Int J Technol Assess Health Care. 2022 Aug 1;38(1):e64. doi: 10.1017/S0266462322000459.

ABSTRACT

OBJECTIVES: Our aim was to assess the value of nintedanib for non-idiopathic progressive fibrosing interstitial lung disease (non-IPF PF-ILD) and systemic sclerosis-associated ILD (SSc-ILD) in the Spanish context, using a multi-criteria decision analysis (MCDA).

METHODS: Following an adaptation of the Evidence and Value: Impact on DEcision Making (EVIDEM) MCDA methodology, the estimated value of nintedanib was obtained by means of an additive linear model that combined individual weights (100-points distribution) of criteria with the individual scoring of nintedanib in each criterion for every indication, assigned by a multidisciplinary committee of twelve clinicians, patients, pharmacists, and decision-makers. To assess the reproducibility, an alternative weighting method was applied, as well as a re-test of weights and scores at a different moment of time.

RESULTS: The experts committee recognized nintedanib as an intervention with a positive value contribution in comparison to placebo for the treatment of non-IPF PF-ILD (0.50 ± 0.16, on a scale from -1 to 1) and SSc-ILD (0.40 ± 0.12), diseases which were considered as very severe and with high unmet needs. The drug was perceived as a treatment that provides an added therapeutic benefit for patients (0.06-0.07), given its proven clinical efficacy (0.05-0.06), slight improvements in patient-reported outcomes (0.01-0.02), and similar safety profile than placebo (-0.04-0.00), which will likely be positioned as a recommended therapy in the next clinical practice guidelines updates.

CONCLUSIONS: Under this increasingly used methodology, nintedanib has shown to provide a positive value estimate for non-IPF PF-ILD and SSc-ILD when compared to placebo in Spain.

PMID:35912833 | DOI:10.1017/S0266462322000459

Ups J Med Sci. 2022 Jul 11;127. doi: 10.48101/ujms.v127.8739. eCollection 2022.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic, and fatal interstitial lung disease (ILD) of unknown etiology that primarily affects the elderly. Patients with IPF suffer from a heavy symptom burden and usually have a poor quality of life. Dyspnea and dry cough are predominant symptoms of IPF. Although pain is not considered one of the main symptoms of IPF, it can occur for a variety of reasons, such as hypoxia, coughing, muscle and nerve damage, deconditioning, and steroid use. The prevalence of pain in IPF patients varies greatly, ranging from around 30 to 80%, with the prevalence being estimated mostly among patients in the end-of-life period. It manifests itself in the form of muscle pain, joint discomfort, or back and chest pain. Approaches to the treatment of chronic musculoskeletal pain in patients with IPF include pharmacological and non-pharmacological measures that are also important to optimize the treatment of other symptoms (dyspnea and cough) and the optimal treatment of comorbidities. Given the scarcity of data on this symptom in the literature, this article summarizes what is currently known about the etiology and treatment of musculoskeletal pain in IPF.

PMID:35910492 | PMC:PMC9287761 | DOI:10.48101/ujms.v127.8739

Front Pharmacol. 2022 Jul 15;13:890380. doi: 10.3389/fphar.2022.890380. eCollection 2022.

ABSTRACT

Rationale: Idiopathic pulmonary fibrosis (IPF) is characterized by mitochondrial dysfunction. However, details about the non-mitochondrial enzymes that sustain the proliferative nature of IPF are unclear. Aconitases are a family of enzymes that sustain metabolism inside and outside mitochondria. It is hypothesized that aconitase 1 (ACO1) plays an important role in the pathogenesis of IPF given that ACO1 represents an important metabolic hub in the cytoplasm. Objectives: To determine if ACO1 expression in IPF lungs shows specific patterns that may be important in the pathogenesis of IPF. To determine the similarities and differences in ACO1 expression in IPF, bleomycin-treated, and aging lungs. Methods: ACO1 expression in IPF lungs were characterized and compared to non-IPF controls by western blotting, immunostaining, and enzymatic activity assay. ACO1-expressing cell types were identified by multicolor immunostaining. Using similar methods, the expression profiles of ACO1 in IPF lungs versus bleomycin-treated and aged mice were investigated. Measurements and main results: Lower lobes of IPF lungs, unlike non-IPF controls, exhibit significantly high levels of ACO1. Most of the signals colocalize with von Willebrand factor (vWF), a lineage marker for vascular endothelial cells. Bleomycin-treated lungs also show high ACO1 expressions. However, most of the signals colocalize with E-cadherin and/or prosurfactant protein C, representative epithelial cell markers, in remodeled areas. Conclusions: A characteristic ACO1 expression profile observed in IPF vasculatures may be a promising diagnostic target. It also may give clues as to how de novo angiogenesis contributes to the irreversible nature of IPF.

