Oxf Open Immunol. 2023 May 3;4(1):iqad004. doi: 10.1093/oxfimm/iqad004. eCollection 2023.

ABSTRACT

Ageing leads to a sharp decline in immune function, precipitating the development of inflammatory conditions. The combined impact of these processes renders older individuals at greater risk of inflammatory and immune-related diseases, such as cancer and infections. This is compounded by reduced efficacy in interventions aiming to limit disease impact, for instance vaccines being less effective in elderly populations. This state of diminished cellular function is driven by cellular senescence, a process where cells undergo stable growth arrest following exposure to stressful stimuli, and the associated pro-inflammatory secretory phenotype. Removing harmful senescent cells (SnCs) using senolytic therapies is an emerging field holding promise for patient benefit. Current senolytics have been developed either to specifically target SnCs, or repurposed from cancer therapies or vaccination protocols. Herein, we discuss recent developments in senolytic therapies, focusing on how senolytics could be used to combat the age-associated diminution of the immune system. In particular, exploring how these drugs may be used to promote immunity in the elderly, and highlighting recent trials of senolytics in idiopathic pulmonary fibrosis and diabetic kidney disease. Novel immunotherapeutic approaches including chimeric antigen receptor T-cells or monoclonal antibodies targeting SnCs are being investigated to combat the shortcomings of current senolytics and their adverse effects. The flexible nature of senolytic treatment modalities and their efficacy in safely removing harmful SnCs could have great potential to promote healthy immune function in ageing populations.

PMID:37255929 | PMC:PMC10191675 | DOI:10.1093/oxfimm/iqad004

Biomol Ther (Seoul). 2023 May 31. doi: 10.4062/biomolther.2023.056. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) can be defined as a progressive chronic pulmonary disease showing scarring in the lung parenchyma, thereby resulting in increase in mortality and decrease in the quality of life. The pathophysiologic mechanism of fibrosis in IPF is still unclear. Repetitive microinjuries to alveolar epithelium with genetical predisposition and an abnormal restorative reaction accompanied by excessive deposition of collagens are involved in the pathogenesis. Although the two FDA-approved drugs, pirfenidone and nintedanib, are under use for retarding the decline in lung function of patients suffered from IPF, they are not able to improve the survival rate or quality of life. Therefore, a novel therapeutic agent acting on the major steps of the pathogenesis of disease and/or, at least, managing the clinical symptoms of IPF should be developed for the effective regulation of this incurable disease. In the present review, we tried to find a potential of managing the clinical symptoms of IPF by natural products derived from medicinal plants used for controlling the pulmonary inflammatory diseases in traditional Asian medicine. A multitude of natural products have been reported to exert an antifibrotic effect in vitro and in vivo through acting on the epithelial-mesenchymal transition pathway, transforming growth factor (TGF)-β-induced intracellular signaling, and the deposition of extracellular matrix. However, clinical antifibrotic efficacy of these natural products on IPF have not been elucidated yet. Thus, those effects should be proven by further examinations including the randomized clinical trials, in order to develop the ideal and optimal candidate for the therapeutics of IPF.

PMID:37254717 | DOI:10.4062/biomolther.2023.056

Genes Dis. 2023 May;10(3):1029-1039. doi: 10.1016/j.gendis.2022.08.012.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a dreadful, chronic, and irreversibly progressive disease leading to death with few effective treatments. Our previous study suggested that repetitive hyperbaric oxygen (HBO) treatment alleviates bleomycin-induced pulmonary fibrosis in mice. Here, we investigated the protective mechanism of HBO treatment against pulmonary fibrosis using an integrated approach. Analyzing publicly available expression data from the mouse model of bleomycin-induced pulmonary fibrosis as well as IPF patients, several potential mechanisms of relevance to IPF pathology were identified, including increased epithelial-to-mesenchymal transition (EMT) and glycolysis. High EMT or glycolysis scores in bronchoalveolar lavage (BAL) were strong independent predictors of mortality in multivariate analysis. These processes were potentially driven by hypoxia and blocked by HBO treatment. Together, these data support HBO treatment as a viable strategy against pulmonary fibrosis.

