Front Med (Lausanne). 2021 Oct 4;8:693959. doi: 10.3389/fmed.2021.693959. eCollection 2021.

ABSTRACT

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with unknown etiology and unfavorable prognosis. Ferroptosis is a form of regulated cell death with an iron-dependent way that is involved in the development of various diseases. Whereas the prognostic value of ferroptosis-related genes (FRGs) in IPF remains uncertain and needs to be further elucidated. Methods: The FerrDb database and the previous studies were screened to explore the FRGs. The data of patients with IPF were obtained from the GSE70866 dataset. Wilcoxon's test and univariate Cox regression analysis were applied to identify the FRGs that are differentially expressed between normal and patients with IPF and associated with prognosis. Next, a multigene signature was constructed by the least absolute shrinkage and selection operator (LASSO)-penalized Cox model in the training cohort and evaluated by using calibration and receiver operating characteristic (ROC) curves. Then, 30% of the dataset samples were randomly selected for internal validation. Finally, the potential function and pathways that might be affected by the risk score-related differently expressed genes (DEGs) were further explored. Results: A total of 183 FRGs were identified by the FerrDb database and the previous studies, and 19 of them were differentially expressed in bronchoalveolar lavage fluid (BALF) between IPF and healthy controls and associated with prognosis (p < 0.05). There were five FRGs (aconitase 1 [ACO1], neuroblastoma RAS viral (v-ras) oncogene homolog [NRAS], Ectonucleotide pyrophosphatase/phosphodiesterase 2 [ENPP2], Mucin 1 [MUC1], and ZFP36 ring finger protein [ZFP36]) identified as risk signatures and stratified patients with IPF into the two risk groups. The overall survival rate in patients with high risk was significantly lower than that in patients with low risk (p < 0.001). The calibration and ROC curve analysis confirmed the predictive capacity of this signature, and the results were further verified in the validation group. Risk score-related DEGs were found enriched in ECM-receptor interaction and focal adhesion pathways. Conclusion: The five FRGs in BALF can be used for prognostic prediction in IPF, which may contribute to improving the management strategies of IPF.

PMID:34671612 | PMC:PMC8520927 | DOI:10.3389/fmed.2021.693959

J Bras Pneumol. 2021 Oct 15;47(5):e20210208. doi: 10.36416/1806-3756/e20210208.

NO ABSTRACT

PMID:34669835 | DOI:10.36416/1806-3756/e20210208

Rheumatology (Oxford). 2021 Oct 20:keab772. doi: 10.1093/rheumatology/keab772. Online ahead of print.

ABSTRACT

OBJECTIVES: The nailfold videocapillaroscopy (NVC) has been known to assist with Interstitial Lung Disease (ILD) classification. However, evidence on its diagnostic efficacy is limited, particularly in some connective tissue disease-related interstitial lung diseases (CTD-ILD), and in interstitial pneumonia with autoimmune features (IPAF). This study aimed to address this limitation by conducting a meta-analysis on the efficacy of the NVC in ILD subgroups of CTD-ILD, IPAF and idiopathic pulmonary fibrosis (IPF).

METHODS: MEDLINE, EMBASE, CENTRAL were screened from inception to December 2020 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies that report prevalence of nailfold abnormalities (NVC+) in CTD-ILD, IPAF and IPF cohorts were included. Data were presented as prevalence ratio (PR) with 95% CI using a random-effects model. Quality of evidence was assessed using GRADE criteria.

RESULTS: Twenty one studies were eligible. Prevalence of NVC+ was highest in CTD-ILD; PR [95 CI%] 80.4% [74.3%, 85.3%], followed by IPAF; 27.4% [10.9%, 53.7%], and IPF; 13.8% [5.7%, 29.9%]. Late Scleroderma pattern was the most prevalent nailfold pattern; 40.4% [28.1%, 54.1%] in our CTD-ILD cohort. Quality of evidence was low for CTD-ILD, IPAF and IPF cohorts, moderate for the Late Scleroderma Pattern cohort.

CONCLUSION: NVC can increase the diagnostic accuracy of ILD when used in a multi-disciplinary setting, and appears to have greatest utility in CTD-ILD, followed by IPAF and IPF. The Late Scleroderma Pattern was the most frequent nailfold capillary pattern in SSc-ILD. Future research will allow for greater understanding of the prognostic value of the NVC in ILD.

