Cell Biol Toxicol. 2021 Nov 5. doi: 10.1007/s10565-021-09676-z. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by progressive loss of pulmonary function. Drug-induced interstitial lung disease has been reported as a severe adverse effect of some drugs, such as bleomycin, amiodarone, and methotrexate. Based on good characteristics, drug-induced pulmonary fibrosis (PF) animal model has played a key role in our understanding of the molecular mechanisms of PF pathogenesis and recapitulates the specific pathology in patients and helps develop therapeutic strategies. Here, we summarize the mechanisms and characteristics of given fibrotic drug-induced animal models for PFs. Together with the key publications describing these models, this brief but detailed overview would be helpful for the pharmacological research with animal models of PFs. Potential mechanisms underlying drug induced lung toxicity.

PMID:34741237 | DOI:10.1007/s10565-021-09676-z

Lung. 2021 Nov 6. doi: 10.1007/s00408-021-00490-2. Online ahead of print.

ABSTRACT

Pulmonary hypertension (PH) is associated with decreased survival in patients with pulmonary fibrosis and combined pulmonary fibrosis and emphysema. Main pulmonary artery (PA) diameter and PA diameter/ascending aortic diameter (PA/AA) ratio, as measured on CT, have recently emerged as specific markers for PH. Our single-center retrospective study found that PA/AA ratio > 1 is associated with decreased survival in individuals with pulmonary fibrosis, with or without emphysema. Our study also describes markers of cardiac remodeling, and the echocardiographic diagnosis of PH in this patient population.

PMID:34741227 | DOI:10.1007/s00408-021-00490-2

Sci Rep. 2021 Nov 5;11(1):21712. doi: 10.1038/s41598-021-01069-w.

ABSTRACT

Idiopathic pulmonary fibrosis is a lethal lung fibroproliferative disease with limited therapeutic options. Differential expression profiling of affected sites has been instrumental for involved pathogenetic mechanisms dissection and therapeutic targets discovery. However, there have been limited efforts to comparatively analyse/mine the numerous related publicly available datasets, to fully exploit their potential on the validation/creation of novel research hypotheses. In this context and towards that goal, we present Fibromine, an integrated database and exploration environment comprising of consistently re-analysed, manually curated transcriptomic and proteomic pulmonary fibrosis datasets covering a wide range of experimental designs in both patients and animal models. Fibromine can be accessed via an R Shiny application ( http://www.fibromine.com/Fibromine ) which offers dynamic data exploration and real-time integration functionalities. Moreover, we introduce a novel benchmarking system based on transcriptomic datasets underlying characteristics, resulting to dataset accreditation aiming to aid the user on dataset selection. Cell specificity of gene expression can be visualised and/or explored in several scRNA-seq datasets, in an effort to link legacy data with this cutting-edge methodology and paving the way to their integration. Several use case examples are presented, that, importantly, can be reproduced on-the-fly by a non-specialist user, the primary target and potential user of this endeavour.

PMID:34741074 | DOI:10.1038/s41598-021-01069-w

Eur J Pharmacol. 2021 Nov 2:174613. doi: 10.1016/j.ejphar.2021.174613. Online ahead of print.

ABSTRACT

Pulmonary fibrosis (PF) is a chronic, progressive heterogeneous disease of lung tissues with poor lung function caused by scar tissue. Due to our limited understanding of its mechanism, there is currently no treatment strategy that can prevent the development of PF. In recent years, iron accumulation and mitochondrial damage have been reported to participate in PF, and drugs that reduce iron content and improve mitochondrial function have shown significant efficacy in animal experimental models. Excessive iron leads to mitochondrial impairment, which may be the key cause that results in the dysfunction of various kinds of pulmonary cells and further promotes PF. As an emerging research hotspot, there are few targeted effective therapeutic strategies at present due to limited mechanistic understanding. In this review, the roles of iron homeostasis imbalance and mitochondrial damage in PF are summarized and discussed, highlighting a promising direction for finding truly effective therapeutics for PF.