PMID:35910393 | PMC:PMC9335372 | DOI:10.3389/fphar.2022.890380

Front Genet. 2022 Jul 14;13:939175. doi: 10.3389/fgene.2022.939175. eCollection 2022.

ABSTRACT

N6-methyladenosine (m6A) modification plays a pivotal role in post-transcriptionally regulating gene expression and biological functions. Nonetheless, the roles of m6A modification in the regulation of chronic hypersensitivity pneumonitis (CHP) and idiopathic pulmonary fibrosis (IPF) remain unclear. Twenty-two significant m6A regulators were selected from differential gene analysis between the control and treatment groups from the GSE150910 dataset. Five candidate m6A regulators (insulin-like growth factor binding protein 2, insulin-like growth factor binding protein 3, YTH domain-containing protein 1, zinc finger CCCH domain-containing protein 13, and methyltransferase-like 3) were screened by the application of a random forest model and nomogram model to predict risks of pulmonary fibrosis. The consensus clustering method was applied to divide the treatment samples into two groups with different m6A patterns (clusters A and B) based on the 22 m6A regulators. Our study performed principal component analysis to obtain the m6A-related score of the 288 samples to quantify the two m6A patterns. The study reveals that cluster A was linked to T helper cell (Th) 2-type cytokines, while the immune infiltration of Th1 cytokines was higher in cluster B. Our results suggest that m6A cluster A is likely related to pulmonary fibrosis, indicating m6A regulators play notable roles in the occurrence of pulmonary fibrosis. The m6A patterns could be considered as biomarkers to identify CHP and IPF, which will be helpful to develop immunotherapy strategies for pulmonary fibrosis in the future.

PMID:35910226 | PMC:PMC9329921 | DOI:10.3389/fgene.2022.939175

Inflamm Regen. 2022 Aug 1;42(1):23. doi: 10.1186/s41232-022-00210-0.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease that occurs due to increased fibrosis of lung tissue in response to chronic injury of the epithelium. Therapeutic options for IPF remain limited as current therapies only function to decrease disease progression. Recently, extracellular vesicles (EVs), including exosomes and microvesicles, have been recognized as paracrine communicators through the component cargo. The population of cell-specific microRNAs and proteins present in EVs can regulate gene expressions of recipient cells, resulting in modulation of biological activities. EV cargoes reflect cell types and their physiological and pathological status of donor cells. Many current researches have highlighted the functions of EVs on the epithelial phenotype and fibroproliferative response in the pathogenesis of IPF. Furthermore, some native EVs could be used as a cell-free therapeutic approach for IPF as vehicles for drug delivery, given their intrinsic biocompatibility and specific target activity. EV-based therapies have been proposed as a new potential alternative to cell-based approaches. The advantage is that EVs, depending on their source, may be less immunogenic than their parental cells, likely due to a lower abundance of transmembrane proteins such as major histocompatibility complex (MHC) proteins on the surface. In the last decade, mesenchymal stem cell (MSC)-derived EVs have been rapidly developed as therapeutic products ready for clinical trials against various diseases. Considering EV functional complexity and heterogeneity, there is an urgent need to establish refined systemic standards for manufacturing processes and regulatory requirements of these medicines. This review highlights the EV-mediated cellular crosstalk involved in IPF pathogenesis and discusses the potential for EV-based therapeutics as a novel treatment modality for IPF.

PMID:35909143 | DOI:10.1186/s41232-022-00210-0

Thorax. 2022 Jul 30:thoraxjnl-2021-217822. doi: 10.1136/thorax-2021-217822. Online ahead of print.