PMID:34668513 | DOI:10.1093/rheumatology/keab772

BMJ Case Rep. 2021 Oct 19;14(10):e244472. doi: 10.1136/bcr-2021-244472.

ABSTRACT

A 79-year-old woman presented with a week-long history of shortness of breath. She had a background of idiopathic pulmonary fibrosis (IPF) which was stable and had not required any antifibrotic treatment. A month prior to this presentation, she was admitted with COVID-19 pneumonia, with maximal oxygen requirement of 2 L, but was discharged without need for supplemental oxygen. On readmission, she was found to have severe, rapidly progressive pulmonary fibrosis. After all precipitating causes were ruled out, it was felt her recent COVID-19 infection was the exacerbating factor causing progression of pulmonary fibrosis. COVID-19 infection has been hypothesised to cause long term pulmonary fibrosis, but this is the first case highlighting COVID-19 infection as the causative agent exacerbating IPF.

PMID:34667037 | DOI:10.1136/bcr-2021-244472

BMJ Case Rep. 2021 Oct 19;14(10):e242428. doi: 10.1136/bcr-2021-242428.

NO ABSTRACT

PMID:34667034 | DOI:10.1136/bcr-2021-242428

Respir Res. 2021 Oct 19;22(1):268. doi: 10.1186/s12931-021-01857-y.

ABSTRACT

BACKGROUND: Two antifibrotic drugs, pirfenidone and nintedanib, are licensed for the treatment of patients with idiopathic pulmonary fibrosis (IPF). However, there is neither evidence from prospective data nor a guideline recommendation, which drug should be preferred over the other. This study aimed to compare pirfenidone and nintedanib-treated patients regarding all-cause mortality, all-cause and respiratory-related hospitalizations, and overall as well as respiratory-related health care costs borne by the Statutory Health Insurance (SHI).

METHODS: A retrospective cohort study with SHI data was performed, including IPF patients treated either with pirfenidone or nintedanib. Stabilized inverse probability of treatment weighting (IPTW) based on propensity scores was applied to adjust for observed covariates. Weighted Cox models were estimated to analyze mortality and hospitalization. Weighted cost differences with bootstrapped 95% confidence intervals (CI) were applied for cost analysis.

RESULTS: We compared 840 patients treated with pirfenidone and 713 patients treated with nintedanib. Both groups were similar regarding two-year all-cause mortality (HR: 0.90 95% CI: 0.76; 1.07), one-year all cause (HR: 1.09, 95% CI: 0.95; 1.25) and respiratory-related hospitalization (HR: 0.89, 95% CI: 0.72; 1.08). No significant differences were observed regarding total (€- 807, 95% CI: €- 2977; €1220) and respiratory-related (€- 1282, 95% CI: €- 3423; €534) costs.

CONCLUSION: Our analyses suggest that the patient-related outcomes mortality, hospitalization, and costs do not differ between the two currently available antifibrotic drugs pirfenidone and nintedanib. Hence, the decision on treatment with pirfenidone versus treatment with nintedanib ought to be made case-by-case taking clinical characteristics, comorbidities, comedications, individual risk of side effects, and patients' preferences into account.

PMID:34666765 | DOI:10.1186/s12931-021-01857-y

Respir Res. 2021 Oct 19;22(1):265. doi: 10.1186/s12931-021-01863-0.

ABSTRACT

RATIONALE: αv integrins, key regulators of transforming growth factor-β activation and fibrogenesis in in vivo models of pulmonary fibrosis, are expressed on abnormal epithelial cells (αvβ6) and fibroblasts (αvβ1) in fibrotic lungs.

OBJECTIVES: We evaluated multiple αv integrin inhibition strategies to assess which most effectively reduced fibrogenesis in explanted lung tissue from patients with idiopathic pulmonary fibrosis.

METHODS: Selective αvβ6 and αvβ1, dual αvβ6/αvβ1, and multi-αv integrin inhibitors were characterized for potency, selectivity, and functional activity by ligand binding, cell adhesion, and transforming growth factor-β cell activation assays. Precision-cut lung slices generated from lung explants from patients with idiopathic pulmonary fibrosis or bleomycin-challenged mouse lungs were treated with integrin inhibitors or standard-of-care drugs (nintedanib or pirfenidone) and analyzed for changes in fibrotic gene expression or TGF-β signaling. Bleomycin-challenged mice treated with dual αvβ6/αvβ1 integrin inhibitor, PLN-74809, were assessed for changes in pulmonary collagen deposition and Smad3 phosphorylation.

