Enhanced IL-1β Release Following NLRP3 and AIM2 Inflammasome Stimulation Is Linked to mtROS in Airway Macrophages in Pulmonary Fibrosis

Fibrotic Interstitial lung diseases (ILDs) are complex disorders of variable clinical behaviour. The majority of them cause significant morbidity, whilst Idiopathic Pulmonary Fibrosis (IPF) is recognised as the most relentless. NLRP3, AIM2, and NLRC4 inflammasomes are multiprotein complexes driving IL-1β release; a proinflammatory and profibrotic cytokine. Several pathogenetic factors associated with IPF are identified as inflammasome activators, including increases in mtROS and bacterial burden. Mitochondrial oxidation and alterations in bacterial burden in IPF and other ILDs may lead to augmented inflammasome activity in airway macrophages (AMs). IPF (n=14), non-IPF-ILDs (n=12) patients and healthy subjects (n=12) were prospectively recruited and AMs were isolated from bronchoalveolar lavage. IL-1β release resulting from NLRP3, AIM2 and NLRC4 inflammasomes stimulation in AMs were determined and baseline levels of mitochondrial ROS and microbial burden were also measured. Our results showed that NLRP3 was more inducible in IPF and other ILDs compared to controls. Additionally, following AIM2 activation IL-1β release was significantly higher in IPF compared to controls, whereas similar trends were observed in Non-IPF-ILDs. NLRC4 activation was similar across groups. mtROS was significantly associated with heightened NLRP3 and AIM2 activation, and mitochondrial antioxidant treatment limited inflammasome activation. Importantly, microbial burden was linked to baseline IL-1β release and AIM2 and IL-18 relative expression independently of mtROS. In conclusion, the above findings suggested a link between the overactivation of NLRP3 and AIM2 inflammasomes, driven by mitochondrial oxidation, in the pathogenesis of lung fibrosis while changes in the microbiota may prime the inflammasome in the lungs.

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The interplay between inflammasome activation, mitochondrial oxidation and bacterial burden in Interstitial Lung Diseases

10.12681/eadd/50016 ◽

2021 ◽

Author(s):

Αθηνά Τραχαλάκη

Keyword(s):

