The glucocorticoid RU24858 does not distinguish between transrepression and transactivation in primary human eosinophils

BACKGROUND: Glucocorticoids are used to treat chronic inflammatory diseases such as asthma. Induction of eosinophil apoptosis is considered to be one of the main mechanisms behind the anti-asthmatic effect of glucocorticoids. Glucocorticoid binding to its receptor (GR) can have a dual effect on gene transcription. Activated GR can activate transcription (transactivation), or by interacting with other transcription factors such as NF-κB suppress transcription (transrepression). RU24858 has been reported to transrepress but to have little or no transactivation capability in other cell types. The dissociated properties of RU24858 have not been previously studied in non-malignant human cells. As the eosinophils have a very short lifetime and many of the modern molecular biological methods cannot be used, a "dissociated steroid" would be a valuable tool to evaluate the mechanism of action of glucocorticoids in human eosinophils. The aim of this study was to elucidate the ability of RU24858 to activate and repress gene expression in human eosinophils in order to see whether it is a dissociated steroid in human eosinophils. METHODS: Human peripheral blood eosinophils were isolated under sterile conditions and cultured in the presence and/or absence RU24858. For comparison, dexamethasone and mometasone were used. We measured chemokine receptor-4 (CXCR4) and Annexin 1 expression by flow cytometry and cytokine production by ELISA. Apoptosis was measured by DNA fragmentation and confirmed by morphological analysis. RESULTS: RU24858 (1 μM) increased CXCR4 and Annexin 1 expression on eosinophils to a similar extent as mometasone (1 μM) and dexamethasone (1 μM). Like dexamethasone and mometasone, RU24858 did suppress IL-8 and MCP-1 production in eosinophils. RU24858 also increased spontaneous eosinophil apoptosis to a similar degree as dexamethasone and mometasone, but unlike dexamethasone and mometasone it did not reverse IL-5- or GM-CSF-induced eosinophil survival. CONCLUSION: Our results suggest that in human eosinophils RU24858 acts as transactivator and transrepressor like classical glucocorticoids. Thus, RU24858 seems not to be a "dissociated steroid" in primary human eosinophils in contrast to that reported in animal cells. In addition, functionally RU24858 seems to be a less potent glucocorticoid as it did not reverse IL-5- and GM-CSF-afforded eosinophil survival similarly to dexamethasone and mometasone

Virtual communication is commonly used in Finnish interstitial lung disease multidisciplinary meetings

Multidisciplinary meeting (MDM) is a core element in the diagnosis of interstitial lung diseases (ILD). The aim of the study was to investigate the implementation and key elements related to ILD MDMs in Finnish specialized care, which is characterized by long travel distances and a large number of small centers treating patients suffering from ILDs. An electronic questionnaire was sent to ILD experts working at five academic centers of Finland regarding the implementation of ILD MDMs with the focus on utilization of virtual communication. Responses were received from all academic centers of Finland (n = 5) whose catchment areas cover all of Finland. ILD MDMs were organized in each center approximately every two weeks and the core participants included a radiologist, respiratory physicians, junior staff, pathologist and a rheumatologist. All non-academic centers could refer their patients to be evaluated in ILD MDM of an academic center. Virtual communication was utilized by all academic centers in the implementation of ILD MDMs, being most common among small centers located in Eastern and Northern Finland. Virtual access to ILD MDM of an academic center was available in most parts of Finland, enabling small centers to benefit from the ILD expertise of academic centers.Peer reviewe

Changes in the societal burden caused by sleep apnoea in Finland from 1996 to 2018 : A national registry study