MEASUREMENTS AND MAIN RESULTS: Inhibition of integrins αvβ6 and αvβ1 was additive in reducing type I collagen gene expression in explanted lung tissue slices from patients with idiopathic pulmonary fibrosis. These data were replicated in fibrotic mouse lung tissue, with no added benefit observed from inhibition of additional αv integrins. Antifibrotic efficacy of dual αvβ6/αvβ1 integrin inhibitor PLN-74809 was confirmed in vivo, where dose-dependent inhibition of pulmonary Smad3 phosphorylation and collagen deposition was observed. PLN-74809 also, more potently, reduced collagen gene expression in fibrotic human and mouse lung slices than clinically relevant concentrations of nintedanib or pirfenidone.

CONCLUSIONS: In the fibrotic lung, dual inhibition of integrins αvβ6 and αvβ1 offers the optimal approach for blocking fibrogenesis resulting from integrin-mediated activation of transforming growth factor-β.

PMID:34666752 | DOI:10.1186/s12931-021-01863-0

Am J Med Sci. 2021 Oct 16:S0002-9629(21)00360-8. doi: 10.1016/j.amjms.2021.06.027. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common type of fatal interstitial lung disease and IPF patients usually have a poor prognosis. Biomarkers that can predict the occurrence, process and prognosis of IPF will be useful for its diagnosis and treatment. This study aimed to identify the potential biomarkers of IPF and analyze the regulation of upstream miRNAs.

METHODS: The miRNA and gene expression profiles were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and miRNAs (DEMs) between IPF and normal groups were identified. After co-expression gene pair analysis, functional enrichment analysis was performed. Then, the potential biomarkers of IPF were screened and validated. Finally, the upstream regulatory miRNA of biomarkers was predicted.

RESULTS: A total of 343 DEGs and 21 DEMs were identified between IPF and normal samples. CLDN18, COL6A3, MYRF, PRSS8, RRAS, and SBNO1 were identified as potential IPF biomarkers. In addition, 17 miRNA-target relationship pairs were obtained. The up-regulation of hsa-miR-657, hsa-miR-671-5p, hsa-miR-198, and hsa-miR-940 could regulate the down-regulation of MYRF and the up-regulation of hsa-miR-198 and hsa-miR-373-3p could regulate the down-regulation of RRAS and CLDN18, respectively. Our data indicated that PRSS8, hsa-miR-614, and hsa-miR-503-5p might be involved in the migration and invasion of IPF related cells.

CONCLUSIONS: CLDN18, COL6A3, MYRF, PRSS8, RRAS, and SBNO1 might be potential IPF biomarkers. However, the specific role of these genes and miRNA in IPF needs further experimental research.

PMID:34666057 | DOI:10.1016/j.amjms.2021.06.027

Eur J Drug Metab Pharmacokinet. 2021 Oct 18. doi: 10.1007/s13318-021-00728-7. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: Nintedanib is a tyrosine kinase inhibitor approved for the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD), idiopathic pulmonary fibrosis, and other chronic fibrosing ILDs with a progressive phenotype. As nintedanib may cause foetal harm, patients taking nintedanib should avoid pregnancy. The objective of this study was to investigate the effect of nintedanib co-administration on the pharmacokinetics of Microgynon (ethinylestradiol and levonorgestrel) in female patients with SSc-ILD.

METHODS: This was an open-label, two-period, fixed-sequence, drug-drug interaction study. Female patients with SSc and ≥ 10% extent of fibrotic ILD on a high-resolution computed tomography scan were eligible to participate. In Period 1, patients received one Microgynon tablet (ethinylestradiol 30 μg and levonorgestrel 150 μg) ≥ 3 days before the first administration of nintedanib in Period 2. In Period 2, patients received one Microgynon tablet following intake of nintedanib 150 mg twice daily for ≥ 10 consecutive days. The primary pharmacokinetic endpoints were the areas under the plasma concentration-time curve of ethinylestradiol and levonorgestrel over the time interval from 0 to the last quantifiable data point (AUC0-tz) and the maximum measured concentrations of ethinylestradiol and levonorgestrel in plasma (Cmax). The secondary pharmacokinetic endpoint was the area under the plasma concentration-time curve of ethinylestradiol and levonorgestrel over the time interval from 0 extrapolated to infinity (AUC0-∞). The relative exposures of ethinylestradiol and levonorgestrel when administered alone and in combination with nintedanib were assessed using an ANOVA model.