ABSTRACT

Although interstitial lung disease (ILD) causes significant morbidity and mortality in rheumatoid arthritis (RA), it is difficult to predict the development or progression of ILD, emphasising the need for improved discovery through minimally invasive diagnostic tests. Aptamer-based proteomic profiling was used to assess 1321 proteins from 159 patients with rheumatoid arthritis with interstitial lung disease (RA-ILD), RA without ILD, idiopathic pulmonary fibrosis and healthy controls. Differential expression and gene set enrichment analyses revealed molecular signatures that are strongly associated with the presence and severity of RA-ILD and provided insight into unexplored pathways of disease. These warrant further study as non-invasive diagnostic tools and future therapeutic targets.

PMID:35907639 | DOI:10.1136/thorax-2021-217822

Front Pharmacol. 2022 Jul 12;13:921209. doi: 10.3389/fphar.2022.921209. eCollection 2022.

ABSTRACT

Number 2 Feibi Recipe (N2FBR) is a traditional Chinese medicine formula for treating idiopathic pulmonary fibrosis. N2FBR inhibits H2O2-mediated oxidative stress damage in alveolar epithelial cells by increasing autophagy, as we previously demonstrated. However, it is unknown if similar mechanisms occur in vivo. We established a pulmonary fibrosis model by instilling bleomycin (BLM) from the airway to examine the effects of N2FBR on pulmonary fibrosis and investigate its probable mechanism in this work. We discovered that N2FBR treatment effectively alleviated interstitial fibrosis as well as collagen deposition, primarily in upregulating SOD, GSH-Px, T-AOC and downregulating MDA content. N2FBR also increased the expression of LC3B, Beclin-1, LAMP1, TFEB and downregulated the expression of p62, legumain. N2FBR treatment boosted the production of autophagosomes, according to the results of the TEM observation. Furthermore, we explored that N2FBR exerted its anti-oxidative stress and pro-autophagy effects via GSK-3β/mTOR signalling pathway. Therefore, these results provide further evidence for the protective effect of N2FBR in pulmonary fibrosis. Our findings could have ramifications for the development of antifibrosis therapies.

PMID:35903328 | PMC:PMC9315309 | DOI:10.3389/fphar.2022.921209

Sci Rep. 2022 Jul 28;12(1):12935. doi: 10.1038/s41598-022-17290-0.

ABSTRACT

The present study aimed to evaluate whether serum heme oxygenase (HO)-1 could be a reliable blood biomarker for diagnosing acute exacerbations (AEs) of both idiopathic interstitial pneumonia (IIP) and secondary interstitial pneumonia (SIP). Serum HO-1 levels of newly diagnosed patients with IP were measured, and the relationships between serum HO-1 and other serum biomarkers and high-resolution CT scores, were evaluated. Blood samples were collected from 90 patients with IIP, including 32 having an AE, and 32 with SIP, including 9 having an AE. The patients having an AE had significantly higher HO-1 levels than those not having an AE (35.2 ng/mL vs. 16.4 ng/mL; p < 0.001). On receiver operating characteristics (ROC) curve analysis for serum HO-1 ability to detect an AE, the area under the ROC curve (AUC) was 0.87 in patients with IIPs and 0.86 in those with SIPs. Also, in patients with both IIPs and SIPs, the combination of the serum HO-1 level and the GGO score showed favorable AUCs (IIPs: 0.92, SIPs: 0.83), though HO-1-not-including model (combination of LDH and GGO) also showed acceptable AUCs. Serum HO-1 could be a clinically useful biomarker for the accurate diagnosis of patients with AEs.

PMID:35902685 | PMC:PMC9334264 | DOI:10.1038/s41598-022-17290-0

PLoS One. 2022 Jul 28;17(7):e0271608. doi: 10.1371/journal.pone.0271608. eCollection 2022.