PMID:34740581 | DOI:10.1016/j.ejphar.2021.174613

Lancet Respir Med. 2021 Nov;9(11):1342. doi: 10.1016/S2213-2600(21)00416-1.

NO ABSTRACT

PMID:34739887 | DOI:10.1016/S2213-2600(21)00416-1

J Med Microbiol. 2021 Nov;70(11). doi: 10.1099/jmm.0.001449.

ABSTRACT

Introduction. Patients with interstitial lung disease (ILD) who subsequently develop a viral infection have high rates of morbidity and mortality.Hypothesis/Gap Statement. Few large-scale epidemiological studies have investigated potential prognostic factors for morbidity and mortality in this patient group.Aim. To evaluate the risk factors for morbidity and mortality in hospitalized patients with ILD and viral infection, as well as the clinical characteristics.Methodology. This retrospective cohort study included patients with ILD who were hospitalized for a viral infection in two tertiary academic hospitals in China, between 1 January 2013 and 31 December 2019. We analysed the prevalence of comorbidities, clinical characteristics, 30 day mortality rates, and prognostic risk factors.Results. A total of 282 patients were included; 195 and 87 were immunocompromised and immunocompetent, respectively. The most common underlying interstitial diseases were idiopathic pulmonary fibrosis (42.9 %) and connective tissue disease (36.9 %). The 30 day mortality rate was 20.6 %. During the influenza season, an increase in influenza virus (IFV) (25.7 %), respiratory syncytial virus (14.9 %) and cytomegalovirus (CMV) (11.3 %) cases was observed in the immunocompromised group. The most frequently detected virus in the immunocompetent group was IFV (44.8 %), followed by respiratory syncytial virus (11.5 %), and human rhinovirus (9.2 %). During the non-influenza season, CMV (34.4 %) was the main virus detected in the immunocompromised group. The 30 day mortality rates of non-IFV patients were higher than those of IFV patients. Older age (>60 years), respiratory failure, persistent lymphocytopenia, invasive mechanical ventilation and non-IFV virus infection were significantly associated with increased 30 day mortality.Conclusion. Patients with ILD who develop viral infection have high rates of morbidity and mortality, which are associated with increased age (>60 years), respiratory failure, mechanical ventilation, persistent lymphocytopenia and non-IFV virus infection. These risk factors should be carefully considered when determining treatment strategies for this patient population.

PMID:34738890 | DOI:10.1099/jmm.0.001449

Eur Respir J. 2021 Nov 4:2101396. doi: 10.1183/13993003.01396-2021. Online ahead of print.

ABSTRACT

Proposed criteria for progressive fibrosing interstitial lung disease (PF-ILD) have been linked to increased mortality risk, but lung function trajectory after satisfying individual criterion remains unknown. Because survival is rarely employed as the primary endpoint in therapeutic trials, identifying PF-ILD criteria that best predict subsequent change in forced vital capacity (FVC) could improve clinical trial design. A retrospective, multi-center longitudinal cohort analysis was performed in consecutive patients with fibrotic connective tissue disease-associated ILD (CTD-ILD), chronic hypersensitivity pneumonitis and idiopathic interstitial pneumonia at three US centers (test cohort) and one UK center (validation cohort). One-year change in FVC after satisfying proposed PF-ILD criteria was estimated using joint modeling. Subgroup analyses were performed to determine whether results varied across key subgroups. One thousand two hundred twenty-seven patients were included, with CTD-ILD predominating. Six of nine PF-ILD criteria were associated with differential one-year change in FVC, with radiologic progression of fibrosis, alone and in combination with other features, associated with the largest subsequent decline in FVC. Findings varied significantly by ILD subtype, with CTD-ILD demonstrating little change in FVC after satisfying most PF-ILD criteria, while other ILDs showed significantly larger changes. Findings did not vary after stratification by radiologic pattern or exposure to immunosuppressant therapy. Near-term change in FVC after satisfying proposed PF-ILD criteria was heterogeneous depending on the criterion assessed and was strongly influenced by ILD subtype. These findings may inform future clinical trial design and suggest ILD subtype should be taken into consideration when applying PF-ILD criteria.