Background In the current century, sleep apnoea has become a significant public health problem due to the obesity epidemic. To increase awareness, improve diagnostics, and improve treatment, Finland implemented a national sleep apnoea programme from 2002 to 2010. Here, we present changes in the societal burden caused by sleep apnoea from 1996 to 2018. Methods National register data were collected from the Care Register for Health Care, Statistics Finland, the Social Insurance Institution of Finland, and the Finnish Centre for Pensions. Disease prevalence, use of healthcare and social services, and societal costs were estimated. Findings The number of sleep apnoea patients increased in secondary care from 8 600 in 1996 to 61 000 in 2018. There was a continuous increase in outpatient visits in secondary care from 9 700 in 1996 to 122 000 in 2018 (1 160%) and in primary care from 10 000 in 2015 to 29 000 in 2018 (190%). Accordingly, the cumulative annual number of days off work for sleep apnoea increased from 1 100 to 46 000. However, disability pensions for sleep apnoea decreased from 820 to 550 (33%) during the observation period. Societal costs per patient decreased over 50% during the observation period ((sic) 2 800 to (sic)1 200). Interpretation The number of sleep apnoea patients in Finland increased remarkably during the observation period. To control this burden, diagnostic methods and treatment were revised and follow up was reorganised. Consequently, there was a significant decrease in societal costs per patient. The decrease in disability pensions suggests earlier diagnosis and improved treatment. The national sleep apnoea programme was one of the initiators for these improved outcomes. Funding The Finnish Institute for Health and Welfare and the Hospital District of Helsinki and Uusimaa (HUH), Helsinki, Finland. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)Peer reviewe

Changes in the societal burden caused by sleep apnoea in Finland from 1996 to 2018: A national registry study

BackgroundIn the current century, sleep apnoea has become a significant public health problem due to the obesity epidemic. To increase awareness, improve diagnostics, and improve treatment, Finland implemented a national sleep apnoea programme from 2002 to 2010. Here, we present changes in the societal burden caused by sleep apnoea from 1996 to 2018.MethodsNational register data were collected from the Care Register for Health Care, Statistics Finland, the Social Insurance Institution of Finland, and the Finnish Centre for Pensions. Disease prevalence, use of healthcare and social services, and societal costs were estimated.FindingsThe number of sleep apnoea patients increased in secondary care from 8 600 in 1996 to 61 000 in 2018. There was a continuous increase in outpatient visits in secondary care from 9 700 in 1996 to 122 000 in 2018 (1 160%) and in primary care from 10 000 in 2015 to 29 000 in 2018 (190%). Accordingly, the cumulative annual number of days off work for sleep apnoea increased from 1 100 to 46 000. However, disability pensions for sleep apnoea decreased from 820 to 550 (33%) during the observation period. Societal costs per patient decreased over 50% during the observation period (€2 800 to €1 200).InterpretationThe number of sleep apnoea patients in Finland increased remarkably during the observation period. To control this burden, diagnostic methods and treatment were revised and follow up was reorganised. Consequently, there was a significant decrease in societal costs per patient. The decrease in disability pensions suggests earlier diagnosis and improved treatment. The national sleep apnoea programme was one of the initiators for these improved outcomes.FundingThe Finnish Institute for Health and Welfare and the Hospital District of Helsinki and Uusimaa (HUH), Helsinki, Finland.</p

Reticulation pattern without honeycombing on high-resolution CT is associated with the risk of disease progression in interstitial lung diseases

