Effects of Asthma Combination Therapy on Extracellular Matrix Remodeling in Human Lung Fibroblasts

Fibroblasts, being one of the resident and structural cells of the lung, have the capacity to produce inflammatory mediators, cytokines and extracellular matrix (ECM) proteins perpetuating the inflammation in the airways of asthmatics. Airway remodeling is also a prominent feature of asthma that affects the lung function causing a thickening of the airways. An increased ECM production of proteoglycans, collagens and other ECM molecules, usually accompanied by dysfunction of the ECM degrading enzymes, the metalloproteinases, may not only contribute to a subepithelial fibrosis formation, but it may also be a compartment where accumulating ECM sequesters and stores inflammatory mediators. Lung fibroblasts are the major producers of ECM components within the lung and may initiate, regulate and contribute to the airway remodeling in asthma. Current asthma treatments based on anti-inflammatory glucocorticoids (GC) and bronchodilatory long acting β2-agonists (LABA) are known to improve lung function, especially when administered in combination. Airway remodeling is relatively resistant to treatment with GC, but may respond better if treated with a combination of GC and LABA. The results from this thesis, suggest that indeed, combination of GC and LABA, via complementary and additive actions, has greater potential than GC monotherapy to counteract progression of airway remodeling. By reducing the levels of the major ECM components such as proteoglycans and collagen I, treatment with combination therapy may resolve an accumulating ECM and re-establish normal ECM deposition in asthmatics

Relationship between matrix production by bronchial fibroblasts and lung function and AHR in asthma

SummaryThe reasons for enhanced deposition of extracellular matrix in the airways of asthmatic patients and the subsequent consequences on lung function are uncertain. Here, we investigated the synthesis of procollagen I and proteoglycans, the activity of various metalloproteinases (MMPs) and the production of their inhibitor TIMP-1 in biopsy-derived bronchial fibroblasts from eight patients with stable mild-to-moderate asthma, and how they are related to patients’ lung function and airway hyperreactivity (AHR).Following 24-h fibroblast incubation in 0.4% serum, procollagen I carboxyterminal propeptide (PICP), TIMP-1 and MMP-1 in cell media were analysed by ELISA, MMP-2, MMP-3, MMP-9 by zymography and total proteoglycan production by [35S]-sulphate-incorporation/ion chromatography.Patients’ FEV1% predicted and methacholine log PD20 negatively correlated with PICP synthesized by patients’ bronchial fibroblasts (r = −0.74 and r = −0.71, respectively). PICP and proteoglycan amounts positively correlated (0.8 ≤ r ≤ 0.9) with MMP-2 and MMP-3 activity. A positive correlation (r = 0.75) was also found between proteoglycan production and TIMP-1. There was no correlation between MMP-9 activity and PICP or proteoglycan production. MMP-9 activity positively correlated with patients’ FEV1% predicted (r = 0.97) and methacholine log PD20 (r = 0.86), whereas negative associations (−0.6 ≤ r ≤ −0.7) were observed for MMP-2 and MMP-3.In stable mild-to-moderate asthma, increased procollagen I synthesis and activity of MMP-2 and MMP-3 in bronchial fibroblasts may negatively affect patients’ lung function and AHR. In contrast, MMP-9 activity was not associated with procollagen or proteoglycan production, or worsening of patients’ lung function and AHR. An enhanced production of procollagen I and proteoglycans might be a result of a negative feedback from their degradation by MMP-2 and MMP-3

Budesonide/formoterol effects on metalloproteolytic balance in TGFβ-activated human lung fibroblasts