PMID:34737223 | DOI:10.1183/13993003.01396-2021

Phys Med Biol. 2021 Nov 4. doi: 10.1088/1361-6560/ac36a2. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a restrictive interstitial lung disease that causes lung function decline by lung tissue scarring. Although lung function decline is assessed by the forced vital capacity (FVC), determining the accurate progression of IPF remains a challenge. To address this challenge, we proposed Fibro-CoSANet, a novel end-to-end multi-modal learning based approach, to predict the FVC decline. Fibro-CoSANet utilized CT images and demographic information in convolutional neural network frameworks with a stacked attention layer. Extensive experiments on the OSIC Pulmonary Fibrosis Progression Dataset demonstrated the superiority of our proposed Fibro-CoSANet by achieving the new state-of-the-art modified Laplace Log-Likelihood score of -6.68. This network may benefit research areas concerned with designing networks to improve the prognostic accuracy of IPF.

PMID:34736226 | DOI:10.1088/1361-6560/ac36a2

Ann Transl Med. 2021 Sep;9(18):1459. doi: 10.21037/atm-21-4224.

ABSTRACT

BACKGROUND: Using bioinformatic methods to explore the differentially expressed genes (DEGs) of human idiopathic pulmonary fibrosis (IPF) and to elucidate the pathogenesis of IPF from the genetic level.

METHODS: The GSE110147 gene expression profile was downloaded from the GEO database. The data of lung adenocarcinoma (LUAD) samples, lung squamous cell carcinoma (LUSC) samples and normal samples were downloaded from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. DEGs between IPF patients and healthy donors were analyzed using the GEO2R tool. Use the "clusterprofiler" package in R software to perform gene ontology (GO) and KEGG pathway enrichment analysis, and then perform function annotation and protein-protein interaction (PPI) network construction in the STRING online tool. The Genome Browser tool of the university of california santa cruz (UCSC) online website was used to predict transcription factors (TFs) of genes. In the final, the results were analyzed synthetically.

RESULTS: A total of 9,183 DEGs were identified, of which 4,545 genes were down-regulated, and 4638 were up-regulated. MMP1, SPP1, and BPIFB1 were the top three DEGs with the highest significant up-regulation. These DEGs played an important role in the occurrence of IPF through the MAPK (mitogen-activated protein kinase) signaling pathway. Furthermore, 50 DEGs were enriched in the expression of PD-L1 and the PD-1 checkpoint pathway in cancer, of which 11 genes were re-enriched in the pathway of non-small cell lung cancer. The expression of the 11 genes were extensively regulated by CTCFL, SP2 and ZNF341. Most of them were differentially expressed between lung cancers and normal lung tissues. The overall survival (OS) curve of LUAD were significantly stratified by AKT2, KRAS, PIK3R1, meanwhile the OS curve of LUAC was significantly stratified by MAPK3.

CONCLUSIONS: Bioinformatics analysis revealed that DEGs including MPP1 might be potential targets and biomarkers of IPF, and the MAPK signaling pathway is related to the occurrence and development of IPF. The development of IPF lung cancer complications may be related to the activation of genes enriched in PD-L1 expression and PD-1 checkpoint pathway, which provides clues to the pathogenesis of IPF combined with lung cancer.

PMID:34734011 | PMC:PMC8506768 | DOI:10.21037/atm-21-4224

Ann Transl Med. 2021 Sep;9(18):1424. doi: 10.21037/atm-21-3777.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease that leads to respiratory failure, and for which there is no effective treatment. Apolipoprotein A-1 (ApoA-1) has been reported to ameliorate the bleomycin (BLM)-induced IPF model.

