R I Med J (2013). 2021 Sep 1;104(7):26-29.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias. Its signs and symptoms are relatively non-specific, and patients often present with chronic cough, progressive dyspnea, resting or exertional hypoxemia, and inspiratory crackles on lung auscultation. Definitive diagnosis requires the exclusion of known causes of pulmonary fibrosis and identification of the usual interstitial pneumonia (UIP) pattern of disease either on high-resolution computed tomography (HRCT) scan of the chest or on surgical lung biopsy. Multidisciplinary discussion involving pulmonologists, radiologists, and pathologists with expertise in the diagnosis of IPF and other forms of interstitial lung disease is recommended and often required. Management focuses on anti-fibrotic therapy and early referral to lung transplant centers for those who are candidates. This review will discuss the current recommendations for the diagnosis, prognostication, and management of patients with IPF.

PMID:34437662

Int Immunopharmacol. 2021 Aug 17;99:108075. doi: 10.1016/j.intimp.2021.108075. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (PF) is a type of chronic lung disease. Here, we investigated the effect of induced pluripotent stem cell (iPSC)-derived exosomes (iPSC-exosomes) on M2-type macrophages which play a critical role in pulmonary fibrosis. Exosomes were purified from the conditioned medium of iPSCs. Mice models of pulmonary fibrosis were established by intratracheal instillation with 5 mg/kg bleomycin. Thereafter, the histopathological changes and collagen deposition were detected by HE and masson staining. Meanwhile the level of M2-type macrophages was elevated by immunofluorescence staining with F4/80 and Arg-1. Luciferase reporter assay was conducted to verify the binding of miR-302a-3p to ten-eleven translocation 1 (TET1). Our results showed that, after treatment with iPSC-exosomes, the pulmonary fibrosis induced by bleomycin was relieved, with less collagen deposition. In addition, the increased M2-type macrophages in PF mice were reduced upon treatment with iPSC-exosomes. Moreover, we found that the iPSC-exosomes showed higher level of miR-302a-3p. Interestingly, the level of miR-302a-3p in the lungs of PF mice was increased upon treatment with iPSC-exosomes. Furthermore, we verified that TET1 was a direct target of miR-302a-3p. Up-regulation of miR-302a-3p or TET1 silencing repressed M2-type macrophages. Down-regulation of miR-302a-3p abolished the beneficial effects of iPSC-exosomes on pulmonary fibrosis. Collectively, our study revealed that iPSC-exosomes delivered miR-302a-3p to suppress the M2-type macrophages via targeting TET1, thus mitigating pulmonary fibrosis. This study indicates that iPSC-exosomes may become a potential therapeutic agent for pulmonary fibrosis.

PMID:34435585 | DOI:10.1016/j.intimp.2021.108075

Matrix Biol Plus. 2021 Apr 20;11:100062. doi: 10.1016/j.mbplus.2021.100062. eCollection 2021 Aug.

ABSTRACT

The correct balance between collagen synthesis and degradation is essential for almost every aspect of life, from development to healthy aging, reproduction and wound healing. When this balance is compromised by external or internal stress signals, it very often leads to disease as is the case in fibrotic conditions. Fibrosis occurs in the context of defective tissue repair and is characterized by the excessive, aberrant and debilitating deposition of fibril-forming collagens. Therefore, the numerous proteins involved in the biosynthesis of fibrillar collagens represent a potential and still underexploited source of therapeutic targets to prevent fibrosis. One such target is procollagen C-proteinase enhancer-1 (PCPE-1) which has the unique ability to accelerate procollagen maturation by BMP-1/tolloid-like proteinases (BTPs) and contributes to trigger collagen fibrillogenesis, without interfering with other BTP functions or the activities of other extracellular metalloproteinases. This role is achieved through a fine-tuned mechanism of action that is close to being elucidated and offers promising perspectives for drug design. Finally, the in vivo data accumulated in recent years also confirm that PCPE-1 overexpression is a general feature and early marker of fibrosis. In this review, we describe the results which presently support the driving role of PCPE-1 in fibrosis and discuss the questions that remain to be solved to validate its use as a biomarker or therapeutic target.

