Abstract Chemerin was isolated as the natural ligand of the G protein-coupled receptor ChemR23. Chemerin acts as a chemotactic factor for leukocyte populations expressing ChemR23, particularly ...immature plasmacytoid dendritic cells, but also immature myeloid DCs, macrophages and natural killer cells. Chemerin is expressed by epithelial and non-epithelial cells as an inactive precursor, present at nanomolar concentrations in plasma. Processing of the precursor C-terminus is required for generating bioactive forms of chemerin. Various proteases mediate this processing, including neutrophil serine proteases and proteases from coagulation and fibrinolytic cascades. ChemR23-expressing cells are recruited in human inflammatory diseases, such as psoriasis and lupus. In animal models, both pro-inflammatory and anti-inflammatory roles of chemerin have been reported. Recently, two other receptors for chemerin were described, GPR1 and CCRL2, but their functional relevance is largely unknown. Both chemerin and ChemR23 are also expressed by adipocytes, and the emerging role of chemerin as an adipokine regulating lipid and carbohydrate metabolism is an area of intense research.
Acute exacerbation of interstitial lung disease (ILD) is associated with a poor prognosis and high mortality. Numerous studies have documented acute exacerbation in idiopathic pulmonary fibrosis ...(IPF), but less is known about these events in other ILDs that may present a progressive-fibrosing phenotype. We propose defining acute exacerbation as an acute, clinically significant respiratory deterioration, typically less than 1 month in duration, together with computerised tomography imaging showing new bilateral glass opacity and/or consolidation superimposed on a background pattern consistent with fibrosing ILDs. Drawing on observations in IPF, it is suspected that epithelial injury or proliferation and autoimmunity are risk factors for acute exacerbation in ILDs that may present a progressive-fibrosing phenotype, but further studies are required. Current acute exacerbation management strategies are based on recommendations in IPF, but no randomised controlled trials of acute exacerbation management have been performed. Although there are no formal strategies to prevent the development of acute exacerbation, possible approaches include antifibrotic drugs (such as nintedanib and pirfenidone), and minimising exposure to infection, airborne irritants and pollutants. This review discusses the current knowledge of acute exacerbation of ILDs that may present a progressive-fibrosing phenotype and acknowledges limitations of the data available.
With the increasing use of low dose CT scans, numerous pulmonary nodules are detected. As majority of them are benign, development of efficient non-surgical diagnostic intervention is mandatory. ...Electromagnetic navigation bronchoscopy (ENB) has been developed to reach difficult to access lesions. The aim of the present study was to compare the diagnostic yield of ENB procedures performed in a classical endoscopy suite or in a hybrid room equipped by a cone beam CT (CBCT).
A monocentric randomized study was performed in the Erasme Hospital between January 2020 and December 2021. Lung nodules of maximum 30 mm of diameter were eligible. In both arms (endoscopy or CBCT suites), ENB, fluoroscopic guidance and a radial endobronchial ultrasound were used to reach the lesion. Then six trans-bronchial biopsies (TBB) and one trans-bronchial lung cryobiopsy (TBLC) were performed. Primary outcomes were the diagnostic yield and diagnostic accuracy of the procedure.
Forty-nine patients were randomized (24 in the endoscopy and 25 in the CBCT arms). The lesion size was 15,9 ± 4,6 mm and 16,6 ± 6,0 mm respectively (mean ± SD, p = NS). The diagnostic yield of ENB performed under CBCT guidance was 80% compared to 42% when performed in the endoscopy suite under standard fluoroscopic guidance (p < 0,05). Similarly, the diagnostic accuracy in the CBCT group was 87% compared to 54% for the endoscopy group (p < 0,05). Duration of the procedure in the CBCT and endoscopy arms was 80 ± 23 and 61 ± 13 min respectively (mean ± SD, p < 0,01). Performing TBLC in addition to TBB increased the diagnostic yield by 14% (17 and 12,5% in CBCT and endoscopy suites respectively, p = NS).