METHODS: To examine the function of D-4F, an ApoA-1 mimetic polypeptide, in IPF, we used an in-vivo BLM-induced model. We assigned mice into the following 3 groups: the Blank Group (BLK Group), the Bleomycin Treatment Group (Model Group), and the D-4F Interference Group (Inter Group). The BLM-induced fibrosis was examined by hematoxylin and eosin, Masson's trichrome (M-T) staining and immunohistochemical staining. An untargeted lipidomic and transcriptomic analysis were used to examine the function of D-4F.

RESULTS: There were 35 differentially altered lipids (DALs) in the BLK, Model and Inter Groups. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that glycerophospholipid metabolism was the most highly enriched of the 35 DALs. There were 99 differentially expressed genes (DEGs) in the BLK, Model and Inter Groups. The enriched KEGG pathway analysis showed that the mitogen-activated protein kinase (MAPK) pathway was 1 of the top 10 pathways. The results of the untargeted lipidomic and transcriptomic analysis showed that phospholipase A2 group 4c (Pla2g4c) was a crucial gene in both the MAPK pathway and glycerophospholipid metabolism. Pla2g4c was increased in the Model Group but decreased in the Inter Group.

CONCLUSIONS: It may be that D-4F prevented the BLM-induced pulmonary fibrosis model by inhibiting the expression of pla2g4c. Our findings suggest that D-4F may be a potential treatment of IPF.

PMID:34733976 | PMC:PMC8506780 | DOI:10.21037/atm-21-3777

Front Med (Lausanne). 2021 Oct 18;8:744523. doi: 10.3389/fmed.2021.744523. eCollection 2021.

ABSTRACT

Background: Several studies using bronchoalveolar lavage fluid (BALF) reported that lung microbial communities were associated with the development and clinical outcome of idiopathic pulmonary fibrosis (IPF). However, the microbial communities in IPF lung tissues are not well known. This study is aimed to investigate bacterial microbial communities in lung tissues and determine their impact on the clinical outcomes of patients with IPF. Methods: Genomic DNA extracted from lung tissues of patients with IPF (n = 20; 10 non-survivors) and age- and sex-matched controls (n = 20) was amplified using fusion primers targeting the V3 and V4 regions of the 16S RNA genes with indexing barcodes. Results: Mean age of IPF subjects was 63.3 yr, and 65% were male. Alpha diversity indices did not significantly differ between IPF patients and controls, or between IPF non-survivors and survivors. The relative abundance of Lactobacillus, Paracoccus, and Akkermansia was increased, whereas that of Caulobacter, Azonexus, and Undibacterium decreased in patients with IPF compared with that in the controls. A decreased relative abundance of Pelomonas (odds ratio [OR], 0.352, p = 0.027) and Azonexus (OR, 0.013, p = 0.046) was associated with a diagnosis of IPF in the multivariable logistic analysis adjusted by age and gender. Multivariable Cox analysis adjusted for age and forced vital capacity (FVC) revealed that higher relative abundance of Streptococcus (hazard ratio [HR], 1.993, p = 0.044), Sphingomonas (HR, 57.590, p = 0.024), and Clostridium (HR, 37.189, p = 0.038) was independently associated with IPF mortality. The relative abundance of Curvibacter (r = 0.590) and Thioprofundum (r = 0.373) was correlated positively, whereas that of Anoxybacillus (r = -0.509) and Enterococcus (r = -0.593) was correlated inversely with FVC. In addition, the relative abundance of the Aquabacterium (r = 0.616) and Peptoniphilus (r = 0.606) genera was positively correlated, whereas that of the Fusobacterium (r = -0.464) and Phycicoccus (r = -0.495) genera was inversely correlated with distance during the 6-min walking test. Conclusions: The composition of the microbiome in lung tissues differed between patients with IPF and controls and was associated with the diagnosis, mortality, and disease severity of IPF.