PMID:34435180 | PMC:PMC8377038 | DOI:10.1016/j.mbplus.2021.100062

ERJ Open Res. 2021 Aug 23;7(3):00321-2021. doi: 10.1183/23120541.00321-2021. eCollection 2021 Jul.

ABSTRACT

BACKGROUND: Pulmonary rehabilitation causes short-term improvement in exercise capacity, dyspnoea and health-related quality of life in idiopathic pulmonary fibrosis (IPF); however, long-term maintenance of the improvement is difficult. Nintedanib, an antifibrotic drug, has been shown to delay the worsening of pulmonary function in IPF. Therefore, the concomitant use of nintedanib with pulmonary rehabilitation is anticipated to contribute to the long-term maintenance of the pulmonary rehabilitation effects. The long-term effect of pulmonary rehabilitation under nintedanib treatment in IPF (FITNESS) study is a multicenter, randomised, prospective, parallel-group, open-label trial.

METHODS: The study will enrol 84 patients with IPF who have been treated with nintedanib. Patients in the pulmonary rehabilitation group will receive a programmed short-term induction pulmonary rehabilitation programme, followed by a maintenance home-based pulmonary rehabilitation programme, while patients in the control group will receive usual outpatient care. Patients in both groups will continue to receive nintedanib treatment throughout the study period. The primary end-point of the study is to compare the change in the 6-min walk distance from the baseline to 12 months between the pulmonary rehabilitation and control groups. The main secondary end-point is endurance exercise time, measured using a bicycle ergometer.

DISCUSSION: FITNESS is the first randomised controlled study to evaluate the long-term effects of pulmonary rehabilitation in IPF treated with nintedanib. This study will address the hypothesis that concomitant use of nintedanib contributes to the maintenance of long-term effects of pulmonary rehabilitation, thus leading to a comprehensive therapeutic approach of "nintedanib and pulmonary rehabilitation" in the antifibrotic era.

PMID:34435033 | PMC:PMC8381249 | DOI:10.1183/23120541.00321-2021

Front Mol Biosci. 2021 Aug 9;8:676569. doi: 10.3389/fmolb.2021.676569. eCollection 2021.

ABSTRACT

While epithelial-fibroblast interactions are viewed as the primary drivers of Idiopathic Pulmonary Fibrosis (IPF), evidence gleaned from animal modeling and human studies implicates innate immunity as well. To provide perspective on this topic, this review synthesizes the available data regarding the complex role of innate immunity in IPF. The role of substances present in the fibrotic microenvironment including pathogen associated molecular patterns (PAMPs) derived from invading or commensal microbes, and danger associated molecular patterns (DAMPs) derived from injured cells and tissues will be discussed along with the proposed contribution of innate immune populations such as macrophages, neutrophils, fibrocytes, myeloid suppressor cells, and innate lymphoid cells. Each component will be considered in the context of its relationship to environmental and genetic factors, disease outcomes, and potential therapies. We conclude with discussion of unanswered questions and opportunities for future study in this area.

PMID:34434962 | PMC:PMC8381017 | DOI:10.3389/fmolb.2021.676569

Am J Hosp Palliat Care. 2021 Aug 26:10499091211041724. doi: 10.1177/10499091211041724. Online ahead of print.

ABSTRACT

INTRODUCTION: Advance care planning is recommended in chronic respiratory diseases, including Idiopathic Pulmonary Fibrosis. In practice, uptake remains low due to patient, physician and system-related factors, including lack of time, training and guidance on timing, components and content of conversations. Our aim was to explore perspectives, experiences and needs to inform a framework.

METHODS: We conducted a qualitative study in western Canada, using semi-structured interviews and inductive analysis. Patient, caregiver and health care professional participants described advance care planning experiences with Idiopathic Pulmonary Fibrosis.

RESULTS: Twenty participants were interviewed individually: 5 patients, 5 caregivers, 5 home care and 5 acute care health care professionals. Two categories, perceptions and recommendations, were identified with themes and subthemes. Participant perceptions were insufficient information and conversations occur late. Recommendations were: have earlier conversations; have open conversations; provide detailed information; and plan for end-of-life. Patients and caregivers wanted honesty, openness and clarity. Professionals related delayed timing to poor end-of-life care and distressing deaths. Home care professionals described comfort with and an engaged approach to advance care planning. Acute care professionals perceived lack of clarity of roles and described personal, patient and caregiver distress.