PMID:37251287 | PMC:PMC7614583 | DOI:10.1016/j.gendis.2022.08.012

Pharmacoeconomics. 2023 May 30. doi: 10.1007/s40273-023-01278-3. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease associated with dyspnoea, cough and impaired quality of life affecting around 7500 patients in Spain.

OBJECTIVE: Our aim was to estimate the economic impact of IPF according to forced vital capacity (FVC) % predicted level in adult patients.

METHODS: We conducted a prospective, observational, multicentric study of patients with confirmed IPF in Spain. Total annual IPF-related costs were estimated per patient, and categorised according to the FVC% predicted value (FVC < 50%, FVC 50-80%, FVC > 80%) and total sample. Incurred direct health- and non-health-related costs and indirect costs were calculated considering the IPF-related healthcare resource use and the corresponding unitarian costs. Results were updated to 2023 euros.

RESULTS: Two hundred and four consecutive patients with IPF were included: 77% male, average age (standard deviation) 70.8 (7.6) years. At baseline, FVC% was < 50%, 50-80% and > 80% of predicted value in 10.8%, 74.5% and 14.7% of patients, respectively. The final cost-evaluable population included 180 subjects. The mean (standard deviation) total annual IPF-related cost was €26,997 (17,555), with statistically significant differences (p = 0.0002) between groups: €44,412 (33,389) for the FVC < 50%, €25,803 (14,688) for the FVC 50-80% and €23,242 (13,642) for the FVC > 80%. Annual direct health costs had the greatest weight and included pharmacological treatments [€22,324 (13,773)] and hospitalisation days [€1659 (7362)]. 14 patients had ≥ 1 acute exacerbation of IPF during the study; mean total cost of an acute exacerbation of IPF was €10,372. According to the multivariate analysis, an impaired lung function (FVC < 50%) and use of antifibrotic treatment were determinants of cost (p < 0.0001 both).

CONCLUSIONS: We observed a significantly higher annual IPF-related cost at a lower level of predicted FVC%, the direct cost having the greatest weight to the total costs. Maintaining patients at early disease stages by slowing IPF progression is relevant to reduce the economic impact of IPF.

CLINICAL TRIAL REGISTRATION: EU PAS register number EUPAS19387 (1 June, 2017).

PMID:37249823 | DOI:10.1007/s40273-023-01278-3

J Ethnopharmacol. 2023 May 27:116691. doi: 10.1016/j.jep.2023.116691. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Jia-Wei-Bu-Shen-Yi-Qi formula (JWBSYQF), a classical traditional Chinese herbal formula consisting of five herbs, is used clinically in China to treat inflammatory lung diseases, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Its mechanism for treating asthma and COPD has been reported, however, how it works against IPF remains unclear.

RESEARCH PURPOSE: Our study aims to observe the therapeutic effect of JWBSYQF on pulmonary fibrosis and further identify the potential active ingredients and molecular pathways.

RESEARCH METHODS: In this study, we used a bleomycin-induced mouse model to investigate the therapeutic effect of JWBSYQF on pulmonary fibrosis. To further explore the potential effective ingredients and molecular pathways, we used the network pharmacology approach to construct a drug-ingredient-target network of JWBSYQF. Then, the common target set was established for JWBSYQF, fibroblast, and lung fibrosis. Analyses of the KEGG pathway, GO enrichment, and network topology were performed to identify key biological processes and molecular pathways for the common targets. Finally, a TGF-β-induced NIH/3T3 proliferation and activation model was used to validate the possible active ingredients and signaling pathways.

RESEARCH RESULTS: JWBSYQF reversed BLM-induced balf leukocyte levels, pulmonary inflammatory lesions and fibrotic collagen deposition in mice and reduced the levels of a-SMA, Col1a1 and TGF-β. A total of 86 active ingredients were identified, 12 of which were considered as potential effective ingredients, while only baicalein effectively improved TGF-β-induced proliferation and activation of NIH/3T3. KEGG results showed that PI3K/Akt signaling pathway may be the potential action mechanism, and Western Blot demonstrated that both JWBSYQF and baicalein downregulated the protein levels of p-PI3K and p-Akt. The molecular docking results suggested that baicalein may directly act on the catalytic and regulatory subunits of PI3K, and this a effect is stronger than direct binding to Akt1.