RESULTS: Seventeen patients were treated. Pharmacokinetic data from 15 patients were analysed. Plasma concentration-time profiles of ethinylestradiol and levonorgestrel were similar following administration of Microgynon before and after administration of nintedanib for ≥ 10 consecutive days. Adjusted geometric mean (gMean) ratios [90% confidence intervals (CIs)] for AUC0‒tz (101.4% [92.8, 110.7]) and AUC0‒∞ (101.2% [94.0, 109.1]) indicated that there was no difference in total ethinylestradiol exposure when Microgynon was administered before or after administration of nintedanib. The adjusted gMean ratio for Cmax of ethinylestradiol (116.7% [90% CI 107.6, 126.5]) indicated an increase in peak exposure in the presence of nintedanib. Adjusted gMean ratios [90% CIs] for AUC0-tz (96.4% [91.5, 101.6]) and Cmax (100.9% [89.9, 113.2]) indicated that there was no difference in total or peak levonorgestrel exposure when Microgynon was administered before or after administration of nintedanib. The adjusted gMean ratio for AUC0‒∞ of levonorgestrel indicated a decrease in total exposure in the presence of nintedanib (88.1% [90% CI 80.0, 97.0]).

CONCLUSION: Pharmacokinetic data indicate that there is no relevant effect of nintedanib on plasma exposure to ethinylestradiol and levonorgestrel in female patients with SSc-ILD.

TRIAL REGISTRATION: Clinicaltrials.gov NCT03675581.

PMID:34664183 | DOI:10.1007/s13318-021-00728-7

J Agric Food Chem. 2021 Oct 18. doi: 10.1021/acs.jafc.1c04379. Online ahead of print.

ABSTRACT

Senescent cells (SCs) are associated with the onset and development of multiple chronic diseases. Selective clearance of SCs by senolytic drugs is a potential therapeutic option for a number of age-related diseases. Among senolytic candidates, only dasatinib with quercetin and fisetin meet the rigorous criteria for senolytic drugs, according to a modified version of Koch's postulates. It is astonishing that two of the three agents, i.e., quercetin and fisetin, are flavonoids, although the mechanism by which they preferentially eliminate SCs is unclear. Herein, we propose a possible selective mechanism; prooxidant activities of quercetin or fisetin are inevitably involved in killing apoptosis-resistant SCs. Among the dietary flavonoids, quercetin is a potent redox-active flavonoid with strong prooxidant activities, and transition metals, such as copper and iron, hugely amplify its prooxidant activities. Fisetin, which has higher senolytic activities than quercetin, has higher prooxidant effects than quercetin in the absence or presence of copper. It appears that the prooxidant activity of flavonoids is an important consideration for screening senolytics. SCs accumulate high levels of copper and iron, and the selective mechanism of quercetin or fisetin is probably associated with copper/iron-promoted oxidative damage in SCs. Copper and iron dramatically enhanced the prooxidant effects of the flavonoid, epigallocatechin-3-gallate, having shown a depletion effect on SCs in rats and high therapeutic efficacy in patients with idiopathic pulmonary fibrosis, largely caused by SCs. Further investigation to evaluate whether epigallocatechin-3-gallate is a senolytic drug, according to Koch's postulates, is warranted.

PMID:34662116 | DOI:10.1021/acs.jafc.1c04379

ACS Pharmacol Transl Sci. 2021 Sep 7;4(5):1598-1613. doi: 10.1021/acsptsci.1c00151. eCollection 2021 Oct 8.