INTERPRETATION: Analysis of diverse experiences provided further understanding of advance care planning in Idiopathic Pulmonary Fibrosis. Advance care planning is desired by patients and caregivers early in their illness experience. Health care professionals described a need to clarify role, scope and responsibility. Practical guidance and training must be available to care providers to improve competency and confidence in these conversations.

PMID:34433294 | DOI:10.1177/10499091211041724

Sci Signal. 2021 Aug 24;14(697):eaay1027. doi: 10.1126/scisignal.aay1027.

ABSTRACT

Fibrosis is the final pathological outcome and major cause of morbidity and mortality in many common and chronic inflammatory, immune-mediated, and metabolic diseases. Despite the growing incidence of fibrotic diseases and extensive research efforts, there remains a lack of effective therapies that improve survival. The application of omics technologies has revolutionized our approach to identifying previously unknown therapeutic targets and potential disease biomarkers. The application of metabolomics, in particular, has improved our understanding of disease pathomechanisms and garnered a wave of scientific interest in the role of metabolism in the biology of myofibroblasts, the key effector cells of the fibrogenic response. Emerging evidence suggests that alterations in metabolism not only are a feature of but also may play an influential role in the pathogenesis of fibrosis, most notably in idiopathic pulmonary fibrosis (IPF), the most rapidly progressive and fatal of all fibrotic conditions. This review will detail the role of key metabolic pathways, their alterations in myofibroblasts, and the potential this new knowledge offers for the development of antifibrotic therapeutic strategies.

PMID:34429381 | DOI:10.1126/scisignal.aay1027

Pneumologie. 2021 Aug 24. doi: 10.1055/a-1334-2745. Online ahead of print.

ABSTRACT

Health status and quality of life are impaired in patients with idiopathic pulmonary fibrosis (IPF) and idiopathic non-specific interstitial fibrosis (iNSIP). In Germany exists only the K-BILD questionnaire for patients with ILD 1 in a professional translation by Kreuter et al. 2 This questionnaire focuses on the main problems in patients with progressive lung fibrosis in a limited manner. Therefore a new quality of life questionnaire for patients with idiopathic pulmonary fibrosis was developed and linguistically validated.

METHODS: The linguistic validation of our questionnaire was carried out in a multistage process in collaboration with the developer of the questionnaire and bilingual, professional translators. Review by the developers and back translations as well as clinical assessment by IPF- and iNSIP-patients ensured that the translated questionnaire reflected the intention of the original English version of our questionnaire.Cross-validation was carried out with the St. Georges Respiratory Questionnaire (SGRQ).

RESULTS: The new questionnaire concerning the health status was composed in English and German language. The questions cover five scales (sensitivity, selectivity and symptoms like breathlessness and cough and a visual analog scale on general health status) with 23 items.

CONCLUSIONS: The results show that the FFB maps the special needs of the patients with IPF and iNSIP well and can support clinical and scientific questions and can be helpful in monitoring the clinical course.

PMID:34428830 | DOI:10.1055/a-1334-2745

Phytother Res. 2021 Aug 24. doi: 10.1002/ptr.7253. Online ahead of print.

ABSTRACT

Efficient therapy of idiopathic pulmonary fibrosis (IPF) is still a major challenge. The current studies with single-target drug therapy are the pessimistic approaches due to the complex characteristics of IPF. Here, a combination therapy of Tanshinone IIA and Puerarin for IPF was proposed to alleviate IPF due to their antiinflammatory and anti-fibrotic effects. In vivo, the combination therapy could significantly attenuate the area of ground glass opacification that was presented by 85% percentile density score of the micro-CT images when compared to single conditions. In addition, the combination therapy enormously improved the survival rate and alleviated pathological changes in bleomycin (BLM)-induced IPF mice. By using a wide spectrum of infiltration biomarkers in immunofluorescence assay in pathological sections, we demonstrate that fewer IL6 related macrophage infiltration and fibrosis area after this combination therapy, and further proved that IL6-JAK2-STAT3/STAT1 is the key mechanism of the combination therapy. In vitro, combination therapy markedly inhibited the fibroblasts activation and migration which was induced by TGF-β1 or/and IL6 through JAK2-STAT3/STAT1 signaling pathway. This study demonstrated that combination therapeutic effect of TanIIA and Pue on IPF may be related to the reduced inflammatory response targeting IL6, which could be an optimistic and effective approach for IPF.

