ACS Nano. 2024 Oct 15;18(41):27997-28011. doi: 10.1021/acsnano.4c06139. Epub 2024 Oct 3.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening disease with no early detection, few treatments, and dismal outcomes. Although collagen overdeposition is a hallmark of lung fibrosis, current research mostly focuses on the cellular aspect, leaving collagen, particularly its dynamic remodeling (i.e., degradation and turnover), largely unexplored. Here, using a collagen hybridizing peptide (CHP) that specifically binds unfolded collagen chains, we reveal vast collagen denaturation in human IPF lungs and delineate the spatiotemporal progression of collagen denaturation three-dimensionally within fibrotic lungs in mice. Transcriptomic analyses support that lung collagen denaturation is strongly associated with up-regulated collagen catabolism in mice and patients. We thus show that CHP probing differentiates remodeling responses to antifibrotics and highlights the resolution of established fibrosis by agents up-regulating collagen catabolism. We further develop a radioactive CHP that detects fibrosis in vivo in mice as early as 7 days postlung-injury (Ashcroft score: 2-3) by positron emission tomography (PET) imaging and ex vivo in clinical lung specimens. These findings establish collagen denaturation as a promising marker of fibrotic remodeling for the investigation, diagnosis, and therapeutic development of pulmonary fibrosis.

PMID:39361472 | DOI:10.1021/acsnano.4c06139

Antimicrob Agents Chemother. 2024 Oct 3:e0103524. doi: 10.1128/aac.01035-24. Online ahead of print.

ABSTRACT

Infection with hepatitis E virus (HEV) represents a global problem, with over 20 million people infected annually. No specific antiviral drugs are available for treating HEV infection, necessitating the development of novel targeted therapeutics. Here, we report that the N-methyl-D-aspartate receptor (NMDAR) antagonist ifenprodil, a clinically approved drug used to treat idiopathic pulmonary fibrosis (IPF), is an HEV inhibitor in liver-derived cells. In vitro investigation demonstrates that ifenprodil suppresses viral protein expression in a dose-dependent manner in human hepatoma cells by inhibiting early stages of viral infection. We also found that ifenprodil modulates host cell intrinsic biological processes distinct from virus-induced innate immunity, inhibiting HEV RNA accumulation in primary human hepatocytes. Finally, the inhibitory effect of ifenprodil in vivo was also tested in rabbits challenged with the HEV-3ra CHN-BJ-R14 strain. Fecal virus shedding was below the limit of detection in two animals for both ribavirin-treated and ifenprodil-treated rabbits compared to vehicle-treated control animals. Our data demonstrate that ifenprodil is an effective anti-HEV compound with potential as a therapeutic candidate for the treatment of HEV infection.

PMID:39360823 | DOI:10.1128/aac.01035-24

Pharmacol Res Perspect. 2024 Oct;12(5):e70018. doi: 10.1002/prp2.70018.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease. While recent studies have suggested the potential efficacy of tyrosine kinase inhibitors in managing IPF, masitinib, a clinically used tyrosine kinase inhibitor, has not yet been investigated for its efficacy in fibrotic lung diseases. In a previous study on an in vitro neurodegenerative model, we demonstrated the synergistic antitoxic and antioxidant effects of masitinib combined with cromolyn sodium, an FDA-approved mast cell stabilizer. This study aims to investigate the anti-fibrotic and antioxidant effects of the masitinib-cromolyn sodium combination in an in vitro model of pulmonary fibrosis. Fibroblast cell cultures treated with bleomycin and/or hydrogen peroxide (H2O2) were subjected to masitinib and/or cromolyn sodium, followed by assessments of cell viability, morphological and apoptotic nuclear changes, triple-immunofluorescence labeling, and total oxidant/antioxidant capacities, besides ratio of Bax and Bcl-2 mRNA expressions as an indication of apoptosis. The combined treatment of masitinib and cromolyn sodium effectively prevented the fibroblast myofibroblast transition, a hallmark of fibrosis, and significantly reduced bleomycin / H2O2-induced apoptosis and oxidative stress. This study is the first to demonstrate the additive anti-fibrotic, cell-protective, and antioxidant effects of the masitinib-cromolyn sodium combination in an in vitro fibrosis model, suggesting its potential as an innovative therapeutic approach for pulmonary fibrosis. Combination therapy may be more advantageous in that both drugs could be administered in lower doses, exerting less side effects, and at the same time providing diverse mechanisms of action simultaneously.

