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We previously identified a novel molecular subtype of idiopathic pulmonary fibrosis (IPF) defined by increased expression of cilium-associated genes, airway mucin gene MUC5B, and KRT5 marker of basal cell airway progenitors. Here we show the association of MUC5B and cilia gene expression in human IPF airway epithelial cells, providing further rationale for examining the role of cilium genes in the pathogenesis of IPF. We demonstrate increased multiciliogenesis and changes in motile cilia structure of multiciliated cells both in IPF and bleomycin lung fibrosis models. Importantly, conditional deletion of a cilium gene, Ift88 (intraflagellar transport 88), in Krt5 basal cells reduces Krt5 pod formation and lung fibrosis, whereas no changes are observed in Ift88 conditional deletion in club cell progenitors. Our findings indicate that aberrant injury-activated primary ciliogenesis and Hedgehog signaling may play a causative role in Krt5 pod formation, which leads to aberrant multiciliogenesis and lung fibrosis. This implies that modulating cilium gene expression in Krt5 cell progenitors is a potential therapeutic target for IPF.

The aim of this review was to summarize the recent data concerning interstitial lung disease after COVID-19, a field where knowledge is evolving very quickly.It has been found that a proportion of patients displayed fibrotic-like pattern on chest computed tomography shortly after COVID-19 pneumonia. Those lesions can potentially represent precursors of fibrosis, although most of them will resolve until 1 year postinfection. There was a wide range of the prevalence of post-COVID-19 interstitial lung disease detected in the literature, which can be attributed to the heterogeneous definition of lung abnormalities and the discrepancy of study design. The severity of acute COVID-19 disease has been linked to increased risk of residual imaging and functional abnormalities, while reduced DLco was the most common functional abnormality in long-term survivors. Studies indicated that pathophysiology of post-COVID interstitial lung disease shares common mechanisms with idiopathic pulmonary fibrosis. Regarding therapeutic strategies of post-COVID-19 interstitial lung disease, the role of immunosuppressive and antifibrotic treatment is currently under investigation.We still need to learn about the natural history of COVID-19 disease, allowing for a better targeting of therapeutic interventions through a multidisciplinary approach.

Resume Introduction L’asthme est une maladie frequente dont le diagnostic ne necessite habituellement pas le recours a l’imagerie. Celle-ci occupe en revanche une place cle dans les formes severes. Etat des connaissances Un epaississement parietal, de discretes dilatations ou reductions de lumiere des bronches sont habituels dans l’asthme severe. L’epaisseur parietale est correlee au degre d’obstruction ainsi qu’au remodelage et a l’inflammation parietale. De nombreuses affections pouvant mimer un asthme doivent etre reconnues sur le scanner, incluant tumeurs endobronchiques, pneumopathies interstitielles, maladies bronchectasiantes, bronchiolites. Des plages d’hyperdensite peuvent temoigner d’infiltrats eosinophiles transitoires, d’une infection ou d’une forme associee. Des bronchoceles denses sont tres evocateurs d’aspergillose bronchopulmonaire allergique. Perspectives La morphometrie des voies aeriennes, la mesure du piegeage aerique et des defects ventilatoires, en scanner ou en IRM, permettent d’identifier certains sous-groupes morphologiques de patients ayant des caracteristiques fonctionnelles ou inflammatoires distinctes et emergent en tant que biomarqueurs. Conclusion Le scanner thoracique est indique chez tout asthmatique severe afin d’ecarter un diagnostic alternatif. Le developpement d’outils quantitatifs a ouvert la voie au phenotypage des patients par l’imagerie.

International audience; IPF is a devastating lung disease with limited therapeutic possibilities. FGF19, an endocrine FGF, was recently shown to decrease liver fibrosis. To ask whether FGF19 had anti-fibrotic properties in the lung and decipher its effects on common features associated with lung fibrogenesis. We assessed, by Elisa, FGF19 levels in plasma and bronchoalveolar lavage fluids (BALF)obtained from controls and IPF patients. In vivo, using an intravenously administered adeno11 associated virus (AAV), we overexpressed FGF19 at the fibrotic phase of two experimental models of murine lung fibrosis and assessed its effect on lung morphology, lung collagen content, fibrosis markers and pro fibrotic mediator expression, at mRNA and protein levels. In vitro, we investigated whether FGF19 could modulate the TGFβ-induced differentiation of primary human lung fibroblast into myofibroblast and the apoptosis of murine alveolar type II cell. While FGF19 was not detected in BALF, FGF19 concentration was decreased in the plasma of IPF patients compared to controls. In vivo, the overexpression of FGF19 was associated with a marked decrease of lung fibrosis and fibrosis markers, with a decrease of pro fibrotic mediator expression and lung collagen content. In vitro, FGF19 decreased alveolar type 2 epithelial cell apoptosis through the decrease of the proapoptotic BIM protein expression and prevented TGF-ß induced myofibroblast differentiation through the inhibition of JNK phosphorylation. Altogether these data identify FGF19 as an anti-fibrotic molecule with a potential therapeutic interest in fibrotic lung disorders.

Diagnosis of interstitial lung disease is based on the analysis of clinical, biological, radiological, and pathological findings during a multidisciplinary discussion (MDD). When a definitive diagnosis is not possible, guidelines recommend obtaining lung samples through surgical lung biopsy (SLB). We sought to determine morbidity, mortality, diagnostic yield, and therapeutic impact of SLB in the management of patients with interstitial lung disease.We retrospectively analyzed morbidity, mortality, diagnostic yield, and therapeutic changes after SLB for interstitial lung disease performed electively from January 2015 to May 2019 in a reference center. Each case was reviewed during 2 MDDs, first without and then with the result of the SLB.The study group included 73 patients (56% male, age 66 [interquartile range (IQR), 57-70] years, forced vital capacity 79% [IQR, 69%-91%], diffusing capacity of the lungs for carbon monoxide 52% [IQR, 46%-63%]). Median postoperative hospital length of stay was 2 (IQR, 0-11) days. Thirteen (17%) patients experienced at least 1 complication, including pain at 1 month (n = 8) and residual pneumothorax (n = 6). No serious complication or postoperative death was noticed. After the first retrospective MDD, the working diagnosis was idiopathic nonspecific interstitial pneumonia in 20 (27%), idiopathic pulmonary fibrosis in 18 (25%), fibrotic hypersensitivity pneumonitis in 15 (21%), unclassifiable interstitial lung disease in 5 (7%), and other diagnosis in 15 (21%) patients. After SLB and second retrospective MDD, the final diagnosis was modified in 35 (48%) patients and led to therapeutic changes in 33 (45%) patients.SLB is associated with no serious complication or death and notably changes the diagnosis and treatment of interstitial lung disease.

Matrix remodeling is a salient feature of idiopathic pulmonary fibrosis (IPF). Targeting cells driving matrix production and remodeling could be a promising avenue for IPF treatment. Analysis of public transcriptomic database identified paired-related homeobox protein-1 (PRRX1) as an upregulated mesenchymal transcription factor (TF) in IPF. We confirmed that PRRX1 isoforms were upregulated in IPF lung tissue and strongly expressed by lung fibroblasts. In vitro, PRRX1 expression was up-regulated by cues associated with proliferative and anti-fibrotic properties in lung fibroblasts, while IPF fibroblast-derived matrix increased PRRX1 TFs expression in a PDGFR dependent manner in control ones. Meanwhile, signals promoting myofibroblastic differentiation decreased PRRX1 TF. We demonstrated that PRRX1 inhibition decreased fibroblast proliferation by downregulating the expression of S phase cyclins. PRRX1 inhibition also impacted TGF-{beta} driven myofibroblastic differentiation by inhibiting SMAD2/3 phosphorylation through phosphatase PPM1A upregulation and TGFBR2 downregulation, leading to a TGF-{beta} response global decrease. Finally, targeted inhibition of Prrx1 TFs attenuated fibrotic remodeling both in vivo with intra-tracheal antisense oligonucleotides in the bleomycin mice model of lung fibrosis and ex vivo using mouse and Human precision-cut lung slices stimulated with fibrosis cytokine cocktail. Altogether, our results identified PRRX1 as a mesenchymal transcription factor driving myofibroblastic phenotype and lung fibrogenesis. Brief SummaryInhibition of a single fibroblast-associated transcription factor, namely paired-related homeobox protein 1, is sufficient to dampen lung fibrogenesis.