PMID:34427348 | DOI:10.1002/ptr.7253

Sci Rep. 2021 Aug 23;11(1):17070. doi: 10.1038/s41598-021-96292-w.

ABSTRACT

Anti-melanoma differentiation-associated gene 5-positive dermatomyositis-associated interstitial lung disease (MDA5+ DM-ILD) is a life-threatening disease. This study aimed to develop a novel pulmonary CT visual scoring method for assessing the prognosis of the disease, and an artificial intelligence (AI) algorithm-based analysis and an idiopathic pulmonary fibrosis (IPF)-based scoring were conducted as comparators. A retrospective cohort of hospitalized patients with MDA5+ DM-ILD was analyzed. Since most fatalities occur within the first half year of the disease course, the primary outcome was the six-month all-cause mortality since the time of admission. A ground glass opacity (GGO) and consolidation-weighted CT visual scoring model for MDA5+ DM-ILD, namely 'MDA5 score', was then developed with C-index values of 0.80 (95%CI 0.75-0.86) in the derivation dataset (n = 116) and 0.84 (95%CI 0.71-0.97) in the validation dataset (n = 57), respectively. While, the AI algorithm-based analysis, namely 'AI score', yielded C-index 0.78 (95%CI 0.72-0.84) for the derivation dataset and 0.77 (95%CI 0.64-0.90) for the validation dataset. These findings suggest that the newly derived 'MDA5 score' may serve as an applicable prognostic predictor for MDA5+ DM-ILD and facilitate further clinical trial design. The AI based CT quantitative analysis provided a promising solution for ILD evaluation.

PMID:34426622 | DOI:10.1038/s41598-021-96292-w

Ann Transl Med. 2021 Jul;9(13):1111. doi: 10.21037/atm-2021-5.

ABSTRACT

[This corrects the article DOI: 10.21037/atm-20-4404.].

PMID:34423023 | PMC:PMC8339818 | DOI:10.21037/atm-2021-5

Front Mol Biosci. 2021 Jun 28;8:683267. doi: 10.3389/fmolb.2021.683267. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease causing unremitting extracellular matrix deposition. Transforming growth factor-β (TGF-β) superfamily involves bone morphogenetic proteins (BMPs) and TGF-β, and the balance between the activation of TGF-β-dependent SMADs (Smad2/3) and BMP-dependent SMADs (Smad1/5/8) is essential for fibrosis process. GREM2, initially identified as a TGF-β-inducible gene, encodes a small secreted glycoprotein belonging to a group of matricellular proteins, its role in lung fibrosis is not clear. Here, we identified Gremlin2 as a key regulator of fibroblast activation. Gremlin2 was highly expressed in the serum and lung tissues in IPF patients. Bleomycin-induced lung fibrosis model exhibited high expression of Gremlin2 in the bronchoalveolar lavage fluid (BALF) and lung tissue. Isolation of primary cells from bleomycin-induced fibrosis lung showed a good correlation of Gremlin2 and Acta2 (α-SMA) expressions. Overexpression of Gremlin2 in human fetal lung fibroblast 1 (HFL-1) cells increased its invasion and migration. Furthermore, Gremlin2 regulates fibrosis functions through mediating TGF-β/BMP signaling, in which Gremlin2 may activate TGF-β signaling and inhibit BMP signaling. Therefore, we provided in vivo and in vitro evidence to demonstrate that Gremlin2 may be a potential therapeutic target for the treatment of IPF.

PMID:34422900 | PMC:PMC8377751 | DOI:10.3389/fmolb.2021.683267

Front Med (Lausanne). 2021 Aug 5;8:713698. doi: 10.3389/fmed.2021.713698. eCollection 2021.