ABSTRACT

Transforming growth factor beta (TGF-β) induced myofibroblast differentiation is central to the pathological scarring observed in Idiopathic Pulmonary Fibrosis (IPF) and other fibrotic diseases. Our lab has recently identified expression of GPR68 (Ovarian Cancer Gene Receptor 1, OGR1), a pH sensing G-protein coupled receptor, as a negative regulator of TGF-β induced profibrotic effects in primary human lung fibroblasts (PHLFs). We therefore hypothesized that small molecule activators of GPR68 would inhibit myofibroblast differentiation. Ogerin is a positive allosteric modulator (PAM) of GPR68, inducing a leftward shift of the dose response curve to proton induced signaling. Using PHLFs derived from patients with both non-fibrotic and IPF diagnoses, we show that Ogerin inhibits, and partially reverses TGF-β induced myofibroblast differentiation in a dose dependent manner. This occurs at the transcriptional level without inhibition of canonical TGF-β induced SMAD signaling. Ogerin induces PKA dependent CREB phosphorylation, a marker of Gαs pathway activation. The ability of Ogerin to inhibit both basal and TGF-β induced collagen gene transcription, and induction of Gαs signaling is enhanced at an acidic pH (pH 6.8). Similar findings were also found using fibroblasts derived from dermal, intestinal, and orbital tissue. The biological role of GPR68 in different tissues, cell types, and disease states is an evolving and emerging field. This work adds to the understanding of Gαs coupled GPCRs in fibrotic lung disease, the ability to harness the pH sensing properties of GPR68, and conserved mechanisms of fibrosis across different organ systems.

PMID:35901086 | DOI:10.1371/journal.pone.0271608

FASEB J. 2022 Aug;36(8):e22475. doi: 10.1096/fj.202200406RR.

ABSTRACT

Recent findings suggest that extracellular heat shock protein 90α (eHSP90α) promotes pulmonary fibrosis, but the underlying mechanisms are not well understood. Aging, especially cellular senescence, is a critical risk factor for idiopathic pulmonary fibrosis (IPF). Here, we aim to investigate the role of eHSP90α on cellular senescence in IPF. Our results found that eHSP90α was upregulated in bleomycin (BLM)-induced mice, which correlated with the expression of senescence markers. This increase in eHSP90α mediated fibroblast senescence and facilitated mitochondrial dysfunction. eHSP90α activated TGF-β signaling through the phosphorylation of the SMAD complex. The SMAD complex binding to p53 and p21 promoters triggered their transcription. In vivo, the blockade of eHSP90α with 1G6-D7, a specific eHSP90α antibody, in old mice attenuated the BLM-induced lung fibrosis. Our findings elucidate a crucial mechanism underlying eHSP90α-induced cellular senescence, providing a framework for aging-related fibrosis interventions.

PMID:35899478 | DOI:10.1096/fj.202200406RR

Int J Mol Sci. 2022 Jul 25;23(15):8193. doi: 10.3390/ijms23158193.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease (ILD). Pulmonary fibroblasts play an important role in the development of IPF. Emerging evidence indicates that pulmonary endothelial cells could be the source of pulmonary fibroblasts through endothelial mesenchymal transition (EndoMT), which contributes to pulmonary fibrosis. EndoMT is a complex process in which endothelial cells lose their expression of endothelial markers and give rise to the characteristics of mesenchymal cells, including morphological fibroblast-like change and the expression of mesenchymal markers, which result in cardiac, renal, and dermal fibroses. Furthermore, EndoMT inhibition attenuates pulmonary fibrosis. Herein, we demonstrate that nintedanib, a tyrosine kinase receptor inhibitor, ameliorated murine bleomycin (BLM)-induced pulmonary fibrosis and suppressed the in vivo and in vitro models of EndoMT. We demonstrated that the activity of focal adhesion kinase (FAK), a key EndoMT regulator, increased in murine lung tissues and human pulmonary microvascular endothelial cells after BLM stimulation. Nintedanib treatment inhibited BLM-induced FAK activation and thus suppressed both in vivo and in vitro BLM-induced EndoMT. Importantly, we found that the VEGF/FAK signaling pathway was involved in nintedanib regulating EndoMT. These novel findings help us understand the mechanism and signaling pathway of EndoMT to further develop more efficacious drugs for IPF treatment.

PMID:35897764 | DOI:10.3390/ijms23158193

Am J Respir Cell Mol Biol. 2022 Jul 27. doi: 10.1165/rcmb.2021-0463OC. Online ahead of print.

ABSTRACT

CD55 or decay accelerating factor (DAF), a ubiquitously expressed glycosylphosphatidylinositol (GPI)-anchored protein, confers a protective threshold against complement dysregulation which is linked to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Since lung fibrosis is associated with downregulation of DAF, we hypothesize that overexpression of DAF in fibrosed lungs will limit fibrotic injury by restraining complement dysregulation. Normal primary human alveolar type II epithelial cells (AECs) exposed to exogenous complement 3a or 5a, and primary AECs purified from IPF lungs demonstrated decreased membrane-bound DAF expression with concurrent increase in the endoplasmic reticulum (ER) stress protein, ATF6. Increased loss of extracellular cleaved DAF fragments was detected in normal human AECs exposed to complement 3a or 5a, and in lungs of IPF patients. C3a-induced ATF6 expression and DAF loss was inhibited using pertussis toxin (an enzymatic inactivator of G-protein coupled receptors), in murine AECs. Treatment with soluble DAF abrogated tunicamycin-induced C3a secretion and ER stress (ATF6 and BiP expression) and restored epithelial cadherin. Bleomycin-injured fibrotic mice subjected to lentiviral overexpression of DAF demonstrated diminished levels of local collagen deposition and complement activation. Further analyses showed diminished release of DAF fragments, as well as reduction in apoptosis (TUNEL and caspase 3/7 activity), and ER stress-related transcripts. Loss-of-function studies using Daf1 siRNA demonstrated worsened lung fibrosis detected by higher mRNA levels of Col1a1 and epithelial injury-related Muc1 and Snai1, with exacerbated local deposition of C5b-9. Our studies provide a rationale for rescuing fibrotic lungs via DAF induction that will restrain complement dysregulation and lung injury.

PMID:35895592 | DOI:10.1165/rcmb.2021-0463OC

Int J Mol Sci. 2022 Jul 19;23(14):7943. doi: 10.3390/ijms23147943.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by parenchymal scarring, leading progressively to alveolar architecture distortion, respiratory failure, and eventually death. Currently, there is no effective treatment for IPF. Previously, 3'5-dimaleamylbenzoic acid (3'5-DMBA), a maleimide, demonstrated pro-apoptotic, anti-inflammatory, and anti-cancer properties; however, its potential therapeutic effects on IPF have not been addressed. Bleomycin (BLM) 100 U/kg was administered to CD1 mice through an osmotic minipump. After fourteen days of BLM administration, 3'5-DMBA (6 mg/kg or 10 mg/kg) and its vehicle carboxymethylcellulose (CMC) were administered intragastrically every two days until day 26. On day 28, all mice were euthanized. The 3'5-DMBA effect was assessed by histological and immunohistochemical staining, as well as by RT-qPCR. The redox status on lung tissue was evaluated by determining the glutathione content and the GSH/GSSG ratio. 3'5-DMBA treatment re-established typical lung histological features and decreased the expression of BLM-induced fibrotic markers: collagen, α-SMA, and TGF-β1. Furthermore, 3'5-DMBA significantly reduced the expression of genes involved in fibrogenesis. In addition, it decreased reduced glutathione and increased oxidized glutathione content without promoting oxidative damage to lipids, as evidenced by the decrease in the lipid peroxidation marker 4-HNE. Therefore, 3'5-DMBA may be a promising candidate for IPF treatment.

PMID:35887292 | DOI:10.3390/ijms23147943

Cells. 2022 Jul 18;11(14):2226. doi: 10.3390/cells11142226.

ABSTRACT

Bronchoalveolar lavage (BAL) is an important diagnostic and research tool for the investigation of various lung diseases. In addition to inflammatory and epithelial cells, BAL fluid may contain a small number of stromal cells, such as fibroblasts. During the past 30 years, a number of research groups have cultured BAL-derived fibroblasts for several passages in vitro. In addition to fibroblasts, these cultures have been reported to contain fibrocytes, myofibroblasts, and stem cells. We aim to present a summary of studies that have cultured stromal cells from BAL fluid.

PMID:35883669 | DOI:10.3390/cells11142226

BMC Res Notes. 2022 Jul 26;15(1):263. doi: 10.1186/s13104-022-06156-3.

ABSTRACT

OBJECTIVE: To compare the morphological features of bronchiectasis between patients with different underlying diseases, we performed quantitative analysis of high-resolution computed tomography (HRCT) images of 14 patients with non-tuberculous mycobacteriosis (NTM) and 13 with idiopathic pulmonary fibrosis (IPF). A 3D image of the bronchial structure was made from HRCT data. Bronchiectasis was defined as abnormal dilatation of the bronchi with the diameter greater than that of the accompanying pulmonary artery. We measured the inner and outer diameters, wall area as %total airway cross sectional area (WA%), and wall thickness to airway diameter ratio (T/D) of the 4-8th generations of bronchi.

RESULTS: In patients with IPF, the inner and outer diameters linearly decreased toward the distal bronchi. In contrast, the inner and outer diameters of NTM fluctuated. The coefficient of variation of the outer diameters of the 6-7th generations of bronchi was larger in the NTM patients than in those with IPF, whereas no significant difference was observed in the coefficient of variation of the inner diameters between the groups. In IPF patients, WA% and T/D varied between the generation of bronchi, but the coefficient of variation of WA% and T/D was relatively small in those with NTM.

PMID:35883182 | DOI:10.1186/s13104-022-06156-3

J Gene Med. 2022 Jul 26:e3442. doi: 10.1002/jgm.3442. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and advanced interstitial lung disease with poor prognosis. AHNAK nucleoprotein 2 (AHNAK2) is a macromolecular protein that is important for cell migration and muscle membrane repair. The protein acts via epithelial-mesenchymal transition (EMT), which is a key mechanism in the pathogenesis of IPF. However, very few studies have elucidated the effect of AHNAK2 in the development of IPF. Therefore, we aimed to determine the role of AHNAK2 in IPF development.

METHODS: C57BL/6 mice were induced with bleomycin (BLM), while A549 and Beas-2b pulmonary epithelial cell lines were treated with TGF-β1 to induce IPF model. The expression of AHNAK2 was detected using immunohistochemistry (IHC) staining in vivo, and real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB) in vitro. C57BL/6 mice were injected with adeno-associated virus (AAV)-sh NC or AAV-sh AHNAK2; the pulmonary function and EMT markers expression were measured in mice. The migratory abilities of the two transforming growth factor beta 1 (TGF-β1)-induced cell lines were examined using wound-healing and Transwell assays after transfection with si-NC, si-AHNAK2-1 and -2. EMT markers expression was detected using RT-qPCR and WB. Smad3 and phosphorylated-Smad3 of the two cells were examined using WB. Following Smad3 inhibition by Smad3 phosphorylation inhibitor (SIS3), TGF-β1-induced cell migration and EMT markers expression were evaluated again after different transfections.

RESULTS: AHNAK2 expression was higher in the IPF model than in the normal model in vivo and in vitro. Partial inhibition of AHNAK2 suppressed the EMT process and improved pulmonary ventilation and compliance in the mouse model of IPF. Similarly, knockdown of AHNAK2 suppressed the migration of pulmonary epithelial cells and reversed EMT. Furthermore, Smad3 of the two TGF-β1-induced cell lines was not activated when AHNAK2 was inhibited. When SIS3 inhibited the activation of Smad3, the suppression of AHNAK2 had no effect on A549 and Beas-2b, regardless of TGF-β1 induction.

CONCLUSIONS: Inhibition of AHNAK2 alleviates pulmonary fibrosis and partially reverses EMT by inhibiting the TGF-β1/Smad3 signaling pathway. Therefore, AHNAK2 is a potential therapeutic target for IPF.

PMID:35882062 | DOI:10.1002/jgm.3442

PLoS One. 2022 Jul 26;17(7):e0272047. doi: 10.1371/journal.pone.0272047. eCollection 2022.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF), acutely or slowly progressing into irreversible pulmonary disease, causes severe damage to patients' lung functions, as well as death. In China, Chinese medicine injections (CMIs) have been generally combined with Western medicine (WM) to treat IPF, which are safe and effective. This study aimed to systematically compare the efficacy of 14 CMIs combined with WM in the treatment of IPF based on a systematic review and network meta-analysis (NMA).

MATERIAL AND METHODS: PubMed, Web of Science, Embase, Cochrane Library, MEDLINE, and Chinese databases, including the China National Knowledge Infrastructure, Wanfang Database, Scientific Journal Database, and China Biology Medicine Database were searched from inception to October 31, 2021. The inclusion criterion was randomized controlled trials (RCTs) on CMIs with WM for treating IPF. Reviewers independently screened the literature, extracted data, and evaluated the risk of bias in the included studies. RevMan 5.4 software and Stata software (version 16.0) were used for the data analysis. NMA were carried out for calculating the odd ratios (ORs) with 95% confidence intervals (CI), the surface under cumulative ranking curve (SUCRA) and the probabilities of being the best.