Idiopathic pulmonary fibrosis (IPF) is characterised by an important remodelling of lung parenchyma. Current evidence indicates that the disease is triggered by alveolar epithelium activation following chronic lung injury, resulting in alveolar epithelial type 2 cell hyperplasia and bronchiolisation of alveoli. Signals are then delivered to fibroblasts that undergo differentiation into myofibroblasts. These changes in lung architecture require the activation of developmental pathways that are important regulators of cell transformation, growth and migration. Among others, aberrant expression of profibrotic Wnt-β-catenin, transforming growth factor-β and Sonic hedgehog pathways in IPF fibroblasts has been assessed. In the present review, we will discuss the transcriptional integration of these different pathways during IPF as compared with lung early ontogeny. We will challenge the hypothesis that aberrant transcriptional integration of these pathways might be under the control of a chaotic dynamic, meaning that a small change in baseline conditions could be sufficient to trigger fibrosis rather than repair in a chronically injured lung. Finally, we will discuss some potential opportunities for treatment, either by suppressing deleterious mechanisms or by enhancing the expression of pathways involved in lung repair. Whether developmental mechanisms are involved in repair processes induced by stem cell therapy will also be discussed.

Backgound: Severe eosinophil asthma (SEA) can be treated with mepolizumab (MEPO), an anti-IL-5 Ab, or benralizumab (BENRA), an anti-IL-5R Ab. No data exist on the efficacy of switching from one drug to another that targets the same inflammatory pathway. The aim of this study was to evaluate the impact on asthma control of BENRA, given as a second-line treatment for patients with a non-optimal response to MEPO. Methods: Retrospective evaluation of clinical response to BENRA in patients with SAE and intermediate or poor response to a 12-month trial of MEPO in one asthma expert centre in France. Results: We included 22 patients (36% females; age 49±11, BMI 27±6; FEV1 53±16%). According to the global evaluation of treatment efficiency (GETE), 95.5% of patients had moderate or poor response (score 3-4) to MEPO. Eosinophil count significantly decreased from 521±316 to 167±230 (p=0.039) after MEPO. After a 6-month trial with BENRA, without any wash-out period, 48% of patients had good response (score 1-2) (p=0.012). The proportion of patients with ACT score >20 increased from 15.8% to 25% and that without any exacerbation from 4.5% to 36.6% (p=0.021). Mean ACT score increased from 13±5 to 16±5 and exacerbation rate decreased from 5.7±3.5 to 3±3 (p Conclusions: In real life settings, half of patients with physician-judged incomplete response to MEPO seem to benefit from a switch to BENRA after 6 months, without any significant steroid-sparing effect. Future studies should evaluate the best second-line treatments after anti-IL-5/5R treatment failure.