This study highlighted the additional value to perform ENB procedure under CBCT guidance for small size (less than 2 cm of diameter) pulmonary nodules.
Clinical trial registration number: NCT05257382.
The Dual Role of Chemerin in Lung Diseases Lavis, Philomène; Bondue, Benjamin; Cardozo, Alessandra Kupper
Cells (Basel, Switzerland),
01/2024, Letnik:
13, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Chemerin is an atypical chemokine first described as a chemoattractant agent for monocytes, natural killer cells, plasmacytoid and myeloid dendritic cells, through interaction with its main receptor, ...the G protein-coupled receptor chemokine-like receptor 1 (CMKLR1). Chemerin has been studied in various lung disease models, showing both pro- and anti-inflammatory properties. Given the incidence and burden of inflammatory lung diseases from diverse origins (infectious, autoimmune, age-related, etc.), chemerin has emerged as an interesting therapeutical target due to its immunomodulatory role. However, as highlighted by this review, further research efforts to elucidate the mechanisms governing chemerin's dual pro- and anti-inflammatory characteristics are urgently needed. Moreover, although a growing body of evidence suggests chemerin as a potential biomarker for the diagnosis and/or prognosis of inflammatory lung diseases, this review underscores the necessity for standardizing both sampling types and measurement techniques before drawing definitive conclusions.
Chemerin is the ligand of the ChemR23 receptor and a chemoattractant factor for human immature dendritic cells (DCs), macrophages, and NK cells. In this study, we characterized the mouse ...chemerin/ChemR23 system in terms of pharmacology, structure-function, distribution, and in vivo biological properties. Mouse chemerin is synthesized as an inactive precursor (prochemerin) requiring, as in human, the precise processing of its C terminus for generating an agonist of ChemR23. Mouse ChemR23 is highly expressed in immature plasmacytoid DCs and at lower levels in myeloid DCs, macrophages, and NK cells. Mouse prochemerin is expressed in most epithelial cells acting as barriers for pathogens but not in leukocytes. Chemerin promotes calcium mobilization and chemotaxis on DCs and macrophages and these functional responses were abrogated in ChemR23 knockout mice. In a mouse model of acute lung inflammation induced by LPS, chemerin displayed potent anti-inflammatory properties, reducing neutrophil infiltration and inflammatory cytokine release in a ChemR23-dependent manner. ChemR23 knockout mice were unresponsive to chemerin and displayed an increased neutrophil infiltrate following LPS challenge. Altogether, the mouse chemerin/ChemR23 system is structurally and functionally conserved between human and mouse, and mouse can therefore be considered as a good model for studying the anti-inflammatory role of this system in the regulation of immune responses and inflammatory diseases.
Abstract
Background
Although increasing data supports the use of transbronchial lung cryobiopsies (TBLCs) for the diagnosis of diffuse parenchymal lung diseases (DPLDs), its role as an alternative to ...surgical lung biopsy (SLB) is still under debate. The aim of this study was to assess the benefit of additional SLBs performed in selected patients after TBLCs.
Method
We conducted a multicentric Belgian prospective trial in which SLBs were performed after TBLCs when the pathological diagnosis was uncertain or if a nonspecific interstitial pneumonia (NSIP) pattern was observed hypothesizing that SLB could provide additional information and that a co-existent UIP pattern could be missed.
Results
Eighty-one patients with TBLCs performed for a DPLD were included in the study between April 2015 and December 2019. A specific histological diagnosis was obtained in 52 patients (64%) whereas no pathological diagnosis following TBLCs was obtained in 13 patients (16%) and a pattern suggestive of a NSIP was observed in 16 patients (20%). Fourteen out of these 29 patients had SLBs after TBLCs. SLBs showed a UIP pattern in 11 (79%), a pattern suggestive of a hypersensitivity pneumonitis in two (14%) and a NSIP pattern in one patient (7%). Among the 16 patients with pathological NSIP following TBLCs, six underwent a SLBs showing a UIP in five and confirming a NSIP in one patient only. A retrospective pathological analysis of patients having both procedures showed a lower diagnostic confidence and agreement among pathologists for TBLCs compared to SLBs. Major factors underlying the added value of SLBs were the bigger size of the sample as well as the subpleural localization of the biopsies.