PMID:34733866 | PMC:PMC8559550 | DOI:10.3389/fmed.2021.744523

Sci Rep. 2021 Nov 3;11(1):21549. doi: 10.1038/s41598-021-00943-x.

ABSTRACT

The extracellular matrix (ECM) has historically been explored through proteomic methods. Whether or not global transcriptomics can yield meaningful information on the human matrisome is unknown. Gene expression data from 17,382 samples across 52 tissues, were obtained from the Genotype-Tissue Expression (GTEx) project. Additional datasets were obtained from The Cancer Genome Atlas (TCGA) program and the Gene Expression Omnibus for comparisons. Gene expression levels generally matched proteome-derived matrisome expression patterns. Further, matrisome gene expression properly clustered tissue types, with some matrisome genes including SERPIN family members having tissue-restricted expression patterns. Deeper analyses revealed 382 gene transcripts varied by age and 315 varied by sex in at least one tissue, with expression correlating with digitally imaged histologic tissue features. A comparison of TCGA tumor, TCGA adjacent normal and GTEx normal tissues demonstrated robustness of the GTEx samples as a generalized matrix control, while also determining a common primary tumor matrisome. Additionally, GTEx tissues served as a useful non-diseased control in a separate study of idiopathic pulmonary fibrosis (IPF) matrix changes, while identifying 22 matrix genes upregulated in IPF. Altogether, these findings indicate that the transcriptome, in general, and GTEx in particular, has value in understanding the state of organ ECM.

PMID:34732773 | DOI:10.1038/s41598-021-00943-x

BMC Pulm Med. 2021 Nov 3;21(1):346. doi: 10.1186/s12890-021-01718-w.

ABSTRACT

BACKGROUND: Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) is often positive in patients with interstitial lung disease (ILD), which is also often present in patients with microscopic polyangiitis (MPA). A possible association between MPO-ANCA, MPA, and idiopathic ILD remains unclear. The objective of this study was to determine whether high-resolution computed tomography (HRCT) classification based on recent idiopathic pulmonary fibrosis guideline and specific CT findings can obtain new knowledge of prognostic factors in all MPO-ANCA-positive patients with ILD including both idiopathic ILD and MPA-ILD.

METHODS: We analyzed 101 consecutive MPO-ANCA-positive patients with respiratory disease. We assessed the diagnostic accuracy of CT findings, HRCT pattern, and specific radiological signs. Prognostic predictors were determined using Cox regression models.

RESULTS: Subjects with chronic ILD included 22 patients with MPA-ILD and 39 patients with ILD but without MPA. A quarter of the patients were radiological indeterminate for usual interstitial pneumonia (UIP) pattern, which resulted in a better prognosis than that for UIP pattern. "Increased attenuation around honeycomb and traction bronchiectasis" and "anterior upper lobe honeycomb-like lesion" were found to be highly frequent radiological findings (39% and 30%, respectively). In addition, the latter finding was a significant negative prognostic factor.

CONCLUSIONS: Radiological indeterminate for UIP was a useful HRCT classification in MPO-ANCA-positive patients with ILD. In addition, anterior upper lobe honeycomb-like lesion was found to be specific radiological finding that was a significant prognostic factor. The present results might aid in the assessment of appropriate strategies of diagnosis in these patients.