Introduction Le mepolizumab (MEPO), anticorps anti-IL5, et le benralizumab (BENRA), anti-IL5 recepteur, ont ete developpes pour le traitement de l’asthme severe eosinophile (ASE). A ce jour, il n’y a pas de donnees evaluant le passage d’une biotherapie a une autre ciblant la meme voie inflammatoire. L’objectif de ce travail est d’evaluer la reponse au BENRA prescrit apres une reponse non optimale au MEPO. Methodes Chez les patients ayant un ASE, suivis dans un centre d’asthme, ayant une reponse jugee insuffisante apres 12 mois de MEPO (100 mg/mois) selon le score Global Evaluation Treatment Efficiency (GETE, score 3–4), le traitement a ete arrete et relaye directement par BENRA (30 mg/mois pendant 3 mois puis 30 mg/8 semaines). Nous avons evalue de facon retrospective la reponse au BENRA apres 6 mois selon le score GETE. Resultats Vingt-deux patients ont ete inclus (36 % de femmes, âge moyen 49 ± 11 ans, IMC moyen 27 ± 6 kg/m2, 37 % de fumeurs/ex-fumeurs, 55 % avec polypes nasaux, VEMS moyen 53 ± 16 %). Apres 6 mois de BENRA, 48 % des patients etaient consideres comme de bons ou excellents repondeurs (GETE 1-2). Aucun patient n’a aggrave son asthme (GETE 5). L’evolution des parametres de controle de l’asthme avant MEPO, apres MEPO et a 6 mois BENRA est resumee dans le Tableau 1 . Les bons repondeurs au BENRA (GETE 1-2) avaient plus souvent une polypose (60 vs 44 %, p Conclusion Dans cette evaluation de vraie vie, la moitie des patients avec une reponse insuffisante au MEPO semblent beneficier du relais par BENRA a 6 mois, notamment ceux avec une eosinophilie persistante ou une polypose nasosinusienne. Des etudes randomisees comparant differentes options therapeutiques sont necessaires pour evaluer la meilleure strategie apres un echec de traitement par anti-IL5/IL5R selon le profil du patient.

Herpes viruses have been thought to play a pathogenic role in the pathophysiology of idiopathic pulmonary fibrosis (IPF). We aimed to assess the presence of Human herpes viruses and of the simian herpes virus Saimiri in lung samples to evaluate their potential role in IPF. Methods: We performed real-time PCR assays to determine the presence of Human α-herpes viruses (HSV-1, HSV-2, VZV), β-herpes viruses (hCMV, HHV-6, HHV-7), γ-herpes viruses (EBV, HHV-8), and of herpes virus Saimiri DNA on IPF explants (n=18) or IPF lung biopsy (n=1). Emphysematous lung samples obtained after transplantation (n=2) or samples distant from lung cancer surgery (n=7) or pneumothorax surgery (n=1) were used as controls. Results: At least one herpes virus DNA was detected in 27/29 (93%) of lung samples, with no difference between IPF (n=18/19) and controls (n=9/10, p=1.00). The mean number of herpes virus DNA detected was 1.52 in IPF patients and 1.10 in controls (p=0.10). The rate of co-infections did not significantly differ between IPF (n=9/19) and control patients (n=2/10, p=0.23). All samples were negative for Human α-herpes viruses. Human CMV DNA was detected in 2/19 (10.5%) IPF samples and in 1/10 (10.0%) controls. EBV was detected in 12/19 (68%) IPF and in 5/10 (50%) control samples (p=0.69). Regarding herpes virus Saimiri, no viral DNA was detected in lung samples, neither from IPF nor control groups, whereas it was detected in control cell lines. Conclusion: We found no difference for the prevalence of Human herpes viruses between IPF and control lung samples. Herpes virus Saimiri DNA was not detected in any of the lung biopsies. These data do not support a role for herpes virus infection in IPF.