PMID:39360479 | PMC:PMC11447456 | DOI:10.1002/prp2.70018

Respir Med. 2024 Sep 30:107824. doi: 10.1016/j.rmed.2024.107824. Online ahead of print.

NO ABSTRACT

PMID:39357679 | DOI:10.1016/j.rmed.2024.107824

Heliyon. 2024 Aug 10;10(16):e36125. doi: 10.1016/j.heliyon.2024.e36125. eCollection 2024 Aug 30.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an irreversible lung disease with unclear pathological mechanisms. In this study, we utilized bidirectional Mendelian randomization (MR) to analyze the relationship between serum metabolites and IPF, and conducted metabolic pathway analysis.

AIM: To determine the causal relationship between serum metabolites and IPF using MR analysis.

METHODS: A two-sample MR analysis was conducted to evaluate the causal relationship between 824 serum metabolites and IPF. The inverse variance weighted (IVW) method was used to estimate the causal relationship between exposure and results. Sensitivity analysis was conducted using MR Egger, weighted median, and maximum likelihood to eliminate pleiotropy. Additionally, metabolic pathway analysis was conducted to identify potential metabolic pathways.

RESULTS: We identified 12 serum metabolites (6 risks and 6 protective) associated with IPF from 824 metabolites. Among them, 11 were known and 1 was unknown. 1-Eicosatrienoylglycophorophospholine and 1-myristoylglycophorophospholine were bidirectional MR positive factors, with 1-myristoylglycophorophospholine being a risk factor (1.0013, 1.0097) and 1-eicosatrienoylglycophorine being a protective factor (0.9914, 0.9990). The four lipids (1-linoleoylglycerophoethanolamine*, total cholesterol in large high-density lipoprotein [HDL], cholesterol esters in very large HDL, and phospholipids in very large HDL) and one NA metabolite (degree of unsaturation) were included in the known hazardous metabolites. The known protective metabolites included three types of lipids (carnitine, 1-linoleoylglycerophoethanolamine*, and 1-eicosatrienoylglycerophophophorine), one amino acid (hypoxanthine), and two unknown metabolites (the ratio of omega-6 fatty acids to omega-3 fatty acids, and the ratio of photoshopids to total lipids ratio in chylomicrons and extremely large very low-density lipoprotein [VLDL]). Moreover, sn-Glycerol 3-phosphate and 1-Acyl-sn-glycero-3-phosphocline were found to be involved in the pathogenesis of IPF through metabolic pathways such as Glycerolide metabolism and Glycerophospholipid metabolism.

CONCLUSION: Our study identified 6 causal risks and 6 protective serum metabolites associated with IPF. Additionally, 2 metabolites were found to be involved in the pathogenesis of IPF through metabolic pathways, providing a new perspective for further understanding the metabolic pathway and the pathogenesis of IPF.

PMID:39229516 | PMC:PMC11369467 | DOI:10.1016/j.heliyon.2024.e36125

Front Immunol. 2024 Aug 20;15:1452849. doi: 10.3389/fimmu.2024.1452849. eCollection 2024.

ABSTRACT

BACKGROUND: High interleukin-6 levels correlate with diseases like cancer, autoimmune disorders, and infections. IL-6 receptor inhibitors (IL-6Ri), used for rheumatoid arthritis and COVID-19, may have wider uses. We apply drug-target Mendelian Randomization (MR) to study IL-6Ri's effects.

METHOD: To simulate the effects of genetically blocking the IL-6R, we selected single nucleotide polymorphisms (SNPs) within or near the IL6R gene that show significant genome-wide associations with C-reactive protein. Using rheumatoid arthritis and COVID-19 as positive controls, our primary research outcomes included the risk of asthma, asthmatic pneumonia, cor pulmonale, non-small cell lung cancer, small cell lung cancer, Parkinson's disease, Alzheimer's disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, type 1 diabetes, and type 2 diabetes. The Inverse Variance Weighted (IVW) method served as our principal analytical approach, with the hypotheses of MR being evaluated through sensitivity and colocalization analyses. Additionally, we conducted Bayesian Mendelian Randomization analyses to minimize confounding and reverse causation biases to the greatest extent possible.

RESULTS: IL-6 inhibitors significantly reduced the risk of idiopathic pulmonary fibrosis (OR= 0.278, 95% [CI], 0.138-0.558; P <0.001), Parkinson's disease (OR = 0.354, 95% CI, 0.215-0.582; P <0.001), and positively influenced the causal relationship with Type 2 diabetes (OR = 0.759, 95% CI, 0.637-0.905; P = 0.002). However, these inhibitors increased the risk for asthma (OR = 1.327, 95% CI, 1.118-1.576; P = 0.001) and asthmatic pneumonia (OR = 1.823, 95% CI, 1.246-2.666; P = 0.002). The causal effect estimates obtained via the BWMR method are consistent with those based on the IVW approach. Similarly, sIL-6R also exerts a significant influence on these diseases.Diseases such as Alzheimer's disease, Crohn's disease, pulmonary heart disease, systemic lupus erythematosus, Type 1 diabetes, Non-small cell lung cancer and ulcerative colitis showed non-significant associations (p > 0.05) and were excluded from further analysis. Similarly, Small cell lung cancer were excluded due to inconsistent results. Notably, the colocalization evidence for asthmatic pneumonia (coloc.abf-PPH4 = 0.811) robustly supports its association with CRP. The colocalization evidence for Parkinson's disease (coloc.abf-PPH4 = 0.725) moderately supports its association with CRP.

CONCLUSION: IL-6Ri may represent a promising therapeutic avenue for idiopathic pulmonary fibrosis, Parkinson's disease, and Type 2 diabetes.

PMID:39229261 | PMC:PMC11368790 | DOI:10.3389/fimmu.2024.1452849

BMC Pulm Med. 2024 Sep 3;24(1):435. doi: 10.1186/s12890-024-03198-0.

ABSTRACT

BACKGROUND: The causal relationships between testosterone, estradiol, estrogen sulfotransferase, and idiopathic pulmonary fibrosis (IPF) are not well understood. This study employs a bidirectional two-sample Mendelian Randomization (MR) approach to explore these associations.

METHODS: All genetic data utilized in our study were obtained from the IEU Open GWAS project. For the MR analysis, we employed the inverse variance weighted (IVW), MR-Egger, and weighted median methods to assess the causal relationships. We also conducted a multivariate MR (MVMR) analysis, with adjustments made for smoking. To ensure the robustness of our findings, sensitivity analyses were conducted using Cochran's Q test, MR-Egger regression, the MR-PRESSO global test, and the leave-one-out method.

RESULTS: Genetically predicted increases in serum testosterone levels by one standard deviation were associated with a 58.7% decrease in the risk of developing IPF (OR = 0.413, PIVW=0.029, 95% CI = 0.187 ∼ 0.912), while an increase in serum estrogen sulfotransferase by one standard deviation was associated with a 32.4% increase in risk (OR = 1.324, PIVW=0.006, 95% CI = 1.083 ∼ 1.618). No causal relationship was found between estradiol (OR = 1.094, PIVW=0.735, 95% CI = 0.650 ∼ 1.841) and the risk of IPF. Reverse MR analysis did not reveal any causal relationship between IPF and testosterone (OR = 1.001, PIVW=0.51, 95% CI = 0.998 ∼ 1.004), estradiol (OR = 1.001, PIVW=0.958, 95% CI = 0.982 ∼ 1.019), or estrogen sulfotransferase (OR = 0.975, PIVW=0.251, 95% CI = 0.933 ∼ 1.018). The MVMR analysis demonstrated that the association between testosterone (OR = 0.442, P = 0.037, 95% CI = 0.205 ∼ 0.953) and estrogen sulfotransferase (OR = 1.314, P = 0.001, 95% CI = 1.118 ∼ 1.545) and the risk of IPF persisted even after adjusting for smoking.

CONCLUSIONS: Increased serum levels of testosterone are associated with a reduced risk of IPF, while increased levels of serum estrogen sulfotransferase are associated with an increased risk. No causal relationship was found between estradiol and the development of IPF. No causal relationship was identified between IPF and testosterone, estradiol, or estrogen sulfotransferase.

PMID:39227879 | DOI:10.1186/s12890-024-03198-0

Histopathology. 2024 Sep 2. doi: 10.1111/his.15311. Online ahead of print.

ABSTRACT

AIM: Transbronchial cryobiopsies are increasingly used for the diagnosis of interstitial lung disease (ILD), but there is a lack of published information on the features of specific ILD in cryobiopsies. Here we attempt to provide pathological guidelines for separating usual interstitial pneumonia (UIP) of idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis (FHP) and connective tissue disease-associated ILD (CTD-ILD) in cryobiopsies.

METHODS: We examined 120 cryobiopsies from patients with multidisciplinary discussion (MDD)-established CTD-ILD and compared them to a prior series of 121 biopsies from patients with MDD-established IPF or FHP.

RESULTS: A non-specific interstitial pneumonia (NSIP) pattern alone was seen in 36 of 120 (30%) CTD-ILD, three of 83 (3.6%) FHP and two of 38 (5.2%) IPF cases, statistically favouring a diagnosis of CTD-ILD. The combination of NSIP + OP was present in 29 of 120 (24%) CTD-ILD, two of 83 (2.4%) FHP and none of 38 (0%) IPF cases, favouring a diagnosis of CTD-ILD. A UIP pattern, defined as fibroblast foci plus any of patchy old fibrosis/fibrosis with architectural distortion/honeycombing, was identified in 28 of 120 (23%) CTD-ILD, 45 of 83 (54%) FHP and 27 of 38 (71%) IPF cases and supported a diagnosis of FHP or IPF. The number of lymphoid aggregates/mm2 and fibroblast foci/mm2 was not different in IPF, CTD-ILD or FHP cases with a UIP pattern. Interstitial giant cells supported a diagnosis of FHP or CTD-ILD over IPF, but were infrequent.

CONCLUSIONS: In the correct clinical/radiological context the pathological findings of NSIP, and particularly NSIP plus OP, favour a diagnosis of CTD-ILD in a cryobiopsy, but CTD-ILD with a UIP pattern, FHP with a UIP pattern and IPF generally cannot be distinguished.

PMID:39223069 | DOI:10.1111/his.15311

Naunyn Schmiedebergs Arch Pharmacol. 2024 Sep 2. doi: 10.1007/s00210-024-03417-9. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a disease that causes progressive failure of lung function, and its molecular mechanism remains poorly understood. However, the AnnexinA2-epidermal growth factor receptor (EGFR) signaling pathway has been identified as playing a significant role in its development. Hydroxychloroquine, a common anti-malarial drug, has been found to inhibit this pathway and slow down the progression of IPF. To better understand the role of the AnxA2-EGFR signaling pathway in pulmonary fibrosis, an in vivo study was conducted. In this study, mice were induced with pulmonary fibrosis using bleomycin, and HCQ was administered intraperitoneally the next day of bleomycin induction. The study also employed nintedanib as a positive control. After the induction, the lungs showed increased levels of fibronectin and vimentin, along with enhanced expression of AnxA2, EGFR, and Gal-3, indicating pulmonary fibrosis. Additionally, the study also found that HCQ significantly inhibited these effects and showed antifibrotic properties similar to nintedanib. Overall, these findings suggest that HCQ can attenuate bleomycin-induced pulmonary fibrosis by inhibiting the AnxA2-EGFR signaling pathway. These results are promising for developing new treatments for IPF.

PMID:39222243 | DOI:10.1007/s00210-024-03417-9

RSC Adv. 2024 Aug 30;14(37):27288-27297. doi: 10.1039/d4ra03324h. eCollection 2024 Aug 22.

ABSTRACT

The design and development of engineered micro and nano-carriers offering superior therapeutic performance compared to traditional delivery forms, are crucial in pharmaceutical research. Aerosolization and inhalation of carriers with improved solubility/stability of insoluble drugs, has huge potential for targeted drug delivery (DD) in various pulmonary diseases. Indeed, dedicated carriers must meet specific dimensional rules for proper lung delivery. Particles between 2-10 μm in size are normally deposited in the tracheobronchial region, while particles of 0.5-2 μm may be properly deposited in the alveoli. In this work, we report the development of inhalable nanostructured carries made of a 'green' bio-inspired polymer from aqueous solutions, i.e. silk fibroin (SF), efficiently loaded with a hydrophobic drug, i.e. the thyroid hormone levothyroxine (L-T4), a drug for the treatment of idiopathic pulmonary fibrosis. The aim is to optimize a standard method for the synthesis of SF-based nanocarriers with controlled size and shape, where a fine control of their geometrical properties is aimed at efficiently controlling the pulmonary DD. L-T4 loaded SF particles were synthesized through a one-pot co-precipitation method. Optimized systems were determined by varying the chemo-physical parameters during the synthesis. Ethylenediaminetetraacetic acid (EDTA) was used to remove CaCO3 cores. The proposed synthesis routes have led to two SF structures, whose structural heterogeneity and nanostructured morphology have been demonstrated using fluorescence microscopy, DLS, SEM and EDX. Two systems with varying shape and size have been obtained: (i) a flat disk-like SF structure with an irregular surface and an in-plane length of about 1-2 μm; (ii) solid SF nanospheres, obtained using ethylene glycol as additive, showing two size populations (main diameters of 0.5 μm and 1.7 μm). Solid nanospherical systems, in particular, show a tendency to arrange into agglomerates that, when loosely bound into smaller particles, can facilitate the delivery at the alveoli. Both formulations exhibited similar drug loading efficiencies, evaluated by HPLC analysis. However, SF nanospheres showed greater in vitro drug release after 24 hours. The demonstrated control over the characteristics imparted to the proposed DD systems may be critical to select the most suitable size/shape to achieve high rates of delivery to the appropriate lung compartment.

PMID:39219844 | PMC:PMC11362913 | DOI:10.1039/d4ra03324h

BMC Pulm Med. 2024 Aug 31;24(1):430. doi: 10.1186/s12890-024-03230-3.

ABSTRACT

BACKGROUND: Previous studies have consistently reported a decrease in hospital admissions for respiratory diseases during the coronavirus disease 2019 (COVID-19) pandemic. However, the impact of the pandemic on idiopathic pulmonary fibrosis (IPF) admissions remains unknown.

METHODS: This study used data from the Korean National Health Insurance Service database. IPF was defined based on the International Classification of Diseases 10th Revision (ICD-10) and rare intractable disease (RID) codes. The rate of IPF admissions was calculated by dividing the number of IPF admissions by the prevalence of IPF. The rate of IPF admissions during the COVID-19 pandemic (2020-2021) was compared with the mean rate of admissions during the prepandemic period (2017-2019) and presented as the rate ratio (RR). A sensitivity analysis was conducted on patients treated with systemic corticosteroids during IPF admission.

RESULTS: In patients with IPF defined based on the ICD-10 (analysis 1), the RRs significantly decreased from March in 2020 to December 2021, except for June and September in 2020. Similarly, in patients with IPF defined based on the ICD-10 and RID (analysis 2), the RRs significantly decreased from March 2020 to December 2021, except for June and September 2020. In the sensitivity analysis of analysis 1, the RR significantly decreased in 2020 (0.93; 95%CI: 0.88-0.99; P = 0.029), whereas the RR in 2021 was not significantly different. The RRs in the sensitivity analysis of analysis 2 significantly decreased to 0.85 (0.79-0.92; P < 0.001) in 2020 and 0.82 (0.76-0.88; P < 0.001) in 2021. In the subgroup analysis, the rates of IPF admissions significantly decreased in 2020 and 2021 across both sexes, patients aged ≥ 60 years, and all household income groups.

CONCLUSIONS: The rate of IPF admissions significantly decreased during the COVID-19 pandemic. This result indicates that preventive measures against COVID-19 may effectively mitigate IPF exacerbation. Therefore, it is assumed that there is a close relationship between respiratory viral infections and IPF exacerbations.

PMID:39217306 | DOI:10.1186/s12890-024-03230-3

Pulm Pharmacol Ther. 2024 Aug 29:102319. doi: 10.1016/j.pupt.2024.102319. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal progressive and irreversible ailment associated with the proliferation of fibroblast and accumulation of extracellular matrix (ECM) with gradual scarring of lung tissue. Despite several research studies, the treatments available are not efficient enough for the reversal of the disease and are constantly in progress. No drugs other than Pirfenidone and Nintedanib have been approved for the treatment of IPF, necessitating the exploration of novel therapeutic strategies. Recently, lipid-based nanoparticles (LNPs) have drawn more attention because of their potential to enhance the solubility of drugs, cross biological barriers of the lungs and specifically target lung fibrotic tissues, overcoming various challenges in treating IPF. LNPs offer a versatile platform to encapsulate a wide range of drugs, both hydrophilic and lipophilic, improving their bioavailability, allowing sustained release and reducing toxicity, which radiates their significant role in addressing the complexities of IPF. This review summarizes the pathogenesis and conventional treatment of idiopathic pulmonary fibrosis, along with their drawbacks. The review focuses on different types of lipid-based nanoparticles that have been tested in the treatment of idiopathic pulmonary fibrosis, including nanoemulsions, liposomes, solid lipid nanoparticles, nanostructured lipid carriers, niosomes and lipid-polymer hybrid nanoparticles. The review also highlights the future prospects that can offer a potential approach for developing novel strategies to treat idiopathic pulmonary fibrosis.

PMID:39216596 | DOI:10.1016/j.pupt.2024.102319

Clin Exp Rheumatol. 2024 Aug 20. doi: 10.55563/clinexprheumatol/yg6rck. Online ahead of print.

ABSTRACT

Patients with autoimmune disease-related interstitial lung disease may develop pulmonary fibrosis, which may become progressive. Progressive pulmonary fibrosis (PPF) is associated with poor outcomes. Antifibrotic therapies have shown efficacy as treatments for PPF in patients with autoimmune diseases, but new treatments are needed to slow or halt disease progression. Phosphodiesterases (PDEs) are enzymes that mediate the hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Pre-clinical data suggest that preferential inhibition of PDE4B has the potential to slow the progression of pulmonary fibrosis by inhibiting inflammatory and fibrotic pathways, with a lower risk of gastrointestinal adverse events than associated with pan-PDE4 inhibitors. Nerandomilast (BI 1015550) is a preferential PDE4 inhibitor that has demonstrated anti-inflammatory and antifibrotic effects in pre-clinical studies. In a phase II trial in patients with idiopathic pulmonary fibrosis, nerandomilast (given alone or on top of background antifibrotic therapy) prevented a decrease in lung function over 12 weeks with an acceptable safety and tolerability profile. The phase III FIBRONEER-ILD trial is evaluating the efficacy and safety of nerandomilast, given alone or on top of nintedanib, in patients with PPF, including PPF associated with autoimmune diseases. In this article, we review the potential of PDE4B inhibition in the treatment of ILD associated with autoimmune diseases, including the pre-clinical and early clinical data available to date.

PMID:39212123 | DOI:10.55563/clinexprheumatol/yg6rck

medRxiv [Preprint]. 2024 Aug 8:2024.08.07.24311386. doi: 10.1101/2024.08.07.24311386.

ABSTRACT

RATIONALE: The association between immune-cell-specific transcriptomic profiles and Idiopathic Pulmonary Fibrosis (IPF) mortality is unknown.

OBJECTIVES: To determine immune-cell-specific transcriptomic profiles associated with IPF mortality.

METHODS: We profiled peripheral blood mononuclear cells (PBMC) in 18 participants [University of South Florida: IPF, COVID-19, post-COVID-19 Interstitial Lung Disease (Post-COVID-19 ILD), controls] by single-cell RNA sequencing (scRNA-seq) and identified 16 immune-cell-specific transcriptomic profiles. The Scoring Algorithm of Molecular Subphenotypes (SAMS) was used to calculate Up-scores based on these 16 gene profiles. Their association with outcomes was investigated in peripheral blood, Bronchoalveolar Lavage (BAL) and lung tissue of N=416 IPF patients from six cohorts. Findings were validated in an independent IPF, PBMC scRNA-seq dataset (N=38).

MEASUREMENTS AND MAIN RESULTS: Cox-regression models demonstrated that 230 genes from CD14 + CD163 - HLA-DR low circulating monocytes predicted IPF mortality [Pittsburgh (p=0.02), Chicago (p=0.003)]. PBMC proportions of CD14 + CD163 - HLA-DR low monocytes were higher in progressive versus stable IPF (Yale, 0.13±0.05 versus 0.09±0.05, p=0.034). Receiving operating characteristic identified a 230 gene, Up-score >41.84 (Pittsburgh) predictive of mortality in Chicago (HR: 6.58, 95%CI: 2.15-20.13, p=0.001) and in pooled analysis of BAL cohorts (HR: 2.20, 95%CI: 1.44-3.37, p=0.0003). High-risk patients had decreased expression of the T-cell co-stimulatory genes CD28 , ICOS , ITK and LCK (Pittsburgh and Chicago, p<0.01). 230 gene-up-scores negatively correlated with Forced Vital Capacity (FVC) in IPF lung tissues (LGRC, rho=-0.2, p=0.02). Results were replicated using a subset of 13 genes from the 230-gene signature (pooled PBMC cohorts - HR: 5.34, 95%CI: 2.83-10.06, p<0.0001).

CONCLUSIONS: The transcriptome of CD14 + CD163 - HLA-DR low monocytes is associated with increased IPF mortality.

PMID:39211854 | PMC:PMC11361223 | DOI:10.1101/2024.08.07.24311386

Allergol Select. 2024 Aug 19;8:283-292. doi: 10.5414/ALX02519E. eCollection 2024.

ABSTRACT

Hypersensitivity pneumonitis (HP) is a rare, mostly occupational allergic disease of the lungs. There are many inhalable antigens that can cause HP. Most are organic dusts, rarely chemicals. A clinical case of HP is presented in a cable production worker with exposure to plasticizers who was initially diagnosed with idiopathic pulmonary fibrosis. The presence of specific IgG antibodies (sIgG) to phthalic anhydride in the patient's serum, together with reduced carbon monoxide diffusion capacity, hypoxemia at rest and on exertion, and the findings on computed tomography and histology, seemed to confirm the diagnosis of chronic HP due to phthalates, particularly as exposure to phthalate compounds at work was reported by the Technical Inspection Service. A review of the literature revealed that there is evidence of plasticizer alveolitis. While in four previous case reports phthalic anhydride was suspected as the cause of occupational HP because of work-related symptoms, we were able to detect sIgG to phthalic anhydride for the first time. This case illustrates that phthalates, which have rarely been described as triggers of HP, should be considered in cases of suspected occupational HP.

PMID:39211357 | PMC:PMC11361270 | DOI:10.5414/ALX02519E

bioRxiv [Preprint]. 2024 Jul 31:2023.09.06.556606. doi: 10.1101/2023.09.06.556606.

ABSTRACT

Monocyte-derived macrophages recruited to injured tissues induce a maladaptive fibrotic response characterized by excessive production of collagen by local fibroblasts. Macrophages initiate this programming via paracrine factors, but it is unknown whether reciprocal responses from fibroblasts enhance profibrotic polarization of macrophages. We identify macrophage-fibroblast crosstalk necessary for injury-associated fibrosis, in which macrophages induced interleukin 6 ( IL-6 ) expression in fibroblasts via purinergic receptor P2rx4 signaling, and IL-6, in turn, induced arginase 1 ( Arg1 ) expression in macrophages. Arg1 contributed to fibrotic responses by metabolizing arginine to ornithine, which fibroblasts used as a substrate to synthesize proline, a uniquely abundant constituent of collagen. Imaging of idiopathic pulmonary fibrosis (IPF) lung samples confirmed expression of ARG1 in myeloid cells, and arginase inhibition suppressed collagen expression in cultured precision-cut IPF lung slices. Taken together, we define a circuit between macrophages and fibroblasts that facilitates cross-feeding metabolism necessary for injury-associated fibrosis.

PMID:39211079 | PMC:PMC11360891 | DOI:10.1101/2023.09.06.556606

Mol Divers. 2024 Aug 29. doi: 10.1007/s11030-024-10970-1. Online ahead of print.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a disease characterized by pulmonary interstitial fibrosis and collagen proliferation, currently lacking effective therapeutic options. The combined use of Celastrol and Ligustrazine has been proved to synergistically improve the pathological processes of inflammation and fibrosis. In earlier studies, we designed and synthesized a Celastrol-Ligustrazine compound CL-001, though its role in IPF remains unclear. Here, the effects and mechanisms of CL-001 in bleomycin (BLM)-induced IPF were investigated. In vivo, CL-001 significantly improved lung function, reduced pulmonary inflammation, and decreased collagen deposition, thereby preventing the progression of IPF. In vitro, CL-001 concurrently inhibited both Smad-dependent and Smad-independent pathways, thereby suppressing TGF-β1-induced epithelial-mesenchymal transition (EMT) and epithelial cell migration. This inhibitory effect was superior to that of Celastrol or Ligustrazine administered alone. Additionally, CL-001 significantly increased the level of apoptosis and promoted the expression of apoptosis-related proteins (Caspase-8 and PARP), ultimately leading to widespread apoptosis in activated lung epithelial cells. In summary, CL-001 exhibits excellent anti-IPF effects both in vitro and in vivo, suggesting its potential as a novel candidate drug for IPF, warranting further development.

PMID:39207663 | DOI:10.1007/s11030-024-10970-1

Front Biosci (Landmark Ed). 2024 Aug 22;29(8):305. doi: 10.31083/j.fbl2908305.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease (ILD) whose cause and pathogenesis are not yet well understood. Until now, no animal model of lung fibrosis succeeds in recapitulating all IPF features, thus the use of different rodent models is essential for the evaluation and development of new effective pharmacological treatments. Recently, the alveolar epithelial dysfunction has been emphasized in the etiopathogenesis context of IPF. Remarkably, the role of an aberrant basaloid cell type, primarily found in humans and confirmed in mice, seems to be crucial in the establishment and progression of the disease/model. Our work aimed to characterize for the first time this cell population in a rat model of lung fibrosis induced by a double bleomycin (BLM) administration, demonstrating the translational value of the model and its potential use in the testing of effective new drugs.

METHODS: Rats received an intratracheal BLM administration at day 0 and 4. Animals were sacrificed 21 and 28 days post-BLM. The fibrosis evaluation was carried out through histological (Ashcroft score and automatic image analysis) and immunoenzymatic analysis. Immunofluorescence was used for the characterization of the aberrant basaloid cells markers.

RESULTS: Lung histology revealed an increase in severe grades of Ashcroft scores and areas of fibrosis, resulting in a rise of collagen deposition at both the analyzed time-points. Immunofluorescence staining indicated the presence of KRT8+ cells in bronchial epithelial cells from both controls (saline, SAL) and BLM-treated animals. Interesting, KRT8+ cells were found exclusively in the fibrotic parenchyma (confirmed by the alpha-smooth muscle actin (α-SMA) staining for myofibroblasts) of BLM-treated animals. Moreover, KRT8+ cells co-expressed markers as Prosurfactant protein C (Pro-SPC) and Vimentin, suggesting their intermediate state potentially originating from alveolar type II (AT2) cells, and participating to the abnormal epithelial-mesenchymal crosstalk.

CONCLUSION: Previous preclinical studies demonstrated the presence of KRT8+ aberrant basaloid-like cells in murine models of lung fibrosis. This work investigated the same cell population in a different rodent (the rat) model of lung fibrosis triggered by a double administration of BLM. Our results provided a further confirmation that, in rats, the intratracheal administration of BLM induced the appearance of a population of cells compatible with the KRT8+ alveolar differentiation intermediate (ADI) cells, as described previously in the mouse. This piece of work enforces previous evidence and further support the use of a rat model of BLM resembling the alveolar epithelial dysfunction to evaluate new clinical candidates for development in IPF.

PMID:39206922 | DOI:10.31083/j.fbl2908305

Cureus. 2024 Jul 29;16(7):e65689. doi: 10.7759/cureus.65689. eCollection 2024 Jul.

ABSTRACT

Nintedanib, a tyrosine kinase inhibitor, is a cornerstone in the management of idiopathic pulmonary fibrosis through its anti-fibrotic effects; however, its impact on wound healing is less studied. We present a case of medication-related osteonecrosis of the jaw (MRONJ) following the initiation of nintedanib. The patient's presentation prompted a drug holiday of nintedanib, resulting in a marked improvement in her symptoms. MRONJ is a disease requiring a high index of suspicion, and the number of inciting medications continues to rise. Nintedanib, as an inhibitor of angiogenesis, may have contributed to poor wound healing following dental extraction, subsequently leading to MRONJ.

PMID:39205781 | PMC:PMC11357727 | DOI:10.7759/cureus.65689

Int J Mol Sci. 2024 Aug 16;25(16):8946. doi: 10.3390/ijms25168946.

ABSTRACT

Idiopathic pulmonary fibrosis remains a relevant problem of the healthcare system with an unfavorable prognosis for patients due to progressive fibrous remodeling of the pulmonary parenchyma. Starting with the damage of the epithelial lining of alveoli, pulmonary fibrosis is implemented through a cascade of complex mechanisms, the crucial of which is the TGF-β/SMAD-mediated pathway, involving various cell populations. Considering that a number of the available drugs (pirfenidone and nintedanib) have only limited effectiveness in slowing the progression of fibrosis, the search and justification of new approaches aimed at regulating the immune response, cellular aging processes, programmed cell death, and transdifferentiation of cell populations remains relevant. This literature review presents the key modern concepts concerning molecular genetics and cellular mechanisms of lung fibrosis development, based mainly on in vitro and in vivo studies in experimental models of bleomycin-induced pulmonary fibrosis, as well as the latest data on metabolic features, potential targets, and effects of vitamin D and its metabolites.

PMID:39201632 | DOI:10.3390/ijms25168946