PMID:34732182 | DOI:10.1186/s12890-021-01718-w

Mol Biol Cell. 2021 Nov 3:mbcE20080536. doi: 10.1091/mbc.E20-08-0536. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic disease of the lung caused by a rampant inflammatory response that results in the deposition of excessive extracellular matrix (ECM). IPF patient lungs also develop fibroblastic foci that consist of activated fibroblasts and myofibroblasts. In concert with ECM deposition, the increased cell density within fibroblastic foci imposes confining forces on lung fibroblasts. In this work, we observed that increased cell density increases the incidence of fibroblast to myofibroblast transition (FMT), but mechanical confinement imposed by micropillars has no effect on FMT incidence. We found that human lung fibroblasts (HLFs) express more α-SMA and deposit more collagen matrix, which are both characteristics of myofibroblasts, in response to TGF-β1 when cells were seeded at a high density compared to a medium or a low density. These results support the hypothesis that HLFs undergo FMT more readily in response to TGF-β1 when cells are densely packed, and this effect could be dependent on increased OB-cadherin expression. This work demonstrates that cell density is an important factor to consider when modelling IPF in vitro, and it may suggest decreasing cell density within fibroblastic foci as a strategy to reduce IPF burden.

PMID:34731044 | DOI:10.1091/mbc.E20-08-0536

Eur Rev Med Pharmacol Sci. 2021 Oct;25(20):6326-6332. doi: 10.26355/eurrev_202110_27004.

ABSTRACT

OBJECTIVE: Idiopathic Pulmonary Fibrosis is a disease characterized by a devastating fibrosing process. Two anti-fibrotic agents, pirfenidone and nintedanib, have been found to alter the disease progression. In this study, we sought to determine whether switching treatment to nintedanib is feasible and safe in patients that had to discontinue treatment with pirfenidone due to side effects.

PATIENTS AND METHODS: We analyzed patients that had to discontinue pirfenidone due to side effects. Patients were prospectively enrolled for treatment with nintedanib between March 2015 and June 2019. Side effects and Pulmonary Function Tests were recorded.

RESULTS: 12 patients received nintedanib after discontinuing treatment with pirfenidone. Side-effects that led to discontinuation were diarrhea (33.3%), nausea (16.6%), photosensitivity (33.3%) and difficulty adhering to pirfenidone's dosage scheme (16.6%). After the initiation of nintedanib, diarrhea was the most common side effect (66.6%). Four patients of these patients could not tolerate the full dose of 300 mg daily and had to reduce it to 200 mg daily. No patient has had experienced liver damage. During the last twelve months of treatment with pirfenidone, mean ΔFCV was +2.47 ± 3.69%, mean ΔDLco was -0.36 ± 2.64% and mean difference of the distance walked during the 6MWT was 5 ± 56.48 meters. During the first year of treatment with nintedanib, mean ΔFCV was -1.32 ± 1.12% (p=0.68), mean ΔDLco was -1.59 ± 3.45% (p=0.54) and mean difference of the distance walked during the 6MWT was 14.17 ± 59 meters (p=0.078). 50% of patients had stable disease under pirfenidone (6-month FVC decline < 5% and/or 6-month DLco decline < 10%) vs. 50% under nintedanib, 33.3% had marginal 6-month decline (5% ≤ 6-month FVC ≤ 10% and/or (≤ 10% 6- month DLco decline ≤15%) under pirfenidone vs. 33.3% under nintedanib and 16.6% had disease progression (6-month FVC decline > 10% and/or 6-month DLco decline > 15%) under pirfenidone vs. 16.6% under nintedanib.

CONCLUSIONS: These results suggest that nintedanib is a safe option for the treatment of patients that had to discontinue pirfenidone due to adverse reactions. Further studies with greater patient numbers are needed for accurate results concerning efficacy.

PMID:34730213 | DOI:10.26355/eurrev_202110_27004

Respirology. 2021 Nov 2. doi: 10.1111/resp.14176. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Exercise capacity in idiopathic pulmonary fibrosis (IPF) is limited by exercise-induced hypoxaemia. This study aimed to examine the effect of high-flow nasal cannula oxygen therapy (HFNC) on exercise tolerance in patients with IPF.