Introduction Au cours de la fibrose pulmonaire idiopathique (FPI) les voies de signalisation du developpement telles que la voie des Fibroblast Growth Factors (FGF) sont reactivees. Le recepteur FGFR4 a ete suggere comme possible modulateur de la fibrogenese. L’invalidation de Fgfr4 favoriserait le developpement de la fibrose hepatique apres exposition au tetrachloride carbone chez la souris. Nous nous sommes interesses a l’implication de FGFR4 dans la fibrogenese pulmonaire. Methodes L’expression de FGFR4 a ete determinee dans des extraits de poumons totaux de FPI ou de temoins (Western blot, RT-PCR). Le developpement de la fibrose pulmonaire a ete evalue dans un modele murin apres injection intra-tracheale unique de bleomycine (40 μg) chez des souris Fgfr4 -/- et des souris Wild type (WT) littermates, et apres inhibition pharmacologique specifique de FGFR4 par l’inhibiteur Z chez des souris WT par rapport a un groupe controle recevant le solvant seul. L’inhibiteur Z a ete administre par gavage selon un modele preventif de J-1, veille de l’injection de bleomycine, a J14, et selon un modele therapeutique de J7 a J14. La morphologie pulmonaire, le contenu pulmonaire en hydroxyproline et l’expression en RT-PCR et Western blot de marqueurs de fibrose (collagene, fibronectine, l’α-actine du muscle lisse) ont ete evalues. Resultat L’expression de FGFR4 etait diminuee dans des extraits pulmonaires de patients FPI par rapport aux temoins, au niveau proteique et en ARNm. Les souris Fgfr4-/- ne presentaient pas de difference par rapport aux WT concernant le score de fibrose apres injection de bleomycine. Le niveau d’expression proteique du collagene etait diminue chez les souris Fgfr4-/-, cependant le contenu en hydroyproline n’etait pas modifie. Une augmentation de l’α-actine du muscle lisse etait observee au niveau proteique, sans difference significative pour la fibronectine. L’inhibition de FGFR4 par l’inhibiteur Z, n’induisait aucune difference phenotypique par rapport aux souris controles. Conclusion L’expression pulmonaire de FGFR4 etait diminuee au cours de la FPI. Cependant, l’invalidation de Fgfr4 et l’inhibition pharmacologique de FGFR4 ne modifiaient pas le developpement de la fibrose bleomycine-induite chez la souris. Ces donnees ne soutiennent pas l’hypothese d’une implication de FGFR4 dans la physiopathologie de la FPI.

Introduction L’atteinte pulmonaire de l’infection a SARS-CoV-2, responsable du COVID-19, est grave dans 15–20% des cas, avec une pneumopathie bilaterale presentant les caracteristiques histologiques d’un dommage alveolaire diffus. Les fibrocytes circulants, precurseurs des fibroblastes impliques dans la reparation tissulaire, sont associes a un mauvais pronostic dans les maladies fibrosantes pulmonaires et le syndrome de detresse respiratoire aigue. Notre objectif etait de quantifier les fibrocytes circulants chez les patients atteints de COVID et de determiner leur valeur pronostique. Methodes Les fibrocytes circulants (CD45 + /CD15 -/CD34 + /Collagene-1 +) ont ete quantifies en cytometrie de flux chez 57 patients (42 hommes, âge moyen 60 ans [3–87]) hospitalises pour pneumopathie bilaterale hypoxemiante et 15 sujets sains apparies pour l’âge et le sexe. L’infection a SARS-CoV-2 etait confirmee par une PCR naso-pharyngee. L’etendue scannographique des lesions a ete quantifiee. Resultats Le taux median de fibrocytes circulants etait significativement augmente chez les patients par rapport aux temoins (2,49% vs 1,82%, p 75%: 0,57%). Le % de fibrocytes etait diminue lorsqu’une corticotherapie systemique etait deja en place au moment du prelevement (2,28% vs 2,82%, p = 0,04). Un taux de fibrocytes significativement plus bas (1,25%) etait observe chez les patients decedes (6/57) par rapport aux patients rentres a domicile a J28 (2,52%, p = 0,03). Concernant l’evolution scannographique a 3 mois, une regression complete des lesions (13/32) etait associee a un % initial de fibrocytes significativement plus eleve par rapport aux patients presentant une regression partielle ou une stabilite (2,95% vs 2,18%, p = 0,03). Conclusion Le taux de fibrocytes circulants etait significativement augmente chez les patients hospitalises pour une pneumopathie hypoxemiante COVID-19 par rapport a des sujets sains. Les patients ayant l’atteinte la plus severe avaient des % de fibrocytes plus bas, alors qu’un % de fibrocytes plus eleve etait associe a une regression complete des lesions scannographique a 3 mois.