Background: The disease course of idiopathic pulmonary fibrosis (IPF) is progressive and occasionally, other types of interstitial lung disease (ILD) may progress similarly to IPF. This study aimed to evaluate risk factors for disease progression within 24 months in patients with various ILDs. Methods: This prospective study obtained 97 patients with a suspected ILD who underwent a transbronchial lung cryobiopsy. The extent of several high-resolution computed tomography (HRCT) patterns was assessed. Due to the inclusion criteria the study population presented a low extent of honeycombing and definite usual interstitial pneumonia (UIP) pattern on HRCT suggesting an early stage of ILD. Disease progression within 24 months despite treatment was defined as a relative decline of ≥ 10% in forced vital capacity (FVC), or a relative decline in FVC of ≥ 5% and one of the three additional criteria: (1) a decline in diffusion capacity to carbon monoxide (DLCO) ≥ 15%; (2) increased fibrosis on HRCT; (3) progressive symptoms, or progressive symptoms and increased fibrosis on HRCT. The same definition was utilized in patients with IPF and other ILDs. Risk factors for disease progression were evaluated in a multivariable logistic regression model. Results: Disease progression was revealed in 52% of the patients with ILD, 51% of the patients with IPF, and 53% of the patients with other types of ILD. A high extent of reticulation on HRCT (Odds ratio [OR] 3.11, 95% Confidence interval [CI] 1.21–7.98, P = 0.019) and never smoking (OR 3.11, CI 1.12–8.63, P = 0.029) were associated with disease progression whereas platelet count (OR 2.06 per 100 units increase, CI 0.96–4.45, P = 0.065) did not quite reach statistical significance. Conclusion: Higher extent of reticulation on HRCT and never smoking appeared to associate with the risk of disease progression within 24 months in ILD patients without honeycombing. Approximately half of the patients with ILD revealed disease progression, and similar proportions were observed in patients with IPF and in other types of ILD.publishedVersionPeer reviewe

Role of Histamine in the Regulation of Human Eosinophil Apoptosis

Eosinofiilinen tulehdus on tärkeä tekijä astman ja allergisten sairauksien synnyssä. Myös tulehdussoluista allergeenialtistuksen jälkeen vapautuva histamiini on olennainen allergiaoireiden kehittymisessä. Antihistamiineja käytetäänkin yleisesti allergisten sairauksien hoidossa. Apoptoosia eli ohjelmoitua solukuolemaa pidetään keskeisenä mekanismina, jonka avulla tulehdussoluja poistuu kudoksista ja tulehdus lievittyy. Hannele Hasalan väitöskirjatutkimuksessa arvioitiin histamiinin ja antihistamiinien merkitystä eosinofiilisten valkosolujen apoptoosin säätelyssä. Vapaaehtoisten henkilöiden verestä eristettyjä eosinofiilejä viljeltiin koeolosuhteissa, jonka jälkeen apoptoosia arvioitiin eri menetelmillä. Histamiinin havaittiin osittain kumoavan interleukiini-5-sytokiinin (IL-5:n) eosinofiilejä hengissäpitävää vaikutusta tehostamalla eosinofiilien apoptoosia. Histamiinin eosinofiilien apoptoosia lisäävä vaikutus oli vastaavaa suuruusluokkaa kuin aiemmin havaittu glukokortikoidien aiheuttama eosinofiiliapoptoosin tehostuminen, jonka ajatellaan olevan yksi glukokortikoidien tärkeimmistä eosinofiilistä tulehdusta lievittävistä ominaisuuksista. Histamiinin vaikutus ei näyttänyt välittyvän minkään