ABSTRACT

GPR84 is a poorly characterized, nominally orphan, proinflammatory G protein-coupled receptor that can be activated by medium chain length fatty acids. It is attracting considerable interest as a potential therapeutic target for antagonist ligands in both inflammatory bowel diseases and idiopathic pulmonary fibrosis. Successful screening of more than 300 000 compounds from a small molecule library followed by detailed analysis of some 50 drug-like hits identified 3-((5,6-bis(4-methoxyphenyl)-1,2,4-triazin-3-yl)methyl)-1H-indole as a high affinity and highly selective competitive antagonist of human GPR84. Tritiation of a di-iodinated form of the core structure produced [3H]3-((5,6-diphenyl-1,2,4-triazin-3-yl)methyl)-1H-indole, which allowed effective measurement of receptor levels in both transfected cell lines and lipopolysaccharide-treated THP-1 monocyte/macrophage cells. Although this compound series lacks significant affinity at mouse GPR84, homology modeling and molecular dynamics simulations provided a potential rationale for this difference, and alteration of two residues in mouse GPR84 to the equivalent amino acids in the human orthologue, predicted to open the antagonist binding pocket, validated this model. Sequence alignment of other species orthologues further predicted binding of the compounds as high affinity antagonists at macaque, pig, and dog GPR84 but not at the rat orthologue, and pharmacological experiments confirmed these predictions. These studies provide a new class of GPR84 antagonists that display species selectivity defined via receptor modeling and mutagenesis.

PMID:34661077 | PMC:PMC8506611 | DOI:10.1021/acsptsci.1c00151

Mol Pharm. 2021 Oct 16. doi: 10.1021/acs.molpharmaceut.1c00545. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease with poor prognosis. Evidence has shown that vimentin is a key regulator of lung fibrogenesis. 99mTc-labeled N-acetylglucosamine-polyethyleneimine (NAG-PEI), a vimentin-targeting radiotracer, was used for the early diagnosis of IPF, and NAG-PEI was also used as a therapeutic small interfering RNA (siRNA) delivery vector for the treatment of IPF in this study. Single-photon emission-computed tomography (SPECT) imaging of bleomycin (BM)- and silica-induced IPF mice with 99mTc-labeled NAG-PEI was performed to visualize pulmonary fibrosis and monitor the treatment efficiency of siRNA-loaded NAG-PEI, lipopolysaccharide (LPS, a tolerogenic adjuvant), or zymosan (ZYM, an immunostimulant). The lung uptakes of 99mTc-NAG-PEI in the BM- and silica-induced IPF mice were clearly and directly correlated with IPF progression. The lung uptake of 99mTc-NAG-PEI in the NAG-PEI/TGF-β1-siRNA treatment group or LPS treatment group was evidently lower than that in the control group, while the lung uptake of 99mTc-NAG-PEI was significantly higher in the ZYM treatment group compared to that in the control group. These results demonstrate that NAG-PEI is a potent MicroSPECT imaging-guided theranostic platform for IPF diagnosis and therapy.

PMID:34657437 | DOI:10.1021/acs.molpharmaceut.1c00545

Int Immunopharmacol. 2021 Oct 14;101(Pt B):108212. doi: 10.1016/j.intimp.2021.108212. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease. However, there are insufficient drugs available for IPF treatment, and the currently used drugs are accompanied by many adverse reactions. Deficiency of vitamin D3 (VD3) in the development of IPF and the potential role of VD3 in the treatment of IPF have attracted increasing attention. In vivo experimental results showed that VD3 could increase the survival rate in bleomycin (BLM)-induced models, relieve lung inflammation, reduce hydroxyproline content, and inhibit collagen deposition and cell apoptosis. We further performed proteomics analysis and screened 251 target proteins that reflect VD3 intervention in BLM-induced animal models. These target proteins were involved in acute inflammation, oxidative stress, antioxidant activity and extracellular matrix binding. Combined with the comprehensive analysis of clinical samples, PSAT1 was screened out as a candidate target related to IPF disease and VD3 treatment. Through further computational analysis, the MAPK signaling pathway was considered to be the most probable candidate pathway for VD3 function targeting IPF. In in vivo experiments, VD3 inhibited BLM-induced expression of PSAT1 and phosphorylation of p38 and ERK1/2 in mouse lung tissue. The experiments of cell proliferation and western blot confirmed that VD3 inhibited the expression of PSAT1 and the activation of the mitogen-activated protein kinase (MAPK) pathway in human pulmonary fibroblasts (HPF). Furthermore, experiments with transfection plasmids overexpressing PSAT1 proved that VD3 could attenuate the proliferation and differentiation of HPF by suppressing the effect of PSAT1 on the MAPK signaling pathway. Finally, we confirmed that vitamin D receptor (VDR) could occupy the PSAT1 promoter to reveal the transcriptional regulation effect of VD3 on PSAT1. In conclusion, VD3 exerted a therapeutic effect on IPF by down-regulating the MAPK signaling pathway via targeting the expression of PSAT1.