Introduction Le diagnostic de fibrose pulmonaire idiopathique (FPI) repose sur l’analyse des donnees cliniques, d’imagerie et d’histologie au cours d’une discussion multidisciplinaire (DMD). Lorsque l’imagerie est atypique il est recommande d’envisager une biopsie pulmonaire chirurgicale (BPC). Methodes Nous avons evalue retrospectivement l’apport diagnostique de la BPC chez des patients suspects de FPI, ayant beneficie d’une BPC entre janvier 2015 et mai 2019 a l’hopital Bichat. Chaque dossier etait revu au cours d’une DMD par deux pneumologues et un radiologue expert, d’abord sans puis avec le resultat de l’analyse de la BPC. A l’issue de la premiere DMD, deux diagnostics et une proposition therapeutique etaient formules. A l’issue de la seconde DMD, un diagnostic final et une proposition therapeutique etaient retenus. Resultats Durant la periode de l’etude, 73 patients (42 hommes, 31 femmes) ont ete inclus. L’âge median [quartile 25–75] etait de 66 ans [57–70], CV 79 % de la valeur predite [69–91], DLCO 52 % [46–63]. L’analyse des scanners thoraciques selon les recommandations pour le diagnostic de FPI de 2018 [1] retrouvait un aspect de « PIC probable » dans 9 cas (12 %), de « PIC indetermine » dans 30 cas (41 %) dont un aspect de PIC precoce (« early ») dans 4 cas (5 %), et un aspect « evocateur d’un autre diagnostic » dans 34 cas (47 %). A l’issue de la DMD1, les diagnostics finaux se repartissaient comme suit : pneumopathie interstitielle non specifique fibrosante (PINS) 27 % (n = 20) ; FPI 25 % (n = 18) ; pneumopathie d’hypersensibilite (PHS) 21 % (n = 15) ; fibrose inclassable 7 % (n = 5) ; granulomatose 5 % (n = 4) ; pneumopathie interstitielle lymphoide 4 % (n = 3) ; autre diagnostic 11 % (n = 8). Le resultat histologique obtenu apres BPC modifiait le diagnostic propose dans 48 % des cas (n = 35) et aboutissait a un changement de classe therapeutique dans 45 % des cas (n = 33). La concordance diagnostique entre la DMD1 et la DMD2 etait de 66 % pour le diagnostic de FPI, 53 % pour la PHS et de 35 % pour la PINS fibrosante. Un diagnostic de PINS fibrosante en DMD1 aboutissait finalement au diagnostic de FPI apres obtention d’une histologie dans 45 % des cas (n = 9). Conclusion Ces resultats indiquent que la BPC reste un outil central dans la prise en charge diagnostique et therapeutique des PID avec suspicion de FPI.

Introduction L’implication des Herpes virus humains, de l’Herpes virus Saimiri et du Torque Teno Virus (TTV) a ete evoquee dans la physiopathologie de la fibrose pulmonaire idiopathique (FPI) et dans la survenue des exacerbations. La plupart des etudes ont ete conduites a une epoque ou le traitement immunosuppresseur etait la reference dans cette maladie. Notre objectif etait de determiner la presence de ces virus dans le tissu pulmonaire de patients atteints de FPI ne recevant pas de traitement immunosuppresseur. Methodes L’expression des ADN viraux des α- (HSV-1, HSV-2, VZV), β- (hCMV, HHV-6, HHV-7), γ-Herpes virus humains (EBV, HHV-8), de l’Herpes virus Saimiri et du Torque Teno Virus (TTV) a ete determinee par PCR sur des echantillons de parenchyme pulmonaire provenant de 19 patients atteints de FPI (explants pulmonaires, n = 18 ; biopsie pulmonaire chirurgicale, n = 1) et de 10 patients temoins. Treize patients etaient sous anti-fibrosants, 5 patients n’etaient pas traites. Un patient recevait une corticotherapie orale (prednisone Resultats Au moins un ADN d’Herpes virus humain etait detecte dans 18/19 FPI et 9/10 temoins (p = 1,00). Le nombre moyen d’ADN d’Herpes virus humain detecte etait de 1,52 pour les FPI et 1,10 pour les temoins (p = 0,10). Il n’y avait pas de difference concernant le nombre de co-infections entre les FPI (n = 9/19) et les temoins (n = 2/10, p = 0,23). L’ADN des α -Herpes virus n’etait retrouve dans aucun prelevement. L’ADN du CMV etait detecte dans 2/19 FPI (10,5 %) et 1/10 temoin (10,0 %). L’ADN de l’EBV etait detecte dans 12/19 FPI (68 %) et 5/10 temoins (50 %, p = 0,69). L’expression de TTV ne differait pas entre les deux groupes (2,70 versus 2,45 log 10 copies/10 6 cellules, p = 0,92). L’ADN de l’Herpes virus Saimiri n’etait detecte dans aucun echantillon. Conclusion La prevalence des Herpes virus humain dans le tissu pulmonaire est identique entre les FPI et les temoins. L’ADN de l’Herpes virus Saimiri n’etait detecte dans aucun prelevement. Ces donnees ne soutiennent pas l’hypothese d’un role de l’infection herpetique dans la FPI.

International audience

Interstitial lung diseases (ILDs) are a set of heterogeneous lung diseases characterised by inflammation and, in some cases, fibrosis. These lung conditions lead to dyspnoea, cough, abnormalities in gas exchange, restrictive physiology (characterised by decreased lung volumes), hypoxaemia and, if progressive, respiratory failure. In some cases, ILDs can be caused by systemic diseases or environmental exposures. The ability to treat or cure these ILDs varies based on the subtype and in many cases lung transplantation remains the only curative therapy. There is a growing body of evidence that both common and rare genetic variants contribute to the development and clinical manifestation of many of the ILDs. Here, we review the current understanding of genetic risk and ILD.

Introduction Fibroblast differentiation in myofibroblasts is a key feature of idiopathic pulmonary fibrosis (IPF). Paired-related homeobox (PRRX) transcription factors (TF) regulate mesenchymal cells during development and are key TF at the center of a network coordinating fibroblast differentiation. We hypothesized that PRRX1 modulates fibroblast phenotype in IPF. Material and methods Immunohistochemistry (IHC) and real-time quantitative PCR for PRRX were performed on human lung samples and primary human lung fibroblasts (HLF) cultured from IPF and controls. PRRX1 overexpression was obtained in HLF with plasmid transfection. Functional experiments were performed by seeding HLF on dishes with an elastic modulus (EM) of 1.5 or 28 kPa or on a rigid dish. The effects of the ROCK and PTGS2 inhibitors Fasudil and NS398 on PRRX1 expression were evaluated. Results PRRX1 was upregulated in IPF lung and HLF as compared to controls and was mostly detected in fibroblast foci. PRRX1 expression was controlled by soluble factors and by the extracellular matrix stiffness: Profibrotic factors TGF-β and ET-1 downregulated PRRX1 expression in HLF, while PDGF-AA and PGE2 increased PRRX1 expression only in HLF from IPF patients. Soft matrix (EM 1.5 kPa) enhanced PRRX1 expression in HLF through the activation of PTGS2, while a rigid matrix inhibited PRRX1 expression through ROCK activation. PRRX1 overexpression inhibited PDGF-dependent migration, increased the expression of phosphorylated ERK and promoted control and IPF HLF survival after serum deprivation or FAS-L activation. Conclusion These results indicate that PRRX1 is regulated by the fibrotic environment in the lung and controls lung fibroblast migration and survival.