tunnetun histamiinireseptorin eikä muiden amiinireseptorien epäspesifisen aktivaation kautta, mikä viittaa siihen, että eosinofiileissä saattaa ilmentyä uusi, toistaiseksi tuntematon histamiinireseptori. Vaihtoehtoisesti histamiini saattaa tehostaa eosinofiilien apoptoosia ei-reseptorivälitteisesti. Antihistamiinit difenhydramiini ja kloorifeniramiini lisäsivät histamiinin tavoin eosinofiilien apoptoosia IL-5:n läsnäollessa, kun taas ketotifeeni sai aikaan eosinofiilien nekroottisen solu-kuoleman. Tulosten mukaan histamiinilla voi olla myös tulehdusta hillitsevä vaikutus allergiassa sen tehostaman eosinofiiliapoptoosin takia. Tämä saattaa välittyä uuden, toistaiseksi tuntemattoman histamiinireseptorin kautta. Suora eosinofiilien solukuoleman säätely saattaa myös olla yksi joidenkin antihistamiinien terapeuttisista vaikutuksista allergian hoidossa.Eosinophilic inflammation represents an essential element in the pathogenesis of allergic conditions such as asthma, allergic rhinoconjunctivitis and atopic eczema. Histamine, released from inflammatory cells in response to allergen challenge, is regarded as a key mediator in the development of allergic symptoms. The activation and degranulation of eosinophils in the airways evoke epithelial tissue injury and airway remodelling. With regard to the clearance of eosinophils, apoptosis or programmed cell death is considered as a major mechanism in the resolution of eosinophilic inflammation. Antihistamines (aka histamine H1 receptor antagonists) are widely used in the treatment of allergic disorders although little is known about their effects on eosinophil functions. The present study was designed to evaluate the possible effects of histamine and antihistamines on human eosinophil apoptosis. In addition, the role of c-Jun N-terminal kinase (JNK) in the regulation of constitutive or glucocorticoid- or antihistamine-induced eosinophil apoptosis was elucidated. Isolated human blood eosinophils were cultured in vitro, after which the rate of apoptosis was assessed by flow cytometric analyses of the relative DNA content or Annexin-V binding or by morphological analyses by bright field microscopy or transmission electron microscopy. Histamine partly reversed interleukin (IL)-5-induced human eosinophil survival by enhancing apoptosis via a mechanism that did not apparently involve the activation of any of the currently known histamine receptor subtypes. Two antihistamines, diphenhydramine and chlorpheniramine, also promoted human eosinophil apoptosis in the presence of IL-5 whereas ketotifen was observed to induce primary eosinophil necrosis. In addition, it was observed that JNK does seem to mediate constitutive human eosinophil apoptosis but not to selectively mediate glucocorticoid-induced human eosinophil apoptosis. JNK was also found to be involved in antihistamine-induced apoptosis of eosinophils. In conclusion, the present results suggest that histamine may play an anti-inflammatory role in allergy by enhancing eosinophil apoptosis under the influence of survival-prolonging cytokines. This pro-apoptotic role of histamine may be mediated through a novel, hitherto unidentified histamine receptor. Furthermore, direct regulation of eosinophil longevity via H1 receptor-independent mechanisms may also be involved in the therapeutic actions of antihistamines in the treatment of allergy