PMID:34656907 | DOI:10.1016/j.intimp.2021.108212

Respir Med. 2021 Sep 29;189:106637. doi: 10.1016/j.rmed.2021.106637. Online ahead of print.

ABSTRACT

BACKGROUND: Few data are available on the extent to which clinical practice is aligned with international guidelines for the management of idiopathic pulmonary fibrosis (IPF). We investigated the extent to which management guidelines for IPF have been implemented in the US IPF-PRO Registry and associations between implementation of guidelines and clinical outcomes.

METHODS: We assessed the implementation of eight recommendations in clinical practice guidelines within the 6 months after enrollment: visit to a specialized clinic; pulmonary function testing; use of oxygen in patients with resting hypoxemia and exercise-induced hypoxemia; referral for pulmonary rehabilitation; treatment of gastro-esophageal reflux disease; initiation of anti-fibrotic therapy; referral for lung transplant evaluation. An implementation score was calculated as the number of recommendations achieved divided by the number for which the patient was eligible. Associations between implementation score and outcomes were analyzed using logistic regression and Cox proportional hazards models.

RESULTS: Among 727 patients, median (Q1, Q3) implementation score was 0.6 (0.5, 0.8). Patients with an implementation score >0.6 had greater disease severity than those with a lower score. Implementation was lowest for referral for pulmonary rehabilitation (19.5%) and lung transplant evaluation (22.3%). In unadjusted models, patients with higher implementation scores had a greater risk of death, death or lung transplant, and hospitalization, but no significant associations were observed in adjusted models.

CONCLUSIONS: Management guidelines were more likely to be implemented in patients with IPF with greater disease severity. When adjusted for disease severity, no association was found between implementation of management guidelines and clinical outcomes.

PMID:34656903 | DOI:10.1016/j.rmed.2021.106637

J Clin Pharm Ther. 2021 Oct 15. doi: 10.1111/jcpt.13542. Online ahead of print.

ABSTRACT

WHAT IS KNOWN AND OBJECTIVE: Knowledge regarding the association between photosensitivity and pirfenidone is based mainly on case reports. The purpose of this article was to evaluate the clinical characteristics of photosensitivity associated with pirfenidone.

METHODS: We collected studies on photosensitivity induced by pirfenidone published from 2008 to 31 August 2021 in Chinese and English for a retrospective analysis.

RESULTS AND DISCUSSION: The median age was 70 years (range 57-80) in 22 patients with pirfenidone-induced photosensitivity. The dose at the onset of symptoms ranged from 600 to 2403 mg for the treatment of idiopathic pulmonary fibrosis. Pirfenidone-induced photosensitivity occurred within 1 week in some patients and up to 8 months in others. The most common clinical manifestation of photosensitivity caused by pirfenidone was itching on body parts exposed to sunlight (back of hands, face, neck, and limbs) in 15 patients followed by erythema in 13 patients. Histopathological examination revealed necrotic keratinocytes, lymphocytic inflammatory cell infiltrate, hyperkeratosis and liquefaction degeneration in 5 patients. The photosensitivity test showed a markedly decreased minimum erythema dose (MED) of 7-228 mJ/cm2 UV-B in 4 patients and 4.86-12 J/cm2 UV-A in 5 patients. The clinical symptoms were significantly improved or completely relieved with a median time of 4 weeks (range 1-8) after drug withdrawal, dose reduction or systemic and topical glucocorticoid therapy.

WHAT IS NEW AND CONCLUSION: Clinicians should be aware of the potential phototoxic effects of pirfenidone and should inform patients to take pirfenidone during (or after) a meal, avoid sun exposure, wear protective clothing, and apply broad-spectrum sunscreen with high ultraviolet UVA and UVB protection.

PMID:34655088 | DOI:10.1111/jcpt.13542

Front Med (Lausanne). 2021 Sep 27;8:699644. doi: 10.3389/fmed.2021.699644. eCollection 2021.