CONCLUSIONS: Our study revealed that baicalein may be the material basis for JWBSYQF in the treatment of pulmonary fibrosis, and the PI3K/Akt signaling pathway may be a common pathway of action for JWBSYQF and baicalein.

PMID:37247682 | DOI:10.1016/j.jep.2023.116691

Microcirculation. 2023 May 29:e12817. doi: 10.1111/micc.12817. Online ahead of print.

ABSTRACT

OBJECTIVE: Microvascular remodeling is governed by biomechanical and biochemical cues which are dysregulated in idiopathic pulmonary fibrosis. Understanding how these cues impact endothelial cell-pericyte interactions necessitates a model system in which both variables can be independently and reproducibly modulated. In this study we develop a tunable hydrogel-based angiogenesis assay to study how varying angiogenic growth factors and environmental stiffness affect sprouting and vessel organization.

METHODS: Lungs harvested from mice were cut into 1 mm long segments then cultured on hydrogels having one of seven possible stiffness and growth factor combinations. Time course, brightfield, and immunofluorescence imaging were used to observe and quantify sprout formation.

RESULTS: Our assay was able to support angiogenesis in a comparable manner to Matrigel in soft 2 kPa gels while enabling tunability to study the effects of stiffness on sprout formation. Matrigel and 2 kPa groups contained significantly more samples with sprouts when compared to the stiffer 10 and 20 kPa gels. Growth factor treatment did not have as obvious an effect, although the 20 kPa PDGF + FGF-treated group had significantly longer vessels than the vascular endothelial growth factor-treated group.

CONCLUSIONS: We have developed a novel, tunable hydrogel assay for the creation of lung explant vessel organoids which can be modulated to study the impact of specific environmental cues on vessel formation and maturation.

PMID:37248193 | DOI:10.1111/micc.12817

Cell Biol Toxicol. 2023 May 29. doi: 10.1007/s10565-023-09810-z. Online ahead of print.

ABSTRACT

Endothelial-to-mesenchymal transition (EndMT), the process by which endothelial cells lose their characteristics and acquire mesenchymal phenotypes, participates in the pathogenic mechanism of idiopathic pulmonary fibrosis. Recently, exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-Exos) has been introduced as a promising treatment in organ fibrosis. This study aimed to explore the effects as well as the molecular mechanism for hucMSC-Exo in pulmonary fibrosis. The intravenous administration of hucMSC-Exos alleviated bleomycin-induced pulmonary fibrosis in vivo. Moreover, hucMSC-Exos elevated miR-218 expression and restored endothelial properties weakened by TGF-β in endothelial cells. Knockdown of miR-218 partially abrogated the inhibition effect of hucMSC-Exos on EndMT. Our mechanistic study further demonstrated that MeCP2 was the direct target of miR-218. Overexpressing MeCP2 aggravated EndMT and caused increased CpG islands methylation at BMP2 promoter, which lead to BMP2 post-transcriptional gene silence. Transfection of miR-218 mimic increased BMP2 expression as well, which was downregulated by overexpression of MeCP2. Taken together, these findings indicate exosomal miR-218 derived from hucMSCs may possess anti-fibrotic properties and inhibit EndMT through MeCP2/BMP2 pathway, providing a new avenue of preventive application in pulmonary fibrosis.

PMID:37247103 | DOI:10.1007/s10565-023-09810-z

Eur J Pharmacol. 2023 May 26:175820. doi: 10.1016/j.ejphar.2023.175820. Online ahead of print.

