the management of these patients is challenging. The pathogenesis of asbestos-induced interstitial fibrosis i.e. asbestosis, is poorly understood, and furthermore there is no clinical tool which could monitor the current activity of the asbestos-induced immune response. Although inflammation is important in the pathogenesis of these diseases, their diagnosis and follow-up are not based on measurement of the inflammatory response itself but on revealing the secondary changes either by radiography or by measuring pulmonary function. Clinically useful biomarkers for the detection of the inflammatory process and its activity are therefore needed. Adipokines (also known as adipocytokines) are a group of hormone-like mediators secreted by adipose tissue. They were first described as regulators of energy metabolism, but later also recognized as being produced by inflammatory cells and to be involved in many immune and inflammatory processes in the human body. Recently, adipokines have been found to mediate inflammation responses also in the human lung and associations between some adipokines and obstructive airway diseases have been described, but there is practically no data on wheather adipokines are involved in interstitial lung diseases. The aim of the present study was to investigate if plasma adipokines would be associated with the airway and systemic inflammation and disease severity in asthma (I), COPD (III-IV) and pulmonary fibrosis in asbestos-exposed subjects (II). Another major aim was to examine if adipokines would be related to glucocorticoid-responsiveness in asthma and/or COPD. Steroid-naïve, newly diagnosed patients with asthma (n = 35) and patients with COPD (n = 43) were recruited at the Department of Respiratory Medicine (I, III-IV) and subjects with moderate to heavy occupational exposure to asbestos (n = 85) at the Department of Occupational Medicine (II) at Tampere University Hospital. It was found that the plasma leptin levels were associated with disease severity in non-obese, steroid-naïve asthmatics suggesting that the relationship between leptin and asthma is not restricted to obesity. In addition, high pre-treatment plasma resistin levels predicted a more favourable anti-inflammatory effect of inhaled glucocorticoids indicating that resistin may be a marker of the steroid-sensitive phenotype in asthma. Plasma levels of adiponectin were associated with peripheral airway obstruction and dynamic hyperinflation in COPD and also with favourable relief of symptoms and hyperinflation during glucocorticoid treatment. These findings support the experimental data that adiponectin can act as a pro-inflammatory mediator able to induce tissue matrix degradation and to evoke smooth muscle contraction in COPD. In addition, the present study introduced adipokines nesfatin-1 and visfatin as novel factors associated with systemic inflammation in emphysematous COPD. Plasma levels of adipsin were associated with the degree of interstitial fibrosis, with impairment of pulmonary diffusing capacity and with inflammatory activity in workers with a history of moderate to heavy exposure to asbestos. These findings suggest that adipsin may have a role in the pathogenesis of asbestos-induced lung injury. This study provides new information on the role of adipokines in non-obese patients with asthma and COPD and presents as an original finding the fact that adipsin is associated with asbestos-induced interstitial lung disease. In the light of these results in the future it would be interesting to determine whether the levels of resistin or adiponectin can be used clinically to identify steroid-sensitive phenotypes of asthma and COPD, respectively, or if adipsin could be used as a biomarker of ongoing disease activity in asbestos-exposed subjects

Keuhkoahtaumataudin palliatiivinen hoito

publishedVersionPeer reviewe

Dyspnea on Exercise Is Associated with Overall Symptom Burden in Patients with Chronic Respiratory Insufficiency

Background: Patients with chronic respiratory insufficiency suffer from many symptoms together with dyspnea. Objective: We evaluated the association of dyspnea on exercise with other symptoms in patients with chronic respiratory insufficiency due to chronic obstructive pulmonary disease or interstitial lung disease. Design: This retrospective study included 101 patients in Tampere University Hospital, Finland. Dyspnea on exercise was assessed with modified Medical Research Council (mMRC) dyspnea questionnaire, and other symptoms were assessed with Edmonton Symptom Assessment System (ESAS) and Depression Scale (DEPS). The study was approved by Regional Ethics Committee of Tampere University Hospital, Finland (approval code R15180/December 1, 2015). Results: Patients with mMRC 4 (most severe dyspnea) compared with those with mMRC 0–3 reported higher symptom scores on ESAS in shortness of breath (median 8.0 [IQR 6.0–9.0] vs. 4.0 [2.0–6.0], p < 0.001), dry mouth (7.0 [4.0–8.0] vs. 3.0 [1.0–6.0], p < 0.001), tiredness (6.0 [3.0–7.0] vs. 3.0 [1.0–5.0], p < 0.001), loss of appetite (3.0 [0.0–6.0] vs. 1.0 [0.0–3.0], p = 0.001), insomnia (3.0 [1.0–7.0] vs. 2.0 [0.0–3.0], p = 0.027), anxiety (3.0 [0.0–5.5] vs. 1.0 [0.0–3.0], p = 0.007), and nausea (0.0 [0.0–2.0] vs. 0.0 [0.0–0.3], p = 0.027). Patients with mMRC 4 were more likely to reach the DEPS threshold for depression than those scoring mMRC 0–3 (42.1% vs. 20.8%, p = 0.028). Conclusions: Patients with chronic respiratory insufficiency need comprehensive symptom screening with rel- evant treatment, as they suffer from broad symptom burden worsening with increased dyspnea on exercise.publishedVersionPeer reviewe

Assessing Symptom Burden and Depression in Subjects With Chronic Respiratory Insufficiency

publishedVersionPeer reviewe