Conclusions
TBLCs are useful in the setting of DPLDs with a good diagnostic yield. However, our study suggests that SLB provides critical additional information in case TBLCs are inconclusive or show a pattern suggestive of a NSIP, questioning the accuracy of TBLC to adequately identify this histological pattern.
Abstract
Background
Fibroblast activation protein-α (FAPα) is a marker of activated fibroblasts that can be selectively targeted by an inhibitor (FAPI) and visualised by PET/CT imaging. We evaluated ...whether the measurement of FAPα in bronchoalveolar lavage fluids (BALF) and the uptake of FAPI by PET/CT could be used as biomarkers of fibrogenesis.
Methods
The dynamics of lung uptake of
18
F-labeled FAPI (
18
FFAPI-74) was assessed in the bleomycin mouse model at various time points and using different concentrations of bleomycin by PET/CT. FAPα was measured in BALFs from these bleomycin-treated and control mice. FAPα levels were also assessed in BALFs from controls and patients with idiopathic pulmonary fibrosis (IPF).
Results
Bleomycin-treated mice presented a significantly higher uptake of
18
FFAPI-74 during lung fibrinogenesis (days 10 and 16 after instillation) compared to control mice. No significant difference was observed at initial inflammatory phase (3 days) and when fibrosis was already established (28 days).
18
FFAPI-74 tracer was unable to show a dose-response to bleomycin treatment. On the other hand, BALF FAPα levels were steeply higher in bleomycin-treated mice at day 10 and a significant dose-response effect was observed. Moreover, FAPα levels were strongly correlated with lung fibrosis as measured by the modified Aschroft histological analysis, hydroxyproline and the percentage of weight loss. Importantly, higher levels of FAPα were observed in IPF patients where the disease was progressing as compared to stable patients and controls. Moreover, patients with FAPα BALF levels higher than 192.5 pg/mL presented a higher risk of progression, transplantation or death compared to patients with lower levels.
Conclusions
Our preclinical data highlight a specific increase of
18
FFAPI-74 lung uptake during the fibrotic phase of the bleomycin murine model. The measurement of FAPα in BALF appears to be a promising marker of the fibrotic activity in preclinical models of lung fibrosis and in IPF patients. Further studies are required to confirm the role of FAPα in BALF as biomarker of IPF activity and assess the relationship between FAPα levels in BALF and
18
FFAPI-74 uptake on PET/CT in patients with fibrotic lung disease.
Dendritic cells and macrophages are professional APCs that play a central role in initiating immune responses, linking innate and adaptive immunity. Chemerin is a novel chemoattractant factor that ...specifically attracts APCs through its receptor ChemR23. Interestingly, chemerin is secreted as a precursor of low biological activity, prochemerin, which upon proteolytic removal of a C-terminal peptide, is converted into a potent and highly specific agonist of its receptor. Given the fact that APCs are often preceded by polymorphonuclear cells (PMN) in inflammatory infiltrates, we hypothesized that PMN could mediate chemerin generation. We demonstrate here that human degranulated PMNs release proteases that efficiently convert prochemerin into active chemerin. The use of specific protease inhibitors allowed us to identify the neutrophil serine proteases cathepsin G and elastase as responsible for this process. Mass spectrometry analysis of processed prochemerin showed that each protease generates specifically a distinct form of active chemerin, differing in their C terminus and initially identified in human inflammatory fluids. These findings strongly suggest that bioactive chemerin generation takes place during the early stages of inflammation, underscoring the functional contribution of chemerin as a bridge between innate and adaptive immunity.