Lung Diseases ◽

Interstitial Lung Diseases ◽

Inflammasome Activation ◽

Bacterial Burden ◽

Mitochondrial Oxidation

Οι Διάχυτες Διάμεσες Πνευμονοπάθειες(ΔΔΠ) και πιο συγκεκριμένα η Ιδιοπαθής Πνευμονική Ίνωση (ΙΠΙ) είναι νοσήματα με μεγάλη ετερογένεια όσον αφορά την πρόοδο νόσου καθώς και την ανταπόκριση στην θεραπεία. Στοιχεία πρόσφατων ερευνών έχουν αποκαλύψει κοινά παθογενετικά μονοπάτια στις διαφορετικές ινωτικές διάμεσες πνευμονοπάθειες που οδηγούν στην έναρξη και πρόοδο της ίνωση. Τα μακροφάγα και τα μονοκύτταρα ελέγχουν την ισορροπία μεταξύ επούλωσης και ίνωσης μετά από κάποιο ερέθισμα στους ιστούς. Στους πνεύμονες τα κυψελιδικά μακροφάγα είναι κύτταρα εμβρυικής προελεύσεως με αντι-φλεγμονώδης και αντι-ινωτικες δράσεις και η λειτουργία τους αποσκοπεί στην διατήρηση της ισορροπίας. Μετά από ένα ινωτικό ή φλεγμονώδες ερέθισμα, μονοκύτταρα από τον μυελό τον οστών επιστρατεύονται στους πνεύμονες και παίρνουν χαρακτήρες κυψελιδικών μακροφάγων. Αυτού του είδους τα μονοκύτταρα/μακροφάγα είναι περισσότερο φλεγμονώδη και ινωτικά και έχουν συσχετισθεί με την παθογένεια της ίνωσης. Το φλεγμονόσωμα είναι ενας από τους κεντρικούς μηχανισμούς με τους οποίους τα μακροφάγα παράγουν κυτταροκίνες. Πρόκειται για κυττοσολικά σύμπλοκα πρωτεϊνών που δρουν ως αισθητήρες του ανοσοποιητικού συστήματος. Ο ρόλος τους είναι να μετατρέπουν και να απελευθερώνουν την κυτταροκίνη IL-1β στην ενεργή της μορφή. Η IL-1β είναι μία ισχυρή προ-φλεγμονώδη κυτταροκίνη που έχει συσχετισθεί με οξεία πνευμονική βλάβη και ίνωση. Το NLRP3, το πιο γνωστό φλεγμονόσωμα, ενεργοποιείται από μια ποικιλία ερεθισμάτων συμπεριλαμβανομένων των ATP, nigericin και ROS. Το AIM2 φλεγμονοσωμα ενεργοποιείται από το ελεύθερο δίκλωνο DNA (dsDNA) και το NLRC4 από το μαστίγιο τον βακτηρίων. Αρκετοί παράγοντες ενεργοποίησης των φλεγμονοσωμάτων έχουν αναγνωριστεί ως πιθανοί παθογενετικοί παράγοντες στην ίνωση των πνευμόνων.Η μιτοχονδριακή δυσλειτουργία και η επακόλουθη οξείδωση των μιτοχονδρίων θεωρείται ένα από τα βασικά παθογενετικά μονοπάτιατης ΙΠΙ. Επιπλέον, αλλαγές στο μικροβίωμα έχουν συσχετισθεί με την παθογένεια της νόσου, καθώς η υπερανάπτυξη συγκεκριμένων μικροβιακών ειδών επηρεάζει την πρόοδο της ίνωσης και την απελευθέρωση συγκεκριμένων κυτταροκινών από τα κύτταρα του ανοσοποιητικού συστήματος. Σε αυτήν τη μελέτη υποθέσαμε ότι τα φλεγμονόσωματτα είναι υπερ-ενεργοποιημένα στα κυψελιδικά μακροφάγα ασθενών με ίνωση, ως αποτέλεσμα της μιτοχονδριακής οξείδωσης και της διαταραχής του μικροβιώματος. Στην συγκεκριμένη προοπτική μελέτη συμπεριλήφθηκαν ασθενείς με ίνωση των πνευμόνων (τόσο ασθενείς με ΙΠΙ όσο και ασθενείς με ίνωση διαφορετικής της ΙΠΙ) και υγιείς μάρτυρες. Οι ασθενείς υπεβλήθησαν σε βρογχοσκόπηση και λάβαμε το βρογχοκυψελιδικό έκπλυμα (BALF). Από το έκπλυμα απομονώθηκαν τα κυψελιδικά μακροφάγα που στη συνέχεια καλλιεργήθηκαν με σκοπό την ενεργοποίηση των Φλεγμονοσωμάτων, NLRP3, AIM2 και NLRC4. Παράλληλα, μετρήθηκε το μιτοχονδριακό ROS στα μακροφάγα και μικροβιακό φορτίο στο κυψελιδικό έκπλυμα.Δεν υπήρξε αξιοσημείωτη διαφορά στη βασική ενεργοποίηση των φλεγμονοσωμάτων στην πνευμονική ίνωση. Ωστόσο, μετά από ενεργοποίηση, το NLRP3 μπορούσε να υπερ-ενεργοποιηθεί στην ΙΠΙ και στα άλλα ΔΔΠ, σε σύγκριση με τους υγιείς μάρτυρες. Η ενεργοποίηση του AIM2 ήταν επίσης πιο επαγώγιμη στην ΙΠΙ σε σύγκριση με τους μάρτυρες, με παρόμοιες τάσεις να παρατηρούνται στα άλλα ΔΔΠ. Η ενεργοποίηση του NLRC4 ήταν παρόμοια μεταξύ των ομάδων. Η μιτοχονδριακή οξείδωση(mtROS) συσχετίστηκε σημαντικά με αυξημένη ενεργοποίηση τόσο του NLRP3 όσο και του AIM2 φλεγμονοσώματος. Η ενεργοποίηση του NLRP3 προκαλεί μια έκρηξη μιτοχονδιακού ROS, το οποίο μπορούσε να ανασταλεί έπειτα από μιτοχονδριακή αντιοξειδωτική θεραπεία. Παρομοίως, η αντιοξειδωτική θεραπεία αναστέλλει την ενεργοποίηση του φλεγμονώματος και την απελευθέρωση της IL-1β. Το μικροβιακό φορτίο μετρήθηκε στους ασθενείς με ΔΔΠ και ΙΠΙ και το επίπεδο του σχετιζόταν με την απελευθέρωση της IL-1β από τα καλλιεργούμενα μακροφάγα και επίσης με την έκφραση των ΑΙΜ2 και IL-18 ανεξάρτητα από το mtROS.Η μελέτη αυτή αποτελεί την πρώτη προσπάθεια χαρακτηρισμού της σχέσης μιτοχονδριακής οξείδωσης, μικροβιακού φορτίου και φλεγμονοσωμάτων σε ασθενείς με πνευμονική ίνωση. Τα παραπάνω ευρήματα υποδηλώνουν ότι υπάρχει συσχέτιση υπερ-ενεργοποίσης των Φλεγμονοσωμάτων NLRP3 και AIM2 με αυξημένη μιτοχονδριακή οξείδωση. Επιπλέον το μικροβιακό φορτίο σχετίζεται και αυτό με την σειρά του με προ-ενεργοποίηση των φλεγμονοσωμάτων στους πνεύμονες ασθενών με πνευμονική ίνωση.