SummaryIn the airways of asthmatic patients, activated fibroblasts account for an excessive matrix production including proteoglycans (PGs). Transforming growth factor-β (TGFβ), metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play key roles in matrix turnover. It is unclear whether asthma therapy with combination of inhaled glucocorticoids and long-acting β2-agonists affects metalloproteolytic equilibrium and by that counteracts airway fibrosis.The effects of the glucocorticoid, budesonide, and the long-acting β2-agonist, formoterol, on the PG production and the activity of PGs' main regulators: MMP-3, MMP-9, MMP-2 and TIMP-1 were investigated in human lung fibroblasts (HFL-1) treated for 24h with TGFβ1 (10ng/ml) without/with budesonide (10−9 to 10−6M) and/or formoterol (10−11 to 10−6M).TGFβ1 significantly increased production of PGs and TIMP-1, and the activity of MMP-3, MMP-9 and MMP-2. Concurrent budesonide/formoterol combination counteracted the enhanced: PG and TIMP-1 production, MMP-9 activity and MMP-9/TIMP-1 ratio, whereas MMP-2 and MMP-3 were not affected and so their ratios to TIMP-1 were significantly increased. Budesonide or formoterol alone achieved equal effects as budesonide/formoterol on MMP-9 and MMP-9/TIMP-1 ratio but had no effects on TIMP-1, MMP-2 or MMP-3. In the formoterol absence, higher budesonide concentrations were required to reduce the PG production, whereas formoterol alone had no effects.These results suggest that the budesonide/formoterol combination enhanced metalloproteolytic activity of human lung fibroblasts via a synergistic decrease of TIMP-1, and that this mechanism may be involved in the synergistic inhibition of the TGFβ1-induced PG production. This implies that budesonide/formoterol combination therapy can counteract excessive matrix production and thus pathological airway fibrotic remodeling in asthma

The Effects of Oxygen Therapy on Myocardial Salvage in ST Elevation Myocardial Infarction Treated with Acute Percutaneous Coronary Intervention: The Supplemental Oxygen in Catheterized Coronary Emergency Reperfusion (SOCCER) Study.

Despite a lack of scientific evidence, oxygen has long been a part of standard treatment for patients with acute myocardial infarction (AMI). However, several studies suggest that oxygen therapy may have negative cardiovascular effects. We here describe a randomized controlled trial, i.e. Supplemental Oxygen in Catheterized Coronary Emergency Reperfusion (SOCCER), aiming to evaluate the effect of oxygen therapy on myocardial salvage and infarct size in patients with ST elevation myocardial infarction (STEMI) treated with a primary percutaneous coronary intervention (PCI)

Perceptions of ambulance nurses on their knowledge and competence when assessing psychiatric mental illness

Aims and objectives: To obtain the current perception of the knowledge and competence of pre-hospital emergency specialist nurses (ambulance) in attending patients with psychiatric symptoms. Background: Psychiatric illnesses have increased throughout the population. Consequently, pre-hospital emergency services frequently attend individuals with suspected or known mental illnesses. Design: We employed a set of quantitative and qualitative methods to gain a deeper understanding of ambulance nurses' self-evaluated knowledge. Methods: Seven ambulance nurses received and completed a survey questionnaire prior commencing employment in November 2019. Then, we conducted interviews to explore ambulance nurses' perceptions of their own knowledge and competence when attending individuals with mental disorders. The surveys were analysed with descriptive statistics, followed by content analysis. Results: Three topics emerged: the encounter of patients with mental illness; the awareness of lacking knowledge about mental illnesses; and the expectations for future Prehospital Emergency Psychiatric Response Teams. Although ambulance nurses already possessed basic knowledge regarding psychiatric illnesses, it was insufficient, based on their perception of appropriate care. Ambulance nurses considered that combining pre-hospital and psychiatric expertise in the pre-hospital emergency unit would increase their in-depth knowledge about various psychiatric illnesses, the treatment options and the alternatives regarding where to deliver patients for continued care

A Prehospital Emergency Psychiatric Unit in an Ambulance Care Service from the Perspective of Prehospital Emergency Nurses : A Qualitative Study

The prevalence of mental illness is steadily increasing, and ambulance teams frequently attend cases with suspected mental illness. A pilot project, Psychiatric Emergency Response Team (PAP), was carried out in which a prehospital emergency nurse (PEN) was accompanied by a psychiatric specialist nurse in the assessment of individuals with mental illness. The aim of the present study was to evaluate a prehospital emergency psychiatric unit from the perspective of PENs. A qualitative method using content analysis was applied. Seven senior PENs who had worked for 1 year in a prehospital psychiatric ambulance unit were interviewed individually. The analysis resulted in one main theme, “Transition from limited care and insufficient competence to improved and adequate care for psychiatric patients in ambulance care”. This emerged from six subcategories: inter-professional development, access to patient records, the ambulance vehicle, non-conveyed patients, cooperation with the police and meetings with patients and next of kin. In conclusion, these results suggest that in ambulance care in general, there is a lack of knowledge and skills about mental illnesses and initial care options. The PAP concept opened new avenues for the care of patients with mental illness, which the PENs described very positively as being helpful and valuable

The Experience of Using Video Support in Ambulance Care : An Interview Study with Physicians in the Role of Regional Medical Support