ABSTRACT

Background: Idiopathic pulmonary fibrosis (IPF) is characterized by a male predominance. The aim of the study was to explore gender differences in a well-designed French multicentre prospective IPF cohort (COhorte FIbrose, COFI) with a 5-year follow-up. Methods: Between 2007 and 2010, 236 patients with incident IPF were included in COFI. Gender characteristics were compared using a t-test, Chi-squared test and ANOVA, as appropriate. Survival analyses were performed. Results: Fifty-one (22%) females and 185 (78%) males with an average age at diagnosis of 70.1 ± 9.20 and 67.4 ± 10.9 years, respectively, were included in the cohort. Women were significantly less exposed to tobacco smoke [never n = 32 (62.7%) vs. n = 39 (21.1%), p < 0.001] and to occupational exposure [n = 7 (13.7%) vs. n = 63 (34.1%), p = 0.012]. Baseline forced vital capacity, % of predicted (FVC%) was significantly better in women compare to men (83.0% ± 25.0 v. 75.4% ± 18.7 p = 0.046). At presentation honeycombing and emphysema on CT scan were less common in women [n = 40 (78.4%) vs. n = 167 (90.3%) p = 0.041] and [n = 6 (11.8%) vs. n = 48 (25.9%) p = 0.029], respectively. During follow-up fewer women were transplanted compared to men [n = 1 (1.96%) vs. n = 20 (10.8%) p = 0.039]. Medians of survival were comparable by gender [31 months (CI 95%: 28-40) vs. 40 months (CI 95%: 33-72) p = 0.2]. After adjusting for age and FVC at inclusion, being a woman was not associated to a better survival. Conclusions: Women appear to have less advanced disease at diagnosis, maybe due to less exposure history compare to men. Disease progression and overall survival remains comparable regardless gender, but women have less access to lung transplantation.

PMID:34422868 | PMC:PMC8374893 | DOI:10.3389/fmed.2021.713698

Front Med (Lausanne). 2021 Aug 4;8:711194. doi: 10.3389/fmed.2021.711194. eCollection 2021.

ABSTRACT

Introduction: Pulmonary fibrosis includes a spectrum of diseases and is incurable. There is a variation in disease course, but it is often progressive leading to increased breathlessness, impaired quality of life, and decreased life expectancy. Detection of pulmonary fibrosis is challenging, which contributes to considerable delays in diagnosis and treatment. More knowledge about the diagnostic journey from patients' perspective is needed to improve the diagnostic pathway. The aims of this study were to evaluate the time to diagnosis of pulmonary fibrosis, identify potential reasons for delays, and document patients emotions. Methods: Members of European patient organisations, with a self-reported diagnosis of pulmonary fibrosis, were invited to participate in an online survey. The survey assessed the diagnostic pathway retrospectively, focusing on four stages: (1) time from initial symptoms to first appointment in primary care; (2) time to hospital referral; (3) time to first hospital appointment; (4) time to final diagnosis. It comprised open-ended and closed questions focusing on time to diagnosis, factors contributing to delays, diagnostic tests, patient emotions, and information provision. Results: Two hundred and seventy three participants (214 idiopathic pulmonary fibrosis, 28 sarcoidosis, 31 other) from 13 countries responded. Forty percent of individuals took ≥1 year to receive a final diagnosis. Greatest delays were reported in stage 1, with only 50.2% making an appointment within 3 months. For stage 2, 73.3% reported a hospital referral within three primary care visits. However, 9.9% reported six or more visits. After referral, 76.9% of patients were assessed by a specialist within 3 months (stage 3) and 62.6% received a final diagnosis within 3 months of their first hospital visit (stage 4). Emotions during the journey were overall negative. A major need for more information and support during and after the diagnostic process was identified. Conclusion: The time to diagnose pulmonary fibrosis varies widely across Europe. Delays occur at each stage of the diagnostic pathway. Raising awareness about pulmonary fibrosis amongst the general population and healthcare workers is essential to shorten the time to diagnosis. Furthermore, there remains a need to provide patients with sufficient information and support at all stages of their diagnostic journey.

PMID:34422866 | PMC:PMC8371687 | DOI:10.3389/fmed.2021.711194

Stem Cell Res Ther. 2021 Aug 23;12(1):470. doi: 10.1186/s13287-021-02551-y.