Role of Histamine in the Regulation of Human Eosinophil Apoptosis

Eosinofiilinen tulehdus on tärkeä tekijä astman ja allergisten sairauksien synnyssä. Myös tulehdussoluista allergeenialtistuksen jälkeen vapautuva histamiini on olennainen allergiaoireiden kehittymisessä. Antihistamiineja käytetäänkin yleisesti allergisten sairauksien hoidossa. Apoptoosia eli ohjelmoitua solukuolemaa pidetään keskeisenä mekanismina, jonka avulla tulehdussoluja poistuu kudoksista ja tulehdus lievittyy. Hannele Hasalan väitöskirjatutkimuksessa arvioitiin histamiinin ja antihistamiinien merkitystä eosinofiilisten valkosolujen apoptoosin säätelyssä. Vapaaehtoisten henkilöiden verestä eristettyjä eosinofiilejä viljeltiin koeolosuhteissa, jonka jälkeen apoptoosia arvioitiin eri menetelmillä. Histamiinin havaittiin osittain kumoavan interleukiini-5-sytokiinin (IL-5:n) eosinofiilejä hengissäpitävää vaikutusta tehostamalla eosinofiilien apoptoosia. Histamiinin eosinofiilien apoptoosia lisäävä vaikutus oli vastaavaa suuruusluokkaa kuin aiemmin havaittu glukokortikoidien aiheuttama eosinofiiliapoptoosin tehostuminen, jonka ajatellaan olevan yksi glukokortikoidien tärkeimmistä eosinofiilistä tulehdusta lievittävistä ominaisuuksista. Histamiinin vaikutus ei näyttänyt välittyvän minkään tunnetun histamiinireseptorin eikä muiden amiinireseptorien epäspesifisen aktivaation kautta, mikä viittaa siihen, että eosinofiileissä saattaa ilmentyä uusi, toistaiseksi tuntematon histamiinireseptori. Vaihtoehtoisesti histamiini saattaa tehostaa eosinofiilien apoptoosia ei-reseptorivälitteisesti. Antihistamiinit difenhydramiini ja kloorifeniramiini lisäsivät histamiinin tavoin eosinofiilien apoptoosia IL-5:n läsnäollessa, kun taas ketotifeeni sai aikaan eosinofiilien nekroottisen solu-kuoleman. Tulosten mukaan histamiinilla voi olla myös tulehdusta hillitsevä vaikutus allergiassa sen tehostaman eosinofiiliapoptoosin takia. Tämä saattaa välittyä uuden, toistaiseksi tuntemattoman histamiinireseptorin kautta. Suora eosinofiilien solukuoleman säätely saattaa myös olla yksi joidenkin antihistamiinien terapeuttisista vaikutuksista allergian hoidossa.Eosinophilic inflammation represents an essential element in the pathogenesis of allergic conditions such as asthma, allergic rhinoconjunctivitis and atopic eczema. Histamine, released from inflammatory cells in response to allergen challenge, is regarded as a key mediator in the development of allergic symptoms. The activation and degranulation of eosinophils in the airways evoke epithelial tissue injury and airway remodelling. With regard to the clearance of eosinophils, apoptosis or programmed cell death is considered as a major mechanism in the resolution of eosinophilic inflammation. Antihistamines (aka histamine H1 receptor antagonists) are widely used in the treatment of allergic disorders although little is known about their effects on eosinophil functions. The present study was designed to evaluate the possible effects of histamine and antihistamines on human eosinophil apoptosis. In addition, the role of c-Jun N-terminal kinase (JNK) in the regulation of constitutive or glucocorticoid- or antihistamine-induced eosinophil apoptosis was elucidated. Isolated human blood eosinophils were cultured in vitro, after which the rate of apoptosis was assessed by flow cytometric analyses of the relative DNA content or Annexin-V binding or by morphological analyses by bright field microscopy or transmission electron microscopy. Histamine partly reversed interleukin (IL)-5-induced human eosinophil survival by enhancing apoptosis via a mechanism that did not apparently involve the activation of any of the currently known histamine receptor subtypes. Two antihistamines, diphenhydramine and chlorpheniramine, also promoted human eosinophil apoptosis in the presence of IL-5 whereas ketotifen was observed to induce primary eosinophil necrosis. In addition, it was observed that JNK does seem to mediate constitutive human eosinophil apoptosis but not to selectively mediate glucocorticoid-induced human eosinophil apoptosis. JNK was also found to be involved in antihistamine-induced apoptosis of eosinophils. In conclusion, the present results suggest that histamine may play an anti-inflammatory role in allergy by enhancing eosinophil apoptosis under the influence of survival-prolonging cytokines. This pro-apoptotic role of histamine may be mediated through a novel, hitherto unidentified histamine receptor. Furthermore, direct regulation of eosinophil longevity via H1 receptor-independent mechanisms may also be involved in the therapeutic actions of antihistamines in the treatment of allergy