RESULTS: A total of 63 eligible RCTs involving 14 CMIs were included in this NMA. More CMIs can significantly improve the clinical effectiveness rate (CER); Shuxuening injection (SXN)+WM (OR 8.91, 95% CI 3.81-20.83), Shuxuetong injection (SXT)+WM (OR 7.36, 95% CI 3.30-16.00), Shenxiong injection (SX)+WM (OR 5.42, 95% CI 2.90-10.13), Danhong injection (DH)+WM (OR 4.06, 95% CI 2.62-6.29), and Huangqi injection (HQ)+WM (OR 3.47, 95% CI 1.55-7.77) were the top five treatment strategies. Furthermore, DH +WM ranked relatively high in the SUCRA value of the nine outcome indicators, oxygen partial pressure (PaO2) (OR -13.39; 95% CI -14.90,-11.89; SUCRA 83.7%), carbon dioxide partial pressure (PaCO2) (OR -4.77; 95% CI -5.55,-3.99; SUCRA 83.3), orced vital capacity (FVC) (OR -1.42; 95% CI -2.47,-0.36; SUCRA 73.5%), total lung capacity (TLC) (OR 0.93; 95% CI 0.51,1.36; SUCRA 89.0%), forced expiratory volume 1/ forced vital capacity (FEV1/FVC%) (OR -10.30; 95% CI -12.98,-7.62; SUCRA 72.7%), type III collagen (IIIC) (OR 13.08; 95% CI 5.11,21.05; SUCRA 54.9%), and transforming growth factor (TGF) (OR -4.22; 95% CI -6.06,-2.37; SUCRA 85.7%) respectively, which seems to indicate that DH+WM had the highest likelihood of being the best treatment.

CONCLUSIONS: This review specified several CMIs combined with WM in the treatment of IPF in China. In contrast to glucocorticoids or antioxidants, CMIs combined with WM delayed the decline in lung function, maintained oxygenation and quality of life in patients with IPF. The combined use of DH, SXN, SX, and safflower yellow sodium chloride injection (HHS) with WM exerted a more positive effect in treating IPF than WM alone. However, there were limitations to the conclusions of this study due to quality control differences in the included trials.

PMID:35881610 | DOI:10.1371/journal.pone.0272047

Am J Physiol Lung Cell Mol Physiol. 2022 Jul 26. doi: 10.1152/ajplung.00061.2022. Online ahead of print.

ABSTRACT

RATIONALE: Previously we have shown that a gain-of-function MUC5B promoter variant (rs35705950) is the strongest risk factor for the development of idiopathic pulmonary fibrosis. We have also found that Muc5b overexpression reduces mucociliary clearance in mice, potentially leading to recurrent injury to the bronchoalveolar epithelia. Hypersensitivity pneumonitis (HP) is induced by inhalation of numerous causative antigens that may be affected by mucociliary clearance.

OBJECTIVES: We conducted this study to determine the role of Muc5b in a mouse model of HP induced by Saccharopolyspora rectivirgula (SR) antigen.

METHODS: We used Muc5b deficient and wild-type (WT) mice to determine whether Muc5b plays a role in inflammation and fibrosis at 3 and 6 weeks in an SR model of HP. We measured cell concentrations and MUC5B expression in whole lung lavage (WLL), and quantified fibrosis using hydroxyproline assay and second harmonic generation.

MEASUREMENTS AND MAIN RESULTS: Muc5b expression in WLL fluid was significantly increased in SR exposed WT mice compared to saline controls. WT mice challenged with SR developed more inflammation and lung fibrosis at 6 weeks compared to 3 weeks post-exposure. Moreover, we found that 6 weeks following challenge with SR, Muc5b deficient mice had less lung inflammation and less lung fibrosis than Muc5b WT mice. Furthermore, Muc5b deficient mice had significantly lower concentrations of TGF-β1 in the WLL compared to Muc5b WT mice at 6 weeks exposures.

CONCLUSION: Muc5b appears to play a role in fibrosis in the animal model of HP and this may have implications for HP in humans.