ABSTRACT

In idiopathic pulmonary fibrosis (IPF), excessive collagen deposition predisposes to irreversible lung function decline, respiratory failure, and ultimately death. Due to the limited therapeutic efficacy of FDA-approved medications, novel drugs are warranted for better treatment outcomes. Dehydrozingerone (DHZ) is an analogue of curcumin that has been investigated against pulmonary fibrosis using a bleomycin-induced pulmonary fibrosis model in rats. In in vitro, TGF-β-induced differentiation models (NHLF, LL29, DHLF and A549 cells) were adopted to assess fibrotic markers expression and explored the mechanism of action. DHZ administration attenuated the bleomycin-induced elevation of lung index, inflammatory cell infiltrations, and hydroxyproline levels in lung tissues. Furthermore, treatment with DHZ mitigated the bleomycin-mediated elevation of extracellular matrix (ECM), epithelial-to-mesenchymal-transition (EMT), and collagen deposition markers and improved lung mechanics. In addition, treatment with DHZ significantly suppressed the BLM-induced apoptosis and rescued the BLM-induced pathological abnormalities in lung tissues. In-vitro assays revealed that DHZ suppressed the expression of TGF-β-elevated collagen deposition, EMT and ECM markers in both mRNA/protein levels. Our findings showed that DHZ has anti-fibrotic effect against pulmonary fibrosis by modulating Wnt/β-catenin signaling, suggesting that DHZ may serve as a potential treatment option for IPF.

PMID:37245857 | DOI:10.1016/j.ejphar.2023.175820

Respir Investig. 2023 May 26;61(4):490-497. doi: 10.1016/j.resinv.2023.04.007. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) predominantly affects people over the age of 60 years and its incidence increases with age. Limited data is available on the use of antifibrotics in the elderly IPF population. We aimed to examine the tolerability and safety of antifibrotics (pirfenidone, nintedanib) in elderly patients with IPF in a real-world setting.

METHODS: Medical records of 284 elderly (≥75 years) and 446 non-elderly IPF patients (<75 years) were retrospectively analyzed in this multi-center study. Patient characteristics, treatments, adverse events (AEs), tolerability, hospitalizations, exacerbations, and mortality were compared between the elderly and non-elderly group.

RESULTS: In the elderly group, the mean age was 79 years and the mean antifibrotic treatment duration was 26.1 months. The most commonly reported AEs were weight loss, loss of appetite and nausea. Elderly IPF patients had a significantly higher incidence of AEs (62.9% vs. 55.1%, p = 0.039) and dose reductions (27.4% vs. 18.1%, p = 0.003) than the non-elderly did, but the rate of discontinuation of antifibrotics was not different between groups (13% vs. 10.8%, p = 0.352). In addition, the severity of the disease, frequency of hospitalizations, exacerbations, and mortality rates were higher in elderly patients.

CONCLUSION: The present study showed that elderly IPF patients experienced significantly increased AEs and dose reductions due to antifibrotic use, while the discontinuation rates of the drugs were similar to those of drugs used by non-elderly patients.

PMID:37245284 | DOI:10.1016/j.resinv.2023.04.007

Pharmacol Ther. 2023 May 25:108460. doi: 10.1016/j.pharmthera.2023.108460. Online ahead of print.

ABSTRACT

Pulmonary fibrotic diseases are characterized by proliferation of lung fibroblasts and myofibroblasts and excessive deposition of extracellular matrix proteins. Depending on the specific form of lung fibrosis, there can be progressive scarring of the lung, leading in some cases to respiratory failure and/or death. Recent and ongoing research has demonstrated that resolution of inflammation is an active process regulated by families of small bioactive lipid mediators termed "specialized pro-resolving mediators." While there are many reports of beneficial effects of SPMs in animal and cell culture models of acute and chronic inflammatory and immune diseases, there have been fewer reports investigating SPMs and fibrosis, especially pulmonary fibrosis. Here, we will review evidence that resolution pathways are impaired in interstitial lung disease, and that SPMs and other similar bioactive lipid mediators can inhibit fibroblast proliferation, myofibroblast differentiation, and accumulation of excess extracellular matrix in cell culture and animal models of pulmonary fibrosis, and we will consider future therapeutic implications of SPMs in fibrosis.