Role of Histamine in the Regulation of Human Eosinophil Apoptosis

Eosinofiilinen tulehdus on tärkeä tekijä astman ja allergisten sairauksien synnyssä. Myös tulehdussoluista allergeenialtistuksen jälkeen vapautuva histamiini on olennainen allergiaoireiden kehittymisessä. Antihistamiineja käytetäänkin yleisesti allergisten sairauksien hoidossa. Apoptoosia eli ohjelmoitua solukuolemaa pidetään keskeisenä mekanismina, jonka avulla tulehdussoluja poistuu kudoksista ja tulehdus lievittyy. Hannele Hasalan väitöskirjatutkimuksessa arvioitiin histamiinin ja antihistamiinien merkitystä eosinofiilisten valkosolujen apoptoosin säätelyssä. Vapaaehtoisten henkilöiden verestä eristettyjä eosinofiilejä viljeltiin koeolosuhteissa, jonka jälkeen apoptoosia arvioitiin eri menetelmillä. Histamiinin havaittiin osittain kumoavan interleukiini-5-sytokiinin (IL-5:n) eosinofiilejä hengissäpitävää vaikutusta tehostamalla eosinofiilien apoptoosia. Histamiinin eosinofiilien apoptoosia lisäävä vaikutus oli vastaavaa suuruusluokkaa kuin aiemmin havaittu glukokortikoidien aiheuttama eosinofiiliapoptoosin tehostuminen, jonka ajatellaan olevan yksi glukokortikoidien tärkeimmistä eosinofiilistä tulehdusta lievittävistä ominaisuuksista. Histamiinin vaikutus ei näyttänyt välittyvän minkään tunnetun histamiinireseptorin eikä muiden amiinireseptorien epäspesifisen aktivaation kautta, mikä viittaa siihen, että eosinofiileissä saattaa ilmentyä uusi, toistaiseksi tuntematon histamiinireseptori. Vaihtoehtoisesti histamiini saattaa tehostaa eosinofiilien apoptoosia ei-reseptorivälitteisesti. Antihistamiinit difenhydramiini ja kloorifeniramiini lisäsivät histamiinin tavoin eosinofiilien apoptoosia IL-5:n läsnäollessa, kun taas ketotifeeni sai aikaan eosinofiilien nekroottisen solu-kuoleman. Tulosten mukaan histamiinilla voi olla myös tulehdusta hillitsevä vaikutus allergiassa sen tehostaman eosinofiiliapoptoosin takia. Tämä saattaa välittyä uuden, toistaiseksi tuntemattoman histamiinireseptorin kautta. Suora eosinofiilien solukuoleman säätely saattaa myös olla yksi joidenkin antihistamiinien terapeuttisista vaikutuksista allergian hoidossa.Eosinophilic inflammation represents an essential element in the pathogenesis of allergic conditions such as asthma, allergic rhinoconjunctivitis and atopic eczema. Histamine, released from inflammatory cells in response to allergen challenge, is regarded as a key mediator in the development of allergic symptoms. The activation and degranulation of eosinophils in the airways evoke epithelial tissue injury and airway remodelling. With regard to the clearance of eosinophils, apoptosis or programmed cell death is considered as a major mechanism in the resolution of eosinophilic inflammation. Antihistamines (aka histamine H1 receptor antagonists) are widely used in the treatment of allergic disorders although little is known about their effects on eosinophil functions. The present study was designed to evaluate the possible effects of histamine and antihistamines on human eosinophil apoptosis. In addition, the role of c-Jun N-terminal kinase (JNK) in the regulation of constitutive or glucocorticoid- or antihistamine-induced eosinophil apoptosis was elucidated. Isolated human blood eosinophils were cultured in vitro, after which the rate of apoptosis was assessed by flow cytometric analyses of the relative DNA content or Annexin-V binding or by morphological analyses by bright field microscopy or transmission electron microscopy. Histamine partly reversed interleukin (IL)-5-induced human eosinophil survival by enhancing apoptosis via a mechanism that did not apparently involve the activation of any of the currently known histamine receptor subtypes. Two antihistamines, diphenhydramine and chlorpheniramine, also promoted human eosinophil apoptosis in the presence of IL-5 whereas ketotifen was observed to induce primary eosinophil necrosis. In addition, it was observed that JNK does seem to mediate constitutive human eosinophil apoptosis but not to selectively mediate glucocorticoid-induced human eosinophil apoptosis. JNK was also found to be involved in antihistamine-induced apoptosis of eosinophils. In conclusion, the present results suggest that histamine may play an anti-inflammatory role in allergy by enhancing eosinophil apoptosis under the influence of survival-prolonging cytokines. This pro-apoptotic role of histamine may be mediated through a novel, hitherto unidentified histamine receptor. Furthermore, direct regulation of eosinophil longevity via H1 receptor-independent mechanisms may also be involved in the therapeutic actions of antihistamines in the treatment of allergy