The PROOF registry is an observational study initiated in October 2013 with the aim to monitor disease progression in a real-world population of patients with idiopathic pulmonary fibrosis (IPF). ...Here, we present longitudinal clinical outcomes from the PROOF registry.
Patients with IPF were enrolled across eight centers in Belgium and Luxembourg. For all patients, clinical outcomes data were collected, including mortality, lung transplant, acute exacerbations, and pulmonary hypertension. For patients treated with pirfenidone at any time during follow-up (2013-2017), for any duration of treatment (the pirfenidone-treated population): pirfenidone treatment patterns were collected; changes in pulmonary function (forced vital capacity FVC and carbon monoxide diffusing capacity DLco) were reviewed up to 24 months post-inclusion; and time-to-event analyses from the time of registry inclusion were performed.
The PROOF registry enrolled a total of 277 patients. During follow-up, 23.1% of patients died, 5.1% received a lung transplant, 5.4% experienced an acute exacerbation, and 6.1% had comorbid pulmonary hypertension. In the pirfenidone-treated population (N = 233, 84.1%), 12.9% of patients had a temporary dose discontinuation and 31.8% had a temporary dose reduction; 4.3% of patients permanently discontinued pirfenidone due to an adverse drug reaction. Mean percent predicted FVC was 81.2% (standard deviation SD 19.0) at Month 0 and 78.3% (SD 25.0) at Month 24, and mean percent predicted DLco was 47.0% (SD 13.2) and 45.0% (SD 16.5), respectively. Rates of ≥ 10% absolute decline in percent predicted FVC and ≥ 15% absolute decline in percent predicted DLco over 24 months were 31.0% and 23.2%, respectively. Mean times from registry inclusion to categorical absolute decline in percent predicted FVC and percent predicted DLco were 20.1 (standard error SE 0.6) months and 23.4 (SE 0.5) months, respectively; mean time from registry inclusion to death was 31.0 (SE 0.9) months.
The PROOF registry is a source of European data characterizing longitudinal clinical outcomes of patients with IPF. Over 12 months of follow-up, pulmonary function remained largely stable in patients with IPF who received pirfenidone for any duration of treatment. Pulmonary function remained similar at 24 months of follow-up, although patient numbers were lower.
PROOF is registered with the relevant authorities in Belgium and Luxembourg, with registration to Comité National d'Éthique et de Recherche (CNER) N201309/03-12 September 2013 and a notification to Comité National de Protection des Données (CNDP) for Luxembourg.
Idiopathic pulmonary fibrosis (IPF) is characterized by a progressive and irreversible respiratory failure. Non-invasive markers of disease activity are essential for prognosis and evaluation of ...early response to anti-fibrotic treatments.
The aims of this study were to determine whether fluorodeoxyglucose (18F-FDG) lung uptake is reduced after initiation of pirfenidone or nintedanib and to assess its possible use as a prognostic factor.
18F-FDG PET/CT was performed in IPF patients and in a murine model of pulmonary fibrosis. PET/CTs were performed at day 8 and day 15 post-instillation of bleomycin in pirfenidone- or vehicule-treated mice. In IPF patients, PET-CT was performed before and 3 months after the initiation of pirfenidone or nintedanib.
In bleomycin-treated mice, pirfenidone significantly reduced the 18F-FDG uptake compared to vehicule-treated mice at day 15 (p < 0.001), whereas no difference was observed at day 8 after bleomycin administration. In IPF patients, 18F-FDG lung uptake before and after 3 months of treatment by nintedanib (n = 11) or pirfenidone (n = 14) showed no significant difference regardless the antifibrotic treatment. Moreover, no difference was noticed between patients with progressive or non-progressive disease at one year of follow up.
Pirfenidone significantly reduces the lung 18F-FDG uptake during the fibrotic phase in a mouse model of IPF. However, these preclinical data were not confirmed in IPF patients 3 months after the initiation of antifibrotic therapy. 18F-FDG seems therefore not useful in clinical practice to assess the early response of IPF patients to nintedanib or pirfenidone.
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