ABSTRACT

Pulmonary fibrosis (PF) is a chronic, progressive, fibrotic interstitial disease of the lung with poor prognosis and without effective treatment currently. Data from previous coronavirus infections, such as the Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome, as well as current clinical evidence from the Coronavirus disease 2019 (COVID-19), support that SARS-CoV-2 infection may lead to PF, seriously impacting patient prognosis and quality of life. Therefore, effective prevention and treatment of PF will improve patient prognosis and reduce the overall social and economic burdens. Stem cells, especially mesenchymal stem cells (MSCs) have many great advantages, including migration to damaged lung tissue and secretion of various paracrine factors, thereby regulating the permeability of endothelial and epithelial cells, reducing inflammatory response, promoting tissue repair and inhibiting bacterial growth. Clinical trials of MSCs for the treatment of acute lung injury, PF and severe and critically ill COVID-19 are ongoing. The purpose of this study is to systematically review preclinical studies, explored the effectiveness of MSCs in the treatment of bleomycin (BLM)-induced pulmonary fibrosis and analyze the potential mechanism, combined with clinical trials of current MSCs for idiopathic pulmonary fibrosis (IPF) and COVID-19, so as to provide support for clinical research and transformation of MSCs. Searching PubMed and Embase (- 2021.4) identified a total of 36 preclinical studies of MSCs as treatment of BLM-induced acute lung injury and PF in rodent models. Most of the studies showed the MSCs treatment to reduce BLM-induced lung tissue inflammatory response, inflammatory cell infiltration, inflammatory cytokine expression, extracellular matrix production and collagen deposition, and to improve Ashcroft score. The results of present studies indicate that MSCs may serve as a potential therapeutic modality for the treatment of PF, including viral-induced PF and IPF.

PMID:34420515 | DOI:10.1186/s13287-021-02551-y

Sleep Breath. 2021 Aug 21. doi: 10.1007/s11325-021-02456-3. Online ahead of print.

ABSTRACT

PURPOSE: Sleep-disordered breathing is recognized as a comorbidity in patients with idiopathic pulmonary fibrosis (IPF). Among them, nocturnal hypoxemia has been reported to be associated with poor prognosis and disease progression. We developed a diagnostic algorithm to classify nocturnal desaturation from percutaneous oxygen saturation (SpO2) waveform patterns: sustained pattern, periodic pattern, and intermittent pattern. We then investigated the prevalence of nocturnal desaturation and the association between the waveform patterns of nocturnal desaturation and clinical findings of patients with IPF.

METHODS: We prospectively enrolled patients with IPF from seven general hospitals between April 2017 and March 2020 and measured nocturnal SpO2 and nasal airflow by using a home sleep apnea test. An algorithm was used to classify the types of nocturnal desaturation. We evaluated the association between sleep or clinical parameters and each waveform pattern of nocturnal desaturation.

RESULTS: Among 60 patients (47 men) who met the eligibility criteria, there were 3 cases with the sustained pattern, 49 cases with the periodic pattern, and 41 cases with the intermittent pattern. Lowest SpO2 during sleep and total sleep time spent with SpO2 < 90% were associated with the sustained pattern, and apnea-hypopnea index was associated with the intermittent pattern.

CONCLUSION: We demonstrated the prevalence of each waveform and association between each waveform and sleep parameters in patients with IPF. This classification algorithm may be useful to predict the degree of hypoxemia or the complication of obstructive sleep apnea.

PMID:34420134 | DOI:10.1007/s11325-021-02456-3

Tuberc Respir Dis (Seoul). 2021 Aug 20. doi: 10.4046/trd.2021.0065. Online ahead of print.

ABSTRACT

Microscopic polyangiitis (MPA) is an anti-neutrophil cytoplasmic antibody (ANCA)-associated necrotizing vasculitis, which mainly affects small vessels resulting in various organ involvement, especially the lung. The two key pulmonary manifestations, interstitial lung disease (ILD) and diffuse alveolar hemorrhage (DAH) increase the morbidity and mortality of patients with MPA. ILD is more common in MPA than in other ANCA-associated vasculitis subsets and is primarily associated with myeloperoxidase (MPO)-ANCA. Unlike alveolar hemorrhage due to pulmonary capillaritis, ILD can initially manifest as isolated pulmonary fibrosis. Of note, its most frequent radiographic pattern is the usual interstitial pneumonia pattern, similar to the characteristic pattern seen in idiopathic pulmonary fibrosis. We herein present the pathogenesis, clinical manifestations, radiographic and histopathologic features of ILD and DAH in MPA in this review. We also briefly summarize the outcome and therapeutic options for the two conditions.

PMID:34418915 | DOI:10.4046/trd.2021.0065

J Biol Chem. 2021 Aug 18:101096. doi: 10.1016/j.jbc.2021.101096. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is the prototypic progressive fibrotic lung disease with a median survival of 2-4 years. Injury to and/or dysfunction of the alveolar epithelium is strongly implicated in IPF disease initiation, but the factors that determine whether fibrosis progresses rather than normal tissue repair occurs remain poorly understood. We previously demonstrated that ZEB1-mediated epithelial-mesenchymal transition (EMT) in human alveolar epithelial type II (ATII) cells augments TGF-β-induced profibrogenic responses in underlying lung fibroblasts via paracrine signalling. Here we investigated bi-directional epithelial-mesenchymal crosstalk and its potential to drive fibrosis progression. RNA sequencing (RNA-seq) of lung fibroblasts exposed to conditioned media from ATII cells undergoing RAS-induced EMT identified many differentially expressed genes including those involved in cell migration and extracellular matrix (ECM) regulation. We confirmed that paracrine signalling between RAS-activated ATII cells and fibroblasts augmented fibroblast recruitment and demonstrated that this involved a ZEB1-tissue plasminogen activator (tPA) axis. In a reciprocal fashion, paracrine signalling from TGF-β-activated lung fibroblasts or IPF fibroblasts induced RAS activation in ATII cells, at least partially through the secreted protein, SPARC, which may signal via the epithelial growth factor receptor (EGFR) via EGF-like (EGFL) repeats. Together, these data identify that aberrant bi-directional epithelial-mesenchymal crosstalk in IPF drives a chronic feedback loop that maintains a wound-healing phenotype and provides self-sustaining pro-fibrotic signals.

PMID:34418430 | DOI:10.1016/j.jbc.2021.101096

Thorax. 2021 Aug 20:thoraxjnl-2021-217882. doi: 10.1136/thoraxjnl-2021-217882. Online ahead of print.

NO ABSTRACT

PMID:34417351 | DOI:10.1136/thoraxjnl-2021-217882

Acad Radiol. 2021 Aug 17:S1076-6332(21)00328-7. doi: 10.1016/j.acra.2021.07.020. Online ahead of print.

ABSTRACT

PURPOSE: To evaluate the feasibility of a chest CT-based body composition analysis in idiopathic pulmonary fibrosis (IPF), and to investigate the respective contribution of lung and muscle CT quantitative analyses to the prognosis of IPF.

METHOD: A total of 71 IPF patients were recruited at diagnosis. All patients underwent a standard chest CT-scan and a bioelectrical impedance analysis considered as reference standard for estimating malnutrition through the use of the fat-free mass index (FFMI). The skeletal muscle index (SMI) was measured on chest-CT at the level of the first lumbar vertebra by two radiologists. Lung fibrosis extent was quantified by three radiologists in consensus. The extent of emphysema, the pulmonary artery to aorta (PA/AO) diameter ratio and lymph node enlargement were also reported. Mortality and hospitalization over a 14-month follow-up were recorded.

RESULTS: A low FFMI defining malnutrition was identified in 26.8% of patients. SMI was significantly lower in these patients (p<0.001) and was correlated with FFMI (r=0.637, p<0.001). Interobserver agreement of SMI measurement was very good (ICC=0.91). For diagnosing malnutrition, SMI showed a 0.79 sensitivity, a 0.69 specificity, a 0.48 PPV and a 0.90 NPV. In univariate analysis, fibrosis extent was significantly associated with death, while SMI did not reach significance. In multivariate analysis, fibrosis extent and PA/AO ratio were independently associated with hospitalization.

CONCLUSIONS: SMI measured on chest CT could be a reliable tool to exclude malnutrition in IPF. A quantitative analysis of both fibrosis and skeletal muscle may allow holistic management of IPF patients.

PMID:34417107 | DOI:10.1016/j.acra.2021.07.020