PMID:35881171 | DOI:10.1152/ajplung.00061.2022

Radiology. 2022 Jul 26:211433. doi: 10.1148/radiol.211433. Online ahead of print.

ABSTRACT

Background Idiopathic pulmonary fibrosis (IPF) is a temporally and spatially heterogeneous lung disease. Identifying whether IPF in a patient is progressive or stable is crucial for treatment regimens. Purpose To assess the role of hyperpolarized (HP) xenon 129 (129Xe) MRI measures of ventilation and gas transfer in IPF generally and as an early signature of future IPF progression. Materials and Methods In a prospective study, healthy volunteers and participants with IPF were consecutively recruited between December 2015 and August 2019 and underwent baseline HP 129Xe MRI and chest CT. Participants with IPF were followed up with forced vital capacity percent predicted (FVC%p), diffusing capacity of the lungs for carbon monoxide percent predicted (DLco%p), and clinical outcome at 1 year. IPF progression was defined as reduction in FVC%p by at least 10%, reduction in DLco%p by at least 15%, or admission to hospice care. CT and MRI were spatially coregistered and a measure of pulmonary gas transfer (red blood cell [RBC]-to-barrier ratio) and high-ventilation percentage of lung volume were compared across groups and across fibrotic versus normal-appearing regions at CT by using Wilcoxon signed rank tests. Results Sixteen healthy volunteers (mean age, 57 years ± 14 [SD]; 10 women) and 22 participants with IPF (mean age, 71 years ± 9; 15 men) were evaluated, as follows: nine IPF progressors (mean age, 72 years ± 7; five women) and 13 nonprogressors (mean age, 70 years ± 10; 11 men). Reduction of high-ventilation percent (13% ± 6.1 vs 8.2% ± 5.9; P = .03) and RBC-to-barrier ratio (0.26 ± 0.06 vs 0.20 ± 0.06; P = .03) at baseline were associated with progression of IPF. Participants with progressive disease had reduced RBC-to-barrier ratio in structurally normal-appearing lung at CT (0.21 ± 0.07 vs 0.28 ± 0.05; P = .01) but not in fibrotic regions of the lung (0.15 ± 0.09 vs 0.14 ± 0.04; P = .62) relative to the nonprogressive group. Conclusion In this preliminary study, functional measures of gas transfer and ventilation measured with xenon 129 MRI and the extent of fibrotic structure at CT were associated with idiopathic pulmonary fibrosis disease progression. Differences in gas transfer were found in regions of nonfibrotic lung. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Gleeson and Fraser in this issue.

PMID:35880982 | DOI:10.1148/radiol.211433

Curr Oncol. 2022 Jul 18;29(7):5077-5083. doi: 10.3390/curroncol29070401.

ABSTRACT

Idiopathic pulmonary fibrosis is a poorly prognosed form of progressive interstitial pneumonia. Patients with IPF have a significantly increased risk of developing lung cancer, which further worsens the course of the disease. The most common histological types of LC among patients with IPF are squamous cell carcinoma and adenocarcinoma. Furthermore, all LC treatment modalities can lead to developing an acute IPF exacerbation. In this report, we present a rare case of coexistence of IPF and small cell lung cancer in a 76-year-old patient with chronic obstructive pulmonary disease, and a former smoker. For over 2 years, the patient was treated with an anti-fibrotic drug-pirfenidone, which slowed down the progression of IPF. Unfortunately, after being diagnosed with an active SCLC, the patient was excluded from further participation in the pirfenidone drug program. SCLC is characterized by high aggressiveness, rapid growth and high metastatic potential; therefore, it is necessary to apply antitumor treatment as soon as possible. The described patient was treated with carboplatin-etoposide chemotherapy. Early treatment tolerance was good and after two cycles of cytotoxic treatment, a partial response was present in CT. The presented case emphasizes the need for further research to determine the treatment regimens in patients with coexisting IPF and LC and the appropriateness of antifibrotic treatment in them. In addition, it can help to choose the treatment method for similar patients, indicating a combination of carboplatin and etoposide as an effective and, at the same time, relatively safes method in terms of the risk of IPF's exacerbation.

PMID:35877261 | DOI:10.3390/curroncol29070401