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Antifibrotic Therapies and Progressive Fibrosing Interstitial Lung Disease (PF-ILD): Building on INBUILD

Journal of Clinical Medicine ◽

10.3390/jcm10112285 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2285

Author(s):

John N. Shumar ◽

Abhimanyu Chandel ◽

Christopher S. King

Keyword(s):

Interstitial Lung Disease ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Lung Disease ◽

Lung Diseases ◽

Interstitial Lung Diseases ◽

Treatment Pathway ◽

Antifibrotic Therapy ◽

New Treatment ◽

Fibrotic Lung Diseases

Progressive fibrosing interstitial lung disease (PF-ILD) describes a phenotypic subset of interstitial lung diseases characterized by progressive, intractable lung fibrosis. PF-ILD is separate from, but has radiographic, histopathologic, and clinical similarities to idiopathic pulmonary fibrosis. Two antifibrotic medications, nintedanib and pirfenidone, have been approved for use in patients with idiopathic pulmonary fibrosis. Recently completed randomized controlled trials have demonstrated the clinical efficacy of antifibrotic therapy in patients with PF-ILD. The validation of efficacy of antifibrotic therapy in PF-ILD has changed the treatment landscape for all of the fibrotic lung diseases, providing a new treatment pathway and opening the door for combined antifibrotic and immunosuppressant drug therapy to address both the fibrotic and inflammatory components of ILD characterized by mixed pathophysiologic pathways.

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When things go wrong: Exploring possible mechanisms driving the progressive fibrosis phenotype in interstitial lung diseases

European Respiratory Journal ◽

10.1183/13993003.04507-2020 ◽

2021 ◽

pp. 2004507

Author(s):

Moisés Selman ◽

Annie Pardo

Keyword(s):

Pulmonary Fibrosis ◽

Lung Diseases ◽

Molecular Mechanisms ◽

Lung Parenchyma ◽

Interstitial Lung Diseases ◽

Unknown Etiology ◽

Clinical Behavior ◽

The Past ◽

Appropriate Treatment ◽

Different Types

Interstitial lung diseases (ILD) comprise a large and heterogeneous group of disorders of known and unknown etiology characterised by diffuse damage of the lung parenchyma. In the past years, it has become evident that patients with different types of ILD are at risk of developing progressive pulmonary fibrosis known as pulmonary fibrosing ILD (PF-ILD). This is a phenotype behaving similar to idiopathic pulmonary fibrosis, the archetypical example of progressive fibrosis. PF-ILD is not a distinct clinical entity but describes a group of ILD with a similar clinical behavior. This phenotype may occur in diseases displaying distinct etiologies and different biopathology during their initiation and development. Importantly, these entities may have the potential for improvement or stabilisation prior to entering in the progressive fibrosing phase. The crucial questions are (1) why a subset of patients develops a progressive and irreversible fibrotic phenotype even with appropriate treatment, and (2) what the pathogenic mechanisms driving progression possibly are. We here provide a framework highlighting putative mechanisms underlying progression, including genetic susceptibility, aging, epigenetics, the structural fibrotic distortion, the aberrant composition and stiffness of the extracellular matrix, and the emergence of distinct profibrotic cell subsets. Understanding the cellular and molecular mechanisms behind PF-ILD will provide the basis for identifying risk factors and appropriate therapeutical strategies.