PMID:37244406 | DOI:10.1016/j.pharmthera.2023.108460

Medicina (Kaunas). 2023 May 22;59(5):999. doi: 10.3390/medicina59050999.

ABSTRACT

Nintedanib is a tyrosine kinase inhibitor that was approved for the treatment of patients with idiopathic pulmonary fibrosis in 2014. The most common side effect of Nintedanib is diarrhea, and thrombocytopenia is a rare side effect of Nintedanib. The exact mechanism is unknown, and the literature lacks case reports of this phenomenon. Here, we report the case of a patient who developed thrombocytopenia 12 weeks after starting treatment with Nintedanib. The patient underwent an extensive work up for infectious, hematological, autoimmune, and neoplastic diseases. The patient's thrombocytopenia resolved following cessation of Nintedanib. This case is significant as it reports a rare side effect that might have detrimental consequences if not recognized and treated timely. Additionally, the onset of thrombocytopenia was delayed, 3 months after the initiation of Nintedanib. We also highlight the various literature regarding drug-induced thrombocytopenia and explore the necessary work-up needed to exclude other potential diagnoses. We hope to advocate for multidisciplinary teams to be aware of patients with pulmonary fibrosis on Nintedanib so that this adverse effect can be recognized promptly.

PMID:37241231 | DOI:10.3390/medicina59050999

J Clin Med. 2023 May 19;12(10):3564. doi: 10.3390/jcm12103564.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common and severe form of idiopathic interstitial pneumonia, and its prevalence increases with age. In the era of pre-antifibrotic agents, the median survival time of Japanese patients with IPF is 35 months, with a 5-year survival rate in western countries ranging from 20% to 40%. The prevalence of IPF is highest in elderly patients aged ≥75 years; however, the efficacy and safety of long-term use of pirfenidone and/or nintedanib are not fully understood.

OBJECTIVE: This study aimed to determine the efficacy and safety of the sole use of antifibrotic agents (pirfenidone or nintendanib) for IPF in the elderly.

METHOD: We retrospectively reviewed patients with IPF who were diagnosed and treated with either pirfenidone or nintedanib in our hospital between 2008 and 2019. We excluded patients with the subsequent use of both antifibrotic agents. We examined the survival probability and frequency of acute exacerbation, with focus on long-term use (≥1 year), elderly patients (≥75 years of age), and disease severity.

RESULTS: We identified 91 patients with IPF (male to female ratio: 63 to 28, age 42 to 90 years). The numbers of patients with disease severity classified by JRS (I/II/III/IV) and GAP stage (I/II/III) were (38/6/17/20) and (39/36/6), respectively. The survival probabilities were comparable between the elderly (n = 46) and non-elderly groups (n = 45, p = 0.877). After the initiation of antifibrotic agents, the cumulative incidence ratio of acute exacerbation of IPF was significantly lower in the early stage (GAP stage I, n = 20) than in the progressive stage of disease (GAP stages II and III, n = 20, p = 0.028). A similar trend was noted in the JRS disease severity classification (I, II vs. III, IV) (n = 27 vs. n = 13, p = 0.072). In the long-term treatment (≥1 year) group (n = 40), the survival probabilities at 2 and 5 years after treatment initiation were 89.0% and 52.4%, respectively, which did not reach the median survival rate.

CONCLUSIONS: Even in elderly patients (≥75 years of age), antifibrotic agents demonstrated positive effects on survival probability and the frequency of acute exacerbation. These positive effects would be improved for earlier JRS/GAP stages or long-term use.

PMID:37240670 | DOI:10.3390/jcm12103564

Biomedicines. 2023 May 19;11(5):1483. doi: 10.3390/biomedicines11051483.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disorder, ultimately leading to respiratory failure and death. Despite great research advances in understanding the mechanisms underlying the disease, its diagnosis, and its treatment, IPF still remains idiopathic without known biological or histological markers able to predict disease progression or response to treatment. The histologic hallmark of IPF is usual interstitial pneumonia (UIP), with its intricate architectural distortion and temporal inhomogeneity. We hypothesize that normal lung alveolar architecture can be compared to fractals, such as the Pythagoras tree with its fractal dimension (Df), and every pathological insult, distorting the normal lung structure, could result in Df variations. In this study, we aimed to assess the UIP histologic fractal dimension in relationship to other morphometric parameters in newly diagnosed IPF patients and its possible role in the prognostic stratification of the disease. Clinical data and lung tissue specimens were obtained from twelve patients with IPF, twelve patients with non-specific interstitial pneumonia (NSIP), and age-matched "healthy" control lung tissue from patients undergoing lung surgery for other causes. Histology and histomorphometry were performed to evaluate Df and lacunarity measures, using the box counting method on the FracLac ImageJ plugin. The results showed that Df was significantly higher in IPF patients compared to controls and fibrotic NSIP patients, indicating greater architectural distortion in IPF. Additionally, high Df values were associated with higher fibroblastic foci density and worse prognostic outcomes in IPF, suggesting that Df may serve as a potential novel prognostic marker for IPF. The scalability of Df measurements was demonstrated through repeated measurements on smaller portions from the same surgical biopsies, which were selected to mimic a cryobiopsy. Our study provides further evidence to support the use of fractal morphometry as a tool for quantifying and determining lung tissue remodeling in IPF, and we demonstrated a significant correlation between histological and radiological Df in UIP pattern, as well as a significant association between Df and FF density. Furthermore, our study demonstrates the scalability and self-similarity of Df measurements across different biopsy types, including surgical and smaller specimens.

PMID:37239155 | DOI:10.3390/biomedicines11051483

Biomedicines. 2023 Apr 26;11(5):1279. doi: 10.3390/biomedicines11051279.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblast proliferation and abnormal accumulation of extracellular matrix in the lungs. After lung injury, M2 macrophages mediate the pathogenesis of pulmonary fibrosis by secreting fibrotic cytokines that promote myofibroblast activation. The TWIK-related potassium channel (TREK-1, also known as KCNK2) is a K2P channel that is highly expressed in cardiac, lung, and other tissues; it worsens various tumors, such as ovarian cancer and prostate cancer, and mediates cardiac fibrosis. However, the role of TREK-1 in lung fibrosis remains unclear. This study aimed to examine the effects of TREK-1 on bleomycin (BLM)-induced lung fibrosis. The results show that TREK-1 knockdown, mediated by the adenovirus or pharmacological inhibition of TREK-1 with fluoxetine, resulted in diminished BLM-induced lung fibrosis. TREK-1 overexpression in macrophages remarkably increased the M2 phenotype, resulting in fibroblast activation. Furthermore, TREK-1 knockdown and fluoxetine administration directly reduced the differentiation of fibroblasts to myofibroblasts by inhibiting the focal adhesion kinase (FAK)/p38 mitogen-activated protein kinases (p38)/Yes-associated protein (YAP) signaling pathway. In conclusion, TREK-1 plays a central role in the pathogenesis of BLM-induced lung fibrosis, which serves as a theoretical basis for the inhibition of TREK-1 as a potential therapy protocol for lung fibrosis.

PMID:37238950 | DOI:10.3390/biomedicines11051279

Diagnostics (Basel). 2023 May 12;13(10):1715. doi: 10.3390/diagnostics13101715.

ABSTRACT

OBJECTIVES: To assess CCL18 and OX40L as biomarkers of interstitial lung disease (ILD) and/or progressive fibrosing (PF-) ILD in idiopathic inflammatory myopathies (IIMs).

METHODS: Patients with IIMs seen in our center from July 2020 to March 2021 were consecutively enrolled. ILD was detected by high-resolution CT. CCL18 and OX40L serum levels were measured by validated ELISA assays in 93 patients and 35 controls. At the 2-year follow-up, PF-ILD was evaluated according to the INBUILD criteria.

RESULTS: ILD was diagnosed in 50 (53.7%) patients. CCL18 serum levels were higher in IIMs patients vs. controls (232.9 [IQR 134.7-399.07] vs. 48.4 [29.9-147.5], p < 0.0001), with no difference for OX40L. IIMs-ILD patients exhibited higher levels of CCL18 than those without ILD (306.8 [190.8-520.5] vs. 162 [75.4-255.8], p < 0.0001). High CCL18 serum levels were independently associated with IIMs-ILD diagnosis. At follow-up, 22/50 (44%) patients developed a PF-ILD. Patients who developed PF-ILD had higher CCL18 serum levels than non-progressors (511 [307-958.7] vs. 207.1 [149.3-381.7], p < 0.0001). Multivariate logistic regression analysis revealed CCL18 as the only independent predictor of PF-ILD (OR 1.006 [1.002-1.011], p = 0.005).

CONCLUSIONS: Although in a relatively small sample, our data suggest that CCL18 is a useful biomarker in IIMs-ILD, particularly in the early identification of patients at risk of developing PF-ILD.

PMID:37238199 | DOI:10.3390/diagnostics13101715

Mod Pathol. 2023 May 24:100221. doi: 10.1016/j.modpat.2023.100221. Online ahead of print.

ABSTRACT

Transbronchial cryobiopsy (TBCB) is increasingly used for the diagnosis of fibrosing interstitial pneumonias, but there are few detailed descriptions of the pathologic findings in such cases. It has been proposed that a combination of patchy fibrosis and fibroblast foci with an absence of alternative features is diagnostic of usual interstitial pneumonia (UIP; i.e., idiopathic pulmonary fibrosis, IPF) in TBCB. Here we reviewed 121 TBCB in which a diagnosis of fibrotic hypersensitivity pneumonitis (FHP, N=83) or IPF (N=38) was made by multidisciplinary discussion and evaluated a range of pathologic features. Patchy fibrosis was found in 65/83 (78%) biopsies from FHP and 32/38 (84%) biopsies from UIP/IPF cases. Fibroblast foci were present in 47/83 (57%) FHP and 27/38 (71%) UIP/IPF cases. Fibroblast foci/patchy fibrosis combined did not favor either diagnosis. Architectural distortion was seen in 54/83 (65%) FHP and 32/38 (84%) UIP/IPF cases (odds ratio (OR) for FHP 0.35, p=0.036) and honeycombing in 18/83 (22%) and17/38 (45%) respectively (OR 0.37, p=0.014). Airspace giant cells/granulomas were present in 13/83 (20%) FHP and 1/38 (2.6%) UIP/IPF cases (OR for FHP 6.87, p=0.068), and interstitial giant cells/granulomas in 20/83 (24%) FHP and 0/38 (0%) UIP/IPF (OR 6.7x106, p=0.000). We conclude that patchy fibrosis plus fibroblast foci can be found in TBCB from both FHP and UIP/IPF. The complete absence of architectural distortion/honeycombing favors a diagnosis of FHP as does the presence of airspace or interstitial giant cells/granulomas, but these measures are insensitive, and many cases of FHP cannot be separated from UIP/IPF on TBCB.

PMID:37236510 | DOI:10.1016/j.modpat.2023.100221

Biofabrication. 2023 May 26. doi: 10.1088/1758-5090/acd95f. Online ahead of print.

ABSTRACT

Despite encouraging progress in the development of in vitro cancer models, in vitro cancer models that simultaneously recapitulate the complexity of the tumor microenvironment and its diverse cellular components and genetic properties remain lacking. Here, an advanced vascularized lung cancer model is proposed, which includes patient-derived lung cancer organoids (LCOs), lung fibroblasts, and perfusable vessels using 3D bioprinting technology. To better recapitulate the biochemical composition of native lung tissues, a porcine lung-derived decellularized extracellular matrix (LudECM) hydrogel was produced to offer physical and biochemical cues to cells in the lung cancer microenvironment. In particular, idiopathic pulmonary fibrosis-derived lung fibroblasts (iLFs) were used to implement fibrotic niches similar to actual human fