Pulm Pharmacol Ther. 2022 Apr 19:102128. doi: 10.1016/j.pupt.2022.102128. Online ahead of print.

ABSTRACT

BACKGROUND: Patients with idiopathic pulmonary fibrosis have a poor overall prognosis and there are few evidence-based drug therapies that reduce mortality.

OBJECTIVE: We aimed to perform a systematic review and meta-analysis to assess whether sildenafil reduces mortality, disease progression and adverse side effects.

METHODS: We reviewed randomized controlled studies (RCTs) from MEDLINE, Cochrane registry of clinical trials, and EMBASE. Our outcomes of interest included mortality, change in FVC, acute exacerbations and hospitalizations and adverse drug effects leading to discontinuation. We used an inverse variance fixed effects meta-analysis method to calculate pooled relative risk (RR) and mean difference (MD).

RESULTS: A total of 4 studies were included in the systematic review. Sildenafil probably reduces mortality when compared to placebo or to standard care, [RR 0.73 (95% CI 0.51 to 1.04); moderate certainty]. Pooled estimates showed sildenafil may not alter the rate of change of FVC [MD 0.61% (95% CI -0.29 to 1.52)], or DLCO [MD 0.97% (95% CI 0.04 to 1.90)] (both low certainty). Pooled estimated showed sildenafil may not reduce the number of hospitalizations or acute exacerbations, [RR 1.10 (95% CI 0.61 to 1.98); low certainty]. There is probably no difference in drug discontinuation due to adverse effects when comparing sildenafil to the control group, [RR 0.79 (95% CI 0.56, 1.10); moderate certainty].

CONCLUSION: Sildenafil probably reduces all-cause mortality in IPF patients. More studies need to be done to confirm the magnitude and reliability of the point estimate.

PMID:35452834 | DOI:10.1016/j.pupt.2022.102128

J Drug Target. 2022 Apr 22:1-11. doi: 10.1080/1061186X.2022.2069781. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by irreversible fibrosis and destruction of the alveolar structure. Receptor for advanced glycation end-products (RAGE) has been identified as one of the key molecules involved in IPF pathogenesis. A RAGE antagonist peptide (RAP) was developed based on the RAGE-binding domain of high mobility group box-1 (HMGB-1). Anti-IPF effects of RAP were evaluated in a bleomycin-induced mouse model of IPF. Bleomycin was administered intratracheally, and then RAP was administrated twice by intratracheal instillation, 1 and 3 days after bleomycin challenge. Seven days after the bleomycin challenge, the mice were sacrificed and the lungs were harvested. The results showed that pulmonary hydroxyproline was reduced in mice administered RAP compared with the control group. Tumor growth factor-β (TGF-β), α-smooth muscle actin (α-SMA), and collagen were also reduced by RAP administration in a dose-dependent manner. Longer-term effects of RAP were investigated in mice challenged with bleomycin. RAP was administered intratracheally every 7 days for 28 days, after which lung samples were harvested and analyzed. The results showed that hydroxyproline, TGF-β, α-SMA, and collagen were reduced by repeated RAP administration. Taken together, the results suggest that RAP is useful for treatment of IPF.

PMID:35451894 | DOI:10.1080/1061186X.2022.2069781

Thorac Cancer. 2022 Apr 22. doi: 10.1111/1759-7714.14418. Online ahead of print.

ABSTRACT

OBJECTIVES: Whether curative-intent radiotherapy could be safely applied to lung cancer patients with interstitial lung diseases (ILD) remains unclear. We aim to evaluate radiation induced lung toxicities (RILTs) and the efficacy of intensity-modulated radiotherapy (IMRT) in these patients. ILD is characterized by inflammation or fibrosis in the interstitial tissue of the lung.

MATERIALS AND METHODS: Stage III non-small cell lung cancer (NSCLC) and ILD patients treated with curative-intent IMRT between 2010 and 2019 were retrospectively reviewed. Pre-radiation computed tomography (CT) was scored according to a thin-section CT scoring system for idiopathic pulmonary fibrosis.

RESULTS: A total of 85 of 1261 stage III NSCLC patients were found with ILD. Seventeen (20%) of them developed G3+ (greater than or equal to grade 3) RILTs. The incidence abruptly dropped to 11.1%, 3.8%, and 0% for patients with honeycombing score ≤1, V20 <20%, or both, respectively. Multivariate analysis showed that honeycombing score >1 and V20 ≥20% were independently associated with higher risk of G3+ RILTs. The median overall survival (OS) and progression-free survival (PFS) were 14.0 months and 7.4 months in the whole group, whereas 26.5 months and 10.6 months in the low-risk group (patients with honeycombing score <1 and V20 <20%). In the univariate analysis for overall survival, G3+ RILTs were evaluated as risk factors (p = 0.026) and low-risk group as the only protective factor (p = 0.063). In the multivariate analysis, G3+ RILTs were the only independent risk factor for OS.

CONCLUSION: Honeycombing score >1 and V20 ≥20% were associated with high incidence of RILTs. However, patients with low risk might benefit from IMRT with acceptable toxicities and durable OS.

PMID:35451221 | DOI:10.1111/1759-7714.14418

Ann Dermatol. 2022 Apr;34(2):136-138. doi: 10.5021/ad.2022.34.2.136. Epub 2022 Mar 24.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and lethal lung disease characterized by progressive dyspnea and irreversible loss of lung function. Pirfenidone is a novel anti-fibrotic and anti-inflammatory drug, which reduces deterioration in the lung function and prolongs progression-free survival in patients with IPF. However, it has adverse effects including gastrointestinal symptoms, hepatic dysfunction or skin photosensitivity, and rash. Lichenoid drug eruption (LDE) refers to lichen planus-like drug eruption usually presenting symmetric eczematous plaques with a purple hue. To date, numerous cases of LDE due to various drugs and pirfenidone-associated photosensitivity have been reported. However, a case of pirfenidone-induced LDE has been very rarely reported to our knowledge. Herein, is a case of pirfenidone-induced LDE so that clinicians can be aware of the possibility of LDE when using pirfenidone.

PMID:35450308 | PMC:PMC8989899 | DOI:10.5021/ad.2022.34.2.136

Respir Res. 2022 Apr 21;23(1):97. doi: 10.1186/s12931-022-02013-w.

ABSTRACT

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are characterized by shared exposures and clinical features, but distinct genetic and pathologic features exist. These features have not been well-studied using large-scale gene expression datasets. We hypothesized that there are divergent gene, pathway, and cellular signatures between COPD and IPF.

METHODS: We performed RNA-sequencing on lung tissues from individuals with IPF (n = 231) and COPD (n = 377) compared to control (n = 267), defined as individuals with normal spirometry. We grouped the overlapping differential expression gene sets based on direction of expression and examined the resultant sets for genes of interest, pathway enrichment, and cell composition. Using gene set variation analysis, we validated the overlap group gene sets in independent COPD and IPF data sets.

RESULTS: We found 5010 genes differentially expressed between COPD and control, and 11,454 genes differentially expressed between IPF and control (1% false discovery rate). 3846 genes overlapped between IPF and COPD. Several pathways were enriched for genes upregulated in COPD and downregulated in IPF; however, no pathways were enriched for genes downregulated in COPD and upregulated in IPF. There were many myeloid cell genes with increased expression in COPD but decreased in IPF. We found that the genes upregulated in COPD but downregulated in IPF were associated with lower lung function in the independent validation cohorts.

CONCLUSIONS: We identified a divergent gene expression signature between COPD and IPF, with increased expression in COPD and decreased in IPF. This signature is associated with worse lung function in both COPD and IPF.

PMID:35449067 | DOI:10.1186/s12931-022-02013-w

Am J Respir Crit Care Med. 2022 Apr 21. doi: 10.1164/rccm.202203-0474ED. Online ahead of print.

NO ABSTRACT

PMID:35446243 | DOI:10.1164/rccm.202203-0474ED

Am J Respir Crit Care Med. 2022 Apr 21. doi: 10.1164/rccm.202111-2590LE. Online ahead of print.

NO ABSTRACT

PMID:35446241 | DOI:10.1164/rccm.202111-2590LE

Am J Respir Crit Care Med. 2022 Apr 21. doi: 10.1164/rccm.202109-2219PP. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is the cumulative manifestation of countless, spatially and temporally distinct, microscopic foci of maladaptive repair in response to recurrent lung injury. However, the key drivers, essential cells, and critical mechanisms of maladaptive repair in IPF remain elusive. Decades of research have focused on alveolar injury and alveolar-mesenchymal crosstalk with their association to type II alveolar epithelial defects, fibroblast activation, and progressive lung fibrosis resulting in diminished organ function. Additionally, it has been well documented that immune and endothelial cell-types are involved in IPF. However, the airway epithelium has been incompletely described in IPF, even with significant evidence of airway-specific involvement. One of the first descriptions of distal airway dysfunction in IPF was over four-decades ago; however, since this discovery, our understanding of distal airway epithelial contributions to IPF pathogenesis has not kept pace with other tissues-types or anatomical regions of the lung. Healthy distal, which is defined here as an airway < 2 mm in internal diameter, airway epithelium is composed primarily of progenitor, mucus-producing, and multiciliated cell populations. Large increases in progenitor population diversity, misexpression of mucus, and possible aberrant ciliation observed in IPF has reinvigorated interest in the distal airway epithelium.

PMID:35446237 | DOI:10.1164/rccm.202109-2219PP

Int J Epidemiol. 2022 Apr 20:dyac076. doi: 10.1093/ije/dyac076. Online ahead of print.

ABSTRACT

BACKGROUND: To summarize modifiable factors for coronavirus disease 2019 (COVID-19) suggested by Mendelian randomization studies.

METHODS: In this systematic review, we searched PubMed, EMBASE and MEDLINE, from inception to 15 November 2021, for Mendelian randomization studies in English. We selected studies that assessed associations of genetically predicted exposures with COVID-19-related outcomes (severity, hospitalization and susceptibility). Risk of bias of the included studies was evaluated based on the consideration of the three main assumptions for instrumental variable analyses.

RESULTS: We identified 700 studies through systematic search, of which 50 Mendelian randomization studies were included. Included studies have explored a wide range of socio-demographic factors, lifestyle attributes, anthropometrics and biomarkers, predisposition to diseases and druggable targets in COVID-19 risk. Mendelian randomization studies suggested that increases in smoking, obesity and inflammatory factors were associated with higher risk of COVID-19. Predisposition to ischaemic stroke, combined bipolar disorder and schizophrenia, attention-deficit and hyperactivity disorder, chronic kidney disease and idiopathic pulmonary fibrosis was potentially associated with higher COVID-19 risk. Druggable targets, such as higher protein expression of histo-blood group ABO system transferase (ABO), interleukin (IL)-6 and lower protein expression of 2'-5' oligoadenylate synthetase 1 (OAS1) were associated with higher risk of COVID-19. There was no strong genetic evidence supporting the role of vitamin D, glycaemic traits and predisposition to cardiometabolic diseases in COVID-19 risk.

CONCLUSION: This review summarizes modifiable factors for intervention (e.g. smoking, obesity and inflammatory factors) and proteomic signatures (e.g. OAS1 and IL-6) that could help identify drugs for treating COVID-19.

PMID:35445260 | DOI:10.1093/ije/dyac076

Eur J Radiol Open. 2022 Apr 7;9:100419. doi: 10.1016/j.ejro.2022.100419. eCollection 2022.

ABSTRACT

Connective tissue diseases (CTDs) demonstrating features of interstitial lung disease (ILD) include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), dermatomyositis (DM) and polymyositis (PM), ankylosing spondylitis (AS), Sjogren syndrome (SS), and mixed connective tissue disease (MCTD). On histopathology of lung biopsy in CTD-related ILDs (CTD-ILDs), multi-compartment involvement is an important clue, and when present, should bring CTD to the top of the list of etiologic differential diagnoses. Diverse histologic patterns including nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), organizing pneumonia, apical fibrosis, diffuse alveolar damage, and lymphoid interstitial pneumonia can be seen on histology in patients with CTD-ILDs. Although proportions of ILDs vary, the NSIP pattern accounts for a large proportion, especially in SSc, DM and/or PM and MCTD, followed by the UIP pattern. In RA patients, interstitial lung abnormality (ILA) is reported to occur in approximately 20-60% of individuals of which 35-45% will have progression of the CT abnormality. Subpleural distribution and greater baseline ILA involvement are risk factors associated with disease progression. Asymptomatic CTD-ILDs or ILA patients with normal lung function and without evidence of disease progression can be followed without treatment. Immunosuppressive or antifibrotic agents for symptomatic and/or fibrosing CTD-ILDs can be used in patients who require treatment.