Background: In order to facilitate more effective patient assessment and diagnostic support by improving the flow of information between ambulance nurses (AN) and physicians in the role of regional medical support (RMS), an application was developed for transmitting real-time video images. Objective: The objective of this study was to elucidate the physicians' experiences using a video application to support the assessment and triage procedure in ambulance care, when patients are deemed to not have an urgent need for emergency care. Design: The design for this research was a qualitative interview study. Ten physicians, working as RMS in ambulance care, were purposively selected to participate. The telemedicine concept studied consisted of a real-time video image application, in addition to the currently used mobile phone. When a patient was deemed eligible for inclusion in the study, the ambulance nurse (AN) contacted the RMS via telephone to initiate a video consultation. To elucidate the RMS experience of using the application, a conventional content analysis was performed. Results: The main theme "a feeling of being satisfied through a sense of increased patient safety" emerged from the following two categories: adds value in diagnosing situations (three subcategories, i.e., support in diagnosing, usability, and technical weakness) and increase communication opportunities (four subcategories, i.e., assessing the level of care, patient dialogue, professional communication, and team learning). Conclusions: Physicians in the role of RMS experienced a positive impact using video image transmission in addition to the currently used mobile phone. This evaluation was derived from a sense of increased patient safety in the assessment situation when patients were considered to be triaged to self-care

TGFβ-induced matrix production by bronchial fibroblasts in asthma: Budesonide and formoterol effects.

To investigate the mechanisms of enhanced airway deposition of subepithelial collagen in asthma and its sensitivity to drug therapy with combination of an inhaled glucocorticosteroid (GC) and a long-acting β(2)-agonist (LABA), a cell model system involving bronchial fibroblasts derived from biopsies from patients with stable mild-to-moderate asthma has been used. To mimic unstable conditions and severe asthma, fibroblasts were stimulated ex vivo with TGFβ1. Primary fibroblasts established from central bronchial biopsies from 8 asthmatic patients were incubated for 24 h with 0.4% serum or TGFβ1 (10 ng/ml) with/without the GC budesonide (BUD; 10 nM) and/or the LABA formoterol (FORM; 0.1 nM). Procollagen peptide I (PICP), metalloproteinase (MMP)-1 and tissue inhibitor of MMPs (TIMP-1) were determined in culture media using ELISA while the activity of MMP-2, -3, -9 by zymography. Metabolically labeled proteoglycans, biglycan and decorin, associated with collagen fibrillation/deposition, were separated using chromatography and SDS-PAGE. The levels of PICP and biglycan were increased 2-fold by TGFβ1 (p < 0.05). The BUD and FORM combination reduced the PICP increase by 58% (p < 0.01) and the biglycan by 36% (p < 0.05) while each drug alone had no effect. Decorin levels were reduced by TGFβ1 in fibroblasts of most patients; BUD alone and BUD and FORM completely counteracted this decrease. MMPs and TIMP-1 were not affected by TGFβ1 or the drugs. These results suggest that BUD and FORM combination therapy, without affecting metalloproteolytic balance, has a potential to counteract enhanced collagen production by bronchial fibroblasts in asthma and to normalize the production of small proteoglycans which may affect collagen fibrillation and deposition

Lung fibroblast proteoglycan production induced by serum is inhibited by budesonide and formoterol

Copyright (C) 2005 by the American Thoracic Society. 1 Proteoglycans contribute to extracellular matrix remodeling in asthmatic airways. We investigated the effects of budesonide, a glucocorticoid, and formoterol, a long-acting ß2adrenergic agonist, on serum-induced proteoglycan production by human lung fibroblasts. In 10 % serum, total proteoglycan production was increased 1.5-fold (p&lt;0.01) compared to basal production in 0.4 % serum. Budesonide (10-8 M) reduced this increase by 44 % (p&lt;0.01), and while formoterol (10-10 –10-8 M) had no inhibitory effects, the drug combination abolished the increase (p&lt;0.01) without affecting fibroblast proliferation. This synergistic effect required functional glucocorticoid and-adrenergic receptors. The production of the proteoglycans decorin, biglycan, perlecan, and versican, was increased 2.5–5-fold (p&lt;0.01) in 10 % serum. Combination treatment with budesonide (10-8 M) and formoterol (10-10 M) abolished this increase to a significantly greater extent than either drug alone. In 10 % serum, only versican mRNA was increased 1.4-fold (p&lt;0.05), while decorin mRNA was reduced to 39 % (p&lt;0.01) of basal expression. These serum effects were counteracted by the drug combination bu