ABSTRACT

Background: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a severe complication associated with a high mortality. However, evidence and guidance on management is sparse. The aim of this international survey was to assess differences in prevention, diagnostic and treatment strategies for AE-IPF in specialised and non-specialised ILD centres worldwide. Material and Methods: Pulmonologists working in specialised and non-specialised ILD centres were invited to participate in a survey designed by an international expert panel. Responses were evaluated in respect to the physicians' institutions. Results: Three hundred and two (65%) of the respondents worked in a specialised ILD centre, 134 (29%) in a non-specialised pulmonology centre. Similarities were frequent with regards to diagnostic methods including radiology and screening for infection, treatment with corticosteroids, use of high-flow oxygen and non-invasive ventilation in critical ill patients and palliative strategies. However, differences were significant in terms of the use of KL-6 and pathogen testing in urine, treatments with cyclosporine and recombinant thrombomodulin, extracorporeal membrane oxygenation in critical ill patients as well as antacid medication and anaesthesia measures as preventive methods. Conclusion: Despite the absence of recommendations, approaches to the prevention, diagnosis and treatment of AE-IPF are comparable in specialised and non-specialised ILD centres, yet certain differences in the managements of AE-IPF exist. Clinical trials and guidelines are needed to improve patient care and prognosis in AE-IPF.

PMID:34646836 | PMC:PMC8502934 | DOI:10.3389/fmed.2021.699644

Cureus. 2021 Aug 26;13(8):e17462. doi: 10.7759/cureus.17462. eCollection 2021 Aug.

ABSTRACT

Vasculitis is classified based on the size of the blood vessels involved. Sub-group Leukocytoclastic vasculitis (LCV) refers to small blood vessel inflammation, which involves cutaneous capillaries and venules. To date, there have been myriad primary and secondary probable causes of LCV. Here, we present a case of an 86-year-old male who presented with non-blanchable purpura involving the ankles, knees, and palms. The patient had idiopathic pulmonary fibrosis (IPF), for which he had been on long-term oxygen therapy and chronic corticosteroids. He was recently started on Bactrim DS (trimethoprim-sulfamethoxazole double strength) for prophylaxis of pneumocystis pneumonia. After a meticulous workup, including a skin biopsy, the causative agent of the LCV was established to be Bactrim DS, and the event was likely triggered by superimposed acute stress of sepsis secondary to UTI and bacteremia. There were several diagnostic dilemmas due to the ongoing chronic medical conditions; however, the occurrence of LCV while being on chronic corticosteroids was concerning as it should have prevented such an untoward occurrence. Eventually, the presentation subsided past an increase in the dose of corticosteroids and discontinuation of Bactrim DS. This raises concern regarding either the dose-dependent immunosuppressive effects of corticosteroids or deficits in our current understanding of the mechanism of action. Additionally, it necessitates further exploration into the causes of LCV and a thorough understanding of its pathogenesis.

PMID:34646589 | PMC:PMC8478687 | DOI:10.7759/cureus.17462

Comput Math Methods Med. 2021 Oct 4;2021:7922594. doi: 10.1155/2021/7922594. eCollection 2021.

ABSTRACT

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is one of the most common idiopathic interstitial pneumonia, which can occur all over the world. The median survival time of patients is about 3-5 years, and the mortality is relatively high.

OBJECTIVE: To reveal the potential molecular characteristics of IPF and deepen the understanding of the molecular mechanism of IPF. In order to provide some guidance for the clinical treatment, new drug development, and prognosis judgment of IPF. Although the preliminary conclusion of this study has certain guiding significance for the treatment of IPF and so on, it needs more accurate analytical approaches and large sample clinical trials to verify.

METHODS: 220 patients with IPF were divided into different subgroups according to the gene expression profiles, which were obtained from the Gene Expression Omnibus (GEO) database. In addition, these subgroups present different expression forms and clinical features. Therefore, weighted gene coexpression analysis (WGCNA) was used to seek the differences between subtypes. And six subgroup-specific WGCNA modules were identified.

RESULTS: Combined with the characteristics of WGCNA and KEGG enrichment modules, the autophagic pathway was only upregulated in subgroup I and enriched significantly. The differentiation pathways of Th1 and Th2 cells were only upregulated and enriched in subgroup II. At the same time, combined with clinical information, IPF patients in subgroup II were older and more serious, which may be closely related to the differentiation of Th1 and Th2 cells. In contrast, the neuroactive ligand-receptor interaction pathway and Ca+ signaling pathway were significantly upregulated and enriched in subgroup III. Although there was no significant difference in prognosis between subgroup I and subgroup III, their intrinsic biological characteristics were very different. These results suggest that the subtypes may represent risk factors of age and intrinsic biological characteristics and may also partly reflect the severity of the disease.