PMID:35445144 | PMC:PMC9014394 | DOI:10.1016/j.ejro.2022.100419

Cell Death Discov. 2022 Apr 20;8(1):213. doi: 10.1038/s41420-022-01020-6.

ABSTRACT

The hippo signaling pathway is a highly conserved evolutionary signaling pathway that plays an important role in regulating cell proliferation, organ size, tissue development, and regeneration. Increasing evidences consider that the hippo signaling pathway is involved in the process of respiratory diseases. Hippo signaling pathway is mainly composed of mammalian STE20-like kinase 1/2 (MST1/2), large tumor suppressor 1/2 (LATS1/2), WW domain of the Sav family containing protein 1 (SAV1), MOB kinase activator 1 (MOB1), Yes-associated protein (YAP) or transcriptional coactivator with PDZ-binding motif (TAZ), and members of the TEA domain (TEAD) family. YAP is the cascade effector of the hippo signaling pathway. The activation of YAP promotes pulmonary arterial vascular smooth muscle cells (PAVSMCs) proliferation, which leads to pulmonary vascular remodeling; thereby the pulmonary arterial hypertension (PAH) is aggravated. While the loss of YAP leads to high expression of inflammatory genes and the accumulation of inflammatory cells, the pneumonia is consequently exacerbated. In addition, overexpressed YAP promotes the proliferation of lung fibroblasts and collagen deposition; thereby the idiopathic pulmonary fibrosis (IPF) is promoted. Moreover, YAP knockout reduces collagen deposition and the senescence of adult alveolar epithelial cells (AECs); hence the IPF is slowed. In addition, hippo signaling pathway may be involved in the repair of acute lung injury (ALI) by promoting the proliferation and differentiation of lung epithelial progenitor cells and intervening in the repair of pulmonary capillary endothelium. Moreover, the hippo signaling pathway is involved in asthma. In conclusion, the hippo signaling pathway is involved in respiratory diseases. More researches are needed to focus on the molecular mechanisms by which the hippo signaling pathway participates in respiratory diseases.

PMID:35443749 | DOI:10.1038/s41420-022-01020-6

J Assoc Physicians India. 2022 Apr;70(4):11-12.

ABSTRACT

Interstitial Lung Disease are heterogeneous group of disorders of the lower respiratory tract. For their smoldering evolution and non specificity of symptoms they may remain undiagnosed and not treated for long time. Spirometry is rarely diagnostic, reduction of lung function help to characterize the extent of disease. Spirometry may provide an estimated prognosis in Interstitial Lung Disease.

MATERIAL: The present study was conducted in department of General Medicine at Dr D Y Patil medical college and hospital, Kolhapur on 32 patients over a period of one year. All those patients who were suspected as case of interstitial Lung Disease on clinical and radiological ground were included. A detailed history along with occupational history was obtained and noted. All patients were examined clinically and underwent Basic investigations and performed spirometry. Correlation between spirometry findings and clinical and radiological profile done.

OBSERVATION: The study group of 32 patients with ILD, Idiopathic Pulmonary Fibrosis was the most comman cause of ILD consists of 22 patients performing 68% of the study group. Average duration of symptoms in ILD patients in this study was 6-8 months. The mean age of patients was 59 year with 12(38%) female and 20(62%) male. Cough and dyspnoea were the most comman features at presentation in our study group, present in all patients of this study. Crepitations on auscaltation were present in 25(78%) patients. Most comman chest Xray feature was reticular opacities which was present in 11(34%) patients. Fibrosis and GGO in HRCT chest were seen in 11(34%) and 25(78%) patients respactively. Most comman spirometric pattern seen in our study was Restrictive pattern which was present in 23(72%) patients.

CONCLUSION: The major spirometric pattern seen in various types of Interstitial Lung Disease is restrictive pattern. Though spirometry show restrictive pattern it is not diagnostic in between various types of Interstitial Lung Disease.

PMID:35443460

Am J Respir Crit Care Med. 2022 Apr 19. doi: 10.1164/rccm.202110-2296OC. Online ahead of print.