METHODS: We conducted a single-centre, open-label, randomized crossover trial to compare HFNC and Venturi mask (VM) therapy in terms of exercise tolerance. Patients underwent constant-load symptom-limited exercise testing at 80% peak work rate with HFNC or a VM in a randomized order. The settings were 60 L/min and a 50% fraction of inspired oxygen (FiO2 ) for HFNC and 12 L/min and 50% FiO2 for VM. The primary outcome was endurance time, and the secondary outcomes were heart rate (HR), percutaneous oxygen saturation (SpO2 ), dyspnoea and leg fatigue, as determined by the modified Borg Scale at the isotime and endpoint, and the level of comfort while using the devices.

RESULTS: Twenty-four participants (75.0% men; age, median [interquartile range]: 77.5 [68.8-83.0] years) were enrolled. Compared with VM, HFNC significantly improved the endurance time (647.5 s [454.0-1014.8] vs. 577.5 s [338.0-861.5]), minimum SpO2 (96.0% [95.0-98.0] vs. 94.0% [92.8-96.0]) and leg fatigue at the isotime (3.0 [1.6-4.0] vs. 5.0 [3.0-6.3]) and endpoint (4.0 [2.8-5.0] vs. 5.0 [3.8-6.3]). Differences in maximum HR, dyspnoea at the isotime and endpoint and comfort were non-significant between HFNC and VM therapy.

CONCLUSION: HFNC increased exercise tolerance in patients with stable IPF experiencing exercise-induced hypoxaemia.

PMID:34729862 | DOI:10.1111/resp.14176

Life Sci Alliance. 2021 Nov 2;5(1):e202101059. doi: 10.26508/lsa.202101059. Print 2022 Jan.

ABSTRACT

Idiopathic pulmonary fibrosis is pathologically represented by usual interstitial pneumonia (UIP). Conventional bleomycin models used to study pathogenic mechanisms of pulmonary fibrosis display transient inflammation and fibrosis, so their relevance to UIP is limited. We developed a novel chronic induced-UIP (iUIP) model, inducing fibrosis in D1CC×D1BC transgenic mice by intra-tracheal instillation of bleomycin mixed with microbubbles followed by sonoporation (BMS). A bimodal fibrotic lung disease was observed over 14 wk, with an acute phase similar to nonspecific interstitial pneumonia (NSIP), followed by partial remission and a chronic fibrotic phase with honeycombing similar to UIP. In this secondary phase, we observed poor vascularization despite elevated PDGFRβ expression. γ2PF- and MMP7-positive epithelial cells, consistent with an invasive phenotype, were predominantly adjacent to fibrotic areas. Most invasive cells were Scgb1a1 and/or Krt5 positive. This iUIP mouse model displays key features of idiopathic pulmonary fibrosis and has identified potential mechanisms contributing to the onset of NSIP and progression to UIP. The model will provide a useful tool for the assessment of therapeutic interventions to oppose acute and chronic fibrosis.

PMID:34728556 | DOI:10.26508/lsa.202101059

Life Sci. 2021 Oct 30:120059. doi: 10.1016/j.lfs.2021.120059. Online ahead of print.

ABSTRACT

AIMS: Bleomycin, an important toxic anti-cancer agent, induces pulmonary fibrosis. The significance of oxidative stress and inflammation in promoting of bleomycin-induced idiopathic pulmonary fibrosis (IPF) has been reported. Thus, we evaluated the protective effects of carnosol as a robust natural antioxidant and anti-inflammatory agent for bleomycin-related IPF in rats.

MAIN METHODS: Male Wistar rats (n = 40) were randomly assigned to five groups. Group 1 was administrated with saline (intratracheally) on day 7 and oral gavage of dimethyl sulfoxide (DMSO, 0.05%) from day 1 to day 28. Group 2 received a single dose of bleomycin (intratracheally, 7.5 UI/kg) on day 7 and oral gavage of saline for 28 days. Groups 3, 4 and 5 were administrated with bleomycin (single dose) on day 7, along with oral administration of carnosol (at doses 10, 20 and 40 mg/kg, respectively) from day 1 to day 28. The lungs were isolated to measure the histopathological and biochemical and inflammatory markers.