CONCLUSION: In conclusion, current studies have improved our understanding of IPF-related molecular mechanisms. At the same time, because the results show that patients from different subgroups may have their own unique gene expression patterns, it reminds us that patients in each subgroup should receive more personalized treatment.

PMID:34646338 | PMC:PMC8505108 | DOI:10.1155/2021/7922594

Cell Death Dis. 2021 Oct 13;12(10):938. doi: 10.1038/s41419-021-04232-3.

ABSTRACT

Alveolar epithelial injury is one of the important pathological changes in idiopathic pulmonary interstitial fibrosis (IPF), but the regulatory mechanism remains unclear. Here, we reported that alveolar epithelial type-II cells (AT II) play important roles in pathological process of pulmonary fibrosis. Through iTRAQ (isobaric tagging for relative and absolute quantification) quantitative proteomics, TSSK4 was identified to be upregulated in bleomycin-induced fibrotic mice model, which was further confirmed in clinical IPF patients' tissue specimens. TSSK4 is a germ-related protein, but its expression in other tissues and the association with other diseases are not reported. Immunofluorescence staining showed that TSSK4 selectively expressed in AT-II cells, which are essential for inflammation-induced AT-II loss during fibrosis. Luciferase assay and other molecular biological experiments proved that TSSK4 expression is regulated by TNF-α-mediated NF-κB signaling. The TSSK4 kinase activity is found to be closely related to the function of HSP90-AKT pathway that TSSK4 can phosphorylate its substrate HSP90β on serine 255, to inhibit the ATPase activity of HSP90β and reduce its molecular chaperone function on AKT. Under this condition, kinase activity of AKT is diminished to interfere its survival function, subsequently facilitating AT-II cellular apoptosis through the mitochondrial death machinery. Our findings highlight the importance of TSSK4 in regulating pulmonary fibrosis by facilitating AT-II loss through HSP90-AKT signaling, all of which suggest TSSK4 and the regulating mechanism as attractive targets for the clinical intervention of pulmonary injury and fibrosis.

PMID:34645797 | DOI:10.1038/s41419-021-04232-3

Mol Biol Rep. 2021 Oct 13. doi: 10.1007/s11033-021-06790-3. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis is characterized by progressive lung tissue remodeling and disproportionate deposition of collagenous proteins with limited therapeutic interventions. The purpose of this study was to determine whether curcumin inhibits bleomycin (BLM)-induced increases in synthesis, degradation and cross-linking of lung collagen in rats.

METHODS AND RESULTS: Following a single intratracheal instillation of BLM to rats (0.75 U/100 g, sacrificed 3, 5, 7, 14 and 28 days post-BLM), lung collagen synthesis (determined by incorporation of 3H-proline) and deposition (determined by lung hydroxyproline content) progressively increased at days 7, 14 and 28 post-BLM injection. Lung lavage fluid hydroxyproline and collagenase levels (a measure of collagen turnover) were increased in BLM rats compared with control groups. In addition, BLM instillation resulted in increased concentrations of collagenase and collagenolytic cathepsin in the lungs. Furthermore, increased cross-linking (as determined by aldehyde content of acid soluble collagen), and decreased susceptibility of fibrotic lung insoluble collagen to denaturing agents occurred in BLM-injured lungs. Significant increases in alveolar macrophage (AM) release of transforming growth factor-β1 (TGF-β1) were noted at various time points (days 3, 5, 7, 14 and 28 post-BLM) during the development and progression of lung fibrosis in rats. Curcumin treatment to BLM rats (300 mg/kg 10 days before and daily thereafter throughout the experimental time period) was associated with marked reductions in lung collagen synthesis and deposition, BALF and lung collagenase activity, BALF hydroxyproline content and lung collagenolytic levels. Additionally, reduced levels of collagen cross-linking and enhanced susceptibility of insoluble lung collagen to denaturing agents were observed in curcumin-treated BLM rats. Finally, curcumin inhibited BLM-induced increases in AM production of TGF-β1.

CONCLUSIONS: Our data demonstrate for the first time that curcumin prevents fibrotic deposits by modulating collagen turnover, assembly and deposition in BLM-instilled rat lungs, and that curcumin treatment protects against BLM activation of macrophages by suppressing the release of TGF-β1.

PMID:34643929 | DOI:10.1007/s11033-021-06790-3