ABSTRACT

Rationale Knowledge on biomarkers of interstitial lung disease is incomplete. Interstitial lung abnormalities (ILA) are radiologic changes that may present in its early stages. Objectives To uncover blood proteins associated with ILA using large-scale proteomics methods. Methods Data from two prospective cohort studies, the AGES-Reykjavik study (n=5,259) for biomarker discovery and the Genetic Epidemiology of COPD (COPDGene) study (n=4,899) for replication, were used. Blood proteins were measured using DNA aptamers, targeting over 4,700 protein analytes. The association of proteins with ILA and ILA progression was assessed with regression modelling, as were associations with genetic risk factors. Adaptive LASSO models were applied to bootstrap data samples to discover sets of proteins predictive of ILA and their progression. Measurements and Main Results Of 287 associations, SFTPB (OR 3.71 [95% CI 3.20-4.30], P 4.28×10-67), SCG3AB1 (OR 2.43 [2.13-2.77], P 8.01×10-40) and WFDC2 (OR 2.42 [2.11-2.78], P 4.01×10-36) were most significantly associated with ILA in AGES-Reykjavik and were replicated in COPDGene. In AGES-Reykjavik, levels of SFTPB were associated with the rs35705950 MUC5B promoter polymorphism and SFTPB and WFDC2 had the strongest associations with ILA progression. Multivariate models of ILA in AGES-Reykjavik, ILA in COPDGene and ILA progression in AGES-Reykjavik, had validated areas under the receiver operating characteristic curve of 0.880, 0.826 and 0.824, respectively. Conclusions Novel, replicated associations of ILA, its progression and genetic risk factors with numerous blood proteins are demonstrated as well as machine-learning based models with favourable predictive potential. Several proteins are revealed as potential markers of early fibrotic lung disease.

PMID:35438610 | DOI:10.1164/rccm.202110-2296OC

Arch Bronconeumol. 2022 Apr 15:S0300-2896(22)00186-7. doi: 10.1016/j.arbres.2021.12.017. Online ahead of print.

ABSTRACT

In addition to idiopathic pulmonary fibrosis (IPF), other diffuse interstitial lung diseases (ILD) are also associated with pulmonary fibrosis and occur in a variable proportion of patients, depending on the entity. The name given to this fibrotic component, that may progress despite treatment, is progressive pulmonary fibrosis (PPF). In this context, PPF is not an entity per se but a common clinical condition or behavior that may occur in association with different types of fibrosing diffuse ILDs, compromising patient prognosis. PPF is identified from worsening clinical, physiological, and/or radiological criteria during patient follow-up. Randomized clinical trials in patients with IPF or progressive non-IPF ILD have shown that treatment with antifibrotic drugs, either nintedanib or pirfenidone, slows progression. We are seeing the start of a new era in the clinical management of this subgroup of patients, offering the perfect opportunity for exploring still uncharted territories.

PMID:35437204 | DOI:10.1016/j.arbres.2021.12.017

Bioengineered. 2022 Apr;13(4):10098-10110. doi: 10.1080/21655979.2022.2063652.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a common pulmonary interstitial disease with a high mortality rate. Adiponectin (APN) is reportedly an effective therapy for fibrosis-related diseases. This study aimed to investigate the potential effects of APN on IPF. Male BALB/c mice were injected with bleomycin (BLM) and treated with different doses of APN (0.1, 0.25, and 0.5 mg/kg). The body weights of the mice were recorded. Immunohistochemical, hematoxylin and eosin, and Masson staining were performed to evaluate pulmonary histopathological changes. Enzyme-linked immunosorbent assay (ELISA) and western blotting were performed to assess tissue inflammation. The human lung fibroblasts HELF were stimulated with TGF-β1 and treated with different doses of APN (2.5, 5, and 10 μg/ml). Cell proliferation, inflammation, and fibrosis were determined by MTT assay, EdU assay, colony formation assay, ELISA, and western blotting. APN significantly attenuated BLM-induced body weight loss, alveolar destruction, and collagen fiber accumulation in mice (p < 0.05). APN decreased the expression of α-SMA and collagen I and reduced the concentration of TNF-α, IL-6, IL-1β, and IL-18 in lung tissues (p < 0.05). In TGF-β1-treated HELF cells, cell proliferation and colony formation were inhibited by APN (p < 0.05). Additionally, the expression of α-SMA, collagen I, and pro-inflammatory cytokines were suppressed by APN (p < 0.05). APN inhibited the phosphorylation of IκB and nuclear translocation of p65. In conclusion, these findings suggest that APN is an effective agent for controlling IPF progression. The antifibrotic effects of APN might be mediated via inhibiting the NF-κB signaling pathway.

PMID:35435119 | DOI:10.1080/21655979.2022.2063652

Respir Investig. 2022 Apr 14:S2212-5345(22)00029-6. doi: 10.1016/j.resinv.2022.03.004. Online ahead of print.

ABSTRACT

Interstitial lung disease (ILD) is a parenchymal lung disease and restrictive disorder that presents as diffuse infiltrative shadows. The initial diagnosis of ILD is important because management strategies depend on the disease pathogenesis. Connective-tissue disease (CTD)-associated ILD including rheumatoid arthritis (RA), systemic sclerosis (SSc) requires a thorough evaluation of chronic respiratory symptoms such as non-productive cough and exertional dyspnea, as well as physical findings. Moreover, myeloperoxidase-positive anti-neutrophilic cytoplasmic antibody (MPO-ANCA)-associated vasculitis with ILD also shows disease progression. In CTD-associated ILD, the first-line treatment is anti-inflammatory drugs such as prednisolone or immunosuppressants. In hypersensitivity pneumonitis (HP), detailed environmental history-taking is crucial. Therefore, systematic standardized questionnaires are needed. However, the causative antigens are often not identified in daily clinical practice. When an antigen is identified or suspected, the first action is avoidance. If antigen avoidance does not contribute to clinical improvement, anti-inflammatory drugs such as prednisolone might be introduced. Regarding sarcoidosis, while most patients do not require treatment for lung involvement, some need anti-inflammatory drugs or immunosuppressants. Additionally, steroid treatment should be considered for the critical status of extrapulmonary sarcoidosis including cardiac, neurogenic and ocular sarcoidosis. Once starting treatment for ILD, multi-dimensional approaches are applied, including symptom tracking, chest imaging, pulmonary function test (PFT), and 6-min walking test. Recently, the concept of progressive-fibrosing interstitial lung disease (PF-ILD) has been proposed as a new disease entity. The definition of PF-ILD includes symptom progression, PFT decline, and extension of chest high-resolution computed tomography (HRCT) findings. This mini-review describes the background, definition, clinical characteristics, management, and challenges of PF-ILD.

PMID:35431170 | DOI:10.1016/j.resinv.2022.03.004

Toxicol Lett. 2022 Apr 14:S0378-4274(22)00067-4. doi: 10.1016/j.toxlet.2022.03.009. Online ahead of print.

ABSTRACT

Following the humidifier disinfectant incident in Korea, polyhexamethylene guanidine phosphate (PHMG-P) has been used to establish lung fibrosis model animals. Herein, we investigated time-dependent changes after a single PHMG-P instillation (22 μg/lung) to identify the underlying pathogenesis and immune response involved in PHMG-P-induced lung fibrosis. Compared to control mice, body weight loss and blood biochemical and hematological changes were more remarkable in PHMG-P-instilled mice, an increase of total cell counts, infiltration of macrophages and neutrophils and necrotic cell death were also more notable in the lungs of PHMG-P-instilled mice. Pathological lesions were detected from Day 1 after exposure, deteriorating with time. In addition, secretion of anti-inflammatory mediators was rapidly inhibited from 6 h after exposure, and level of IL-24, a tissue repair-related cytokine, was up-regulated in the lungs of PHMG-P-instilled mice until Day 21 post-exposure. In vitro tests using BEAS-2B cells showed that PHMG-P disturbed structural and functional homeostasis of organelles and that intracellular ROS increase was considered as an important cause of PHMG-P-induced cell death. Additionally, co-culture with DNA, a polyanionic compound, clearly inhibited PHMG-P-induced necrosis, and increased IL-1β and TNF-α level and decreased IL-6 and IL-8 levels were observed following exposure to PHMG-P. Meanwhile, IL-8 secretion increased in cells exposed to PHMG-P-induced cell debris. Therefore, we suggest that necrotic cell debris may importantly contribute to the PHMG-P-induced inflammatory response and pathogenesis. In addition, PHMG-P-induced necrosis may be initiated by high affinity between PHMG-P and cell membrane.

PMID:35430302 | DOI:10.1016/j.toxlet.2022.03.009

Pulm Ther. 2022 Apr 16. doi: 10.1007/s41030-022-00187-8. Online ahead of print.

ABSTRACT

INTRODUCTION: The PROOF registry is a prospective, observational study that aimed to monitor disease progression in a real-world cohort of patients with idiopathic pulmonary fibrosis (IPF). Here, longitudinal quality-of-life (QoL) outcomes, healthcare resource use (HCRU), and the association between QoL and mortality in patients enrolled in the PROOF registry are presented.

METHODS: QoL outcomes (St. George's Respiratory Questionnaire [SGRQ], EuroQoL-5 dimensions-5 levels Health Questionnaire [EQ-5D-5L], EuroQoL-5 dimensions Health Questionnaire [EQ-5D] visual analogue scale [VAS] and cough VAS) and HCRU were collected for all patients. Associations between baseline QoL and mortality were assessed using univariate and multivariate analyses. During multivariate analyses, individual QoL measures were adjusted for the following covariates: age, sex, percent predicted forced vital capacity, percent predicted diffusing capacity of the lungs for carbon monoxide, smoking status, and supplementary oxygen use at registry inclusion.

RESULTS: In total, 277 patients were enrolled in the PROOF registry. During the follow-up period, worsening in cough VAS score, SGRQ symptom score, and SGRQ activity score was observed, while EQ-5D VAS, SGRQ total score, and SGRQ impact score remained stable. During univariate analyses, EQ-5D VAS and all SGRQ sub-scores and total score at baseline were associated with mortality; however, during multivariate analyses, only the SGRQ total score, SGRQ impact score, and SGRQ symptom score at baseline were associated with mortality. During the follow-up period, 261 (94.2%) patients required an outpatient consultation (IPF- or non-IPF-related) and there were 182 hospitalizations in total, most of which were respiratory related (66.5%).

CONCLUSIONS: The PROOF registry provided valuable, real-world data on the association between baseline QoL and mortality, and longitudinal HCRU and QoL outcomes in patients with IPF over 24 months and identified that SGRQ may be an independent prognostic factor in IPF.

PMID:35429319 | DOI:10.1007/s41030-022-00187-8

Autophagy. 2022 Apr 15:1-20. doi: 10.1080/15548627.2022.2046448. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is characterized by lung scarring and has no effective treatment. Fibroblast-to-myofibroblast differentiation and myofibroblast proliferation and migration are major clinical manifestations of this disease; hence, blocking these processes is a practical treatment strategy. Here, highly upregulated LINC00941/lncIAPF was found to accelerate pulmonary fibrosis by promoting fibroblast-to-myofibroblast differentiation and myofibroblast proliferation and migration. Assay for transposase-accessible chromatin using sequencing and chromatin immunoprecipitation experiments elucidated that histone 3 lysine 27 acetylation (H3K27ac) activated the chromosome region opening in the LINC00941 promoter. As a consequence, the transcription factor ATF3 (activating transcription factor 3) bound to this region, and LINC00941 transcription was enhanced. RNA affinity isolation, RNA immunoprecipitation (RIP), RNase-RIP, half-life analysis, and ubiquitination experiments unveiled that LINC00941 formed a RNA-protein complex with ELAVL1/HuR (ELAV like RNA binding protein 1) to exert its pro-fibrotic function. Dual-fluorescence mRFP-GFP-MAP1LC3/LC3 (microtubule associated protein 1 light chain 3) adenovirus monitoring technology, human autophagy RT2 profiler PCR array, and autophagic flux revealed that the LINC00941-ELAVL1 axis inhibited autophagosome fusion with a lysosome. ELAVL1 RIP-seq, RIP-PCR, mRNA stability, and rescue experiments showed that the LINC00941-ELAVL1 complex inhibited autophagy by controlling the stability of the target genes EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit), STAT1 (signal transducer and activators of transcription 1) and FOXK1 (forkhead box K1). Finally, the therapeutic effect of LINC00941 was confirmed in a mouse model and patients with IPF. This work provides a therapeutic target and a new effective therapeutic strategy related to autophagy for IPF.

PMID:35427207 | DOI:10.1080/15548627.2022.2046448

Eur Respir J. 2022 Apr 14;59(4):2052559. doi: 10.1183/13993003.52559-2020. Print 2022 Apr.

NO ABSTRACT

PMID:35422427 | DOI:10.1183/13993003.52559-2020