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The epidemiology of idiopathic pulmonary fibrosis and interstitial lung diseases at risk of a progressive-fibrosing phenotype

European Respiratory Review ◽

10.1183/16000617.0077-2018 ◽

2018 ◽

Vol 27 (150) ◽

pp. 180077 ◽

Cited By ~ 34

Author(s):

Amy L. Olson ◽

Alex H. Gifford ◽

Naohiko Inase ◽

Evans R. Fernández Pérez ◽

Takafumi Suda

Keyword(s):

At Risk ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Lung Diseases ◽

Epidemiological Data ◽

Interstitial Lung Diseases ◽

Global Distribution ◽

Clinical Classification ◽

Heterogeneous Nature ◽

Broad Overview

The availability of epidemiological data relating to interstitial lung diseases (ILDs) has increased over recent years, but information on the prevalence and incidence of ILDs of different aetiologies remains limited. Despite global distribution, the proportion of patients who develop a progressive phenotype across different ILDs is not well known. Disease behaviour is well documented in idiopathic pulmonary fibrosis but idiosyncratic in other ILDs that may present a progressive fibrosing phenotype. Possible reasons may include the heterogeneous nature of the aetiology, the complexity of diagnosis (and subsequent documentation of cases) and the methods employed to retrospectively analyse patient databases. This review presents a broad overview of the epidemiological data available for ILDs that may present a progressive-fibrosing phenotype, collectively and stratified according to clinical classification. We also note where further data are needed in comparison to the well-studied IPF indication.

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Personalised medicine in interstitial lung diseases

European Respiratory Review ◽

10.1183/16000617.0117-2017 ◽

2018 ◽

Vol 27 (148) ◽

pp. 170117 ◽

Cited By ~ 7

Author(s):

Maria A. Kokosi ◽

George A. Margaritopoulos ◽

Athol U. Wells

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Trial Design ◽

Lung Diseases ◽

Personalised Medicine ◽

Interstitial Lung Diseases ◽

Molecular Pathways ◽

Prognostic Evaluation ◽

Complex Disorders ◽

Distinct Disease ◽

Genetic Profiles

Interstitial lung diseases in general, and idiopathic pulmonary fibrosis in particular, are complex disorders with multiple pathogenetic pathways, various disease behaviour profiles and different responses to treatment, all facets that make personalised medicine a highly attractive concept. Personalised medicine is aimed at describing distinct disease subsets taking into account individual lifestyle, environmental exposures, genetic profiles and molecular pathways. The cornerstone of personalised medicine is the identification of biomarkers that can be used to inform diagnosis, prognosis and treatment stratification. At present, no data exist validating a personalised approach in individual diseases. However, the importance of the goal amply justifies the characterisation of genotype and pathway signatures with a view to refining prognostic evaluation and trial design, with the ultimate aim of selecting treatments according to profiles in individual patients.

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Idiopathic Pulmonary Fibrosis

Chest Imaging ◽

10.1093/med/9780199858064.003.0078 ◽

2019 ◽

pp. 453-457

Author(s):

Cylen Javidan-Nejad

Keyword(s):

Lung Cancer ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Pulmonary Edema ◽

Interstitial Pneumonia ◽

Lung Diseases ◽

Usual Interstitial Pneumonia ◽

Primary Lung Cancer ◽

Interstitial Lung Diseases ◽

Pathologic Diagnosis

Idiopathic pulmonary fibrosis (IPF) represents one of the most common chronic interstitial lung diseases. Usual interstitial pneumonia (UIP) is the pathologic diagnosis of IPF and can be diagnosed when honeycombing is present with a basilar and peripheral predominance and findings not typical of UIP are absent. In the current era, when a diagnosis of UIP is made with confidence on HRCT, biopsy can be avoided. Yet, one must be familiar with mimics of UIP/IPF (most notably pulmonary edema superimposed on emphysema) to avoid confusion misdiagnosis. Radiologists must also be familiar with potential complications of UIP including progression, infection, accelerated fibrosis (which can be lethal) and primary lung cancer (which has an increased incidence in UIP).

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Dynamics in diagnoses and pharmacotherapy before and after diagnosing idiopathic pulmonary fibrosis

ERJ Open Research ◽

10.1183/23120541.00479-2020 ◽

2020 ◽

Vol 6 (4) ◽

pp. 00479-2020

Author(s):

Jesper Rømhild Davidsen ◽

Lars Christian Lund ◽

Christian B. Laursen ◽

Jesper Hallas ◽

Daniel Pilsgaard Henriksen

Keyword(s):

Drug Use ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Lung Diseases ◽

Interstitial Lung Diseases ◽

Opium Alkaloids ◽

Before And After ◽

Oral Corticosteroids ◽

Drug Treatments ◽

Respiratory Drugs

BackgroundIdiopathic pulmonary fibrosis (IPF) is a well-characterised interstitial lung disease. Typically, IPF diagnosis is delayed due to nonspecific symptoms, but can also be delayed due to treatment attempts on false indication or due to treatment targeting common comorbidities. This observational study aimed to assess the dynamics in the medication and diagnosis patterns in the period before and after an IPF diagnosis.MethodsWe identified all Danish patients with IPF between 2002 and 2017. We evaluated new and ongoing drug treatments and incident diagnoses 36 months before and 12 months after an IPF diagnosis by use of Danish nationwide registries. To aid interpretation, 10 random controls were recruited for each case.ResultsA total of 650 IPF patients were identified (median age 73 years (interquartile range 65–78), 70.3% males). Prior to the IPF diagnosis, the most prevalent diagnoses were dyspnoea and non-IPF interstitial lung diseases. For drug use, IPF patients had higher initiation rates for antibiotics, oral corticosteroids and mucolytics. In terms of drug volume, IPF patients used more respiratory drugs, antibiotics, immunosuppressants, corticosteroids, proton pump inhibitors, benzodiazepines and opium alkaloids within the 6 months preceding their IPF diagnosis, compared to the controls. Overall drug use decreased after an IPF diagnosis, mainly due to a reduced glucocorticoid and cardiovascular drug use.ConclusionAmong IPF patients, an increased drug use was observed for diagnoses with symptoms overlapping those of IPF, particularly this was observed during the last 6 months before an IPF diagnosis. This emphasises the need for an increased IPF awareness.

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CA 19-9 serum levels in patients with end-stage idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases (ILDs): Correlation with functional decline

Chronic Respiratory Disease ◽

10.1177/1479973120958428 ◽

2020 ◽

Vol 17 ◽

pp. 147997312095842

Author(s):

Elisabetta Balestro ◽

Gioele Castelli ◽

Nicol Bernardinello ◽

Elisabetta Cocconcelli ◽

Davide Biondini ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Lung Diseases ◽

Lung Transplant ◽

Functional Decline ◽

Serum Levels ◽

Interstitial Lung Diseases ◽

Disease Course ◽

Rapid Progressors ◽

End Stage

Idiopathic pulmonary fibrosis presents a progressive and heterogeneous functional decline. CA 19-9 has been proposed as biomarker to predict disease course, but its role remains unclear. We assessed CA 19-9 levels and clinical data in end-stage ILD patients (48 IPF and 20 non-IPF ILD) evaluated for lung transplant, to correlate these levels with functional decline. Patients were categorized based on their rate of functional decline as slow (n = 20; ΔFVC%pred ≤ 10%/year) or rapid progressors (n = 28; ΔFVC%pred ≥ 10%/year). Nearly half of the entire patients (n = 32; 47%) had CA 19-9 levels ≥37kU/L. CA 19-9 levels in IPF were not different from non-IPF ILD populations, however, the latter group had a median CA 19-9 level above the normal cut-off value of 37 KU/l (60 [17–247] kU/L). Among IPF patients, CA 19-9 was higher in slow than in rapid progressors with a trend toward significance (33vs17kU/L; p = 0.055). In the whole population, CA19-9 levels were inversely related with ΔFVC/year (r = −0.261; p = 0.03), this correlation remained in IPF patients, particularly in rapid progressors (r = −0.51; p = 0.005), but not in non. Moreover, IPF rapid progressors with normal CA 19-9 levels showed the greater ΔFVC/year compared to those with abnormal CA 19-9 (0.95 vs. 0.65 L/year; p = 0.03). In patients with end-stage ILD, CA 19-9 may represent a marker of disease severity, whereas its level is inversely correlated with functional decline, particularly among IPF rapid progressors.

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