KEY FINDINGS: Carnosol treatment significantly reduced malondialdehyde, nitric oxide, protein carbonyl, tumor necrosis factor- α, interleukin-6 levels and myeloperoxidase activity in the lungs of rats exposed to bleomycin. Also, lung glutathione content, catalase, glutathione peroxidase and superoxide dismutase activities significantly increased in the carnosol/bleomycin-treated group than the bleomycin group. Lung index, hydroxyproline content, fibrosis and histopathological changes, also significantly decreased by carnosol therapy.

SIGNIFICANCE: Treatment with carnosol can modulate biochemical and histological alterations caused by bleomycin. Thus, it can be regarded as an appropriate therapeutic approach for IPF.

PMID:34728227 | DOI:10.1016/j.lfs.2021.120059

Front Med (Lausanne). 2021 Oct 13;8:743977. doi: 10.3389/fmed.2021.743977. eCollection 2021.

ABSTRACT

Progressive fibrosing interstitial lung diseases (PF-ILD) consist of a diverse group of interstitial lung diseases (ILD) characterized by a similar clinical phenotype of accelerated respiratory failure, frequent disease exacerbation and earlier mortality. Regardless of underlying disease process, PF-ILD progresses through similar mechanisms of self-sustained dysregulated cell repair, fibroblast proliferation and alveolar dysfunction that can be therapeutically targeted. Antifibrotic therapy with nintedanib or pirfenidone slow lung function decline and are the backbone of treatment for IPF with an expanded indication of PF-ILD for nintedanib. Immunosuppression is utilized for some subtypes of PF-ILD, including connective tissue disease ILD and hypersensitivity pneumonitis. Inhaled treprostinil is a novel therapy that improves exercise tolerance in individuals with PF-ILD and concomitant World Health Organization (WHO) group 3 pulmonary hypertension. Lung transplantation is the only curative therapy and can be considered in an appropriate and interested patient. Supportive care, oxygen therapy when appropriate, and treatment of comorbid conditions are important aspects of PF-ILD management. This review summarizes the current data and recommendations for management of PF-ILD.

PMID:34722582 | PMC:PMC8548364 | DOI:10.3389/fmed.2021.743977

Nutr Metab Insights. 2021 Oct 26;14:11786388211053407. doi: 10.1177/11786388211053407. eCollection 2021.

ABSTRACT

In last decades, healthy aging has become one of research hotspots in life science. It is well known that the nicotinamide adenine dinucleotide oxidized form (NAD+) level in cells decreases with aging and aging-related diseases. Several years ago, one of NAD+ precursors was first demonstrated with its new role in DNA damage repairing in mice, restoring old mice to their physical state at young ones. The finding encourages extensive studies in animal models and patients. NAD+ and its precursors have been popular products in nutrition markets. Alternatively, it was also evidenced that clearance of cellular senescence by senolytics preserved multiorgan (kidney and heart) function and extended healthy lifespan in mice. Subsequent studies confirmed findings in elderly patients subjected with idiopathic pulmonary fibrosis. The senolytic therapy is now focused on various diseases in animal and clinical studies. However, pyruvate, as both a NAD+ substitute and a new senolytic, may be advantageous, on the equimolar basis, over current products above in preventing and treating diseases and aging. Pyruvate-enriched fluids, particularly pyruvate oral rehydration salt, may be a novel intervention for diseases and aging besides critical care. Albeit the direct evidence that benefits healthy aging is still limited to date, pyruvate, as both NAD+ provider and senolytic agent, warrants intensive research to compare NAD+ or senolytics for healthy aging, specifically on the equimolar basis, in effective blood levels. This review briefly discussed the recognition of healthy aging by comparing NAD+ and Senolytics with sodium pyruvate from the clinical point of view.

PMID:34720589 | PMC:PMC8552375 | DOI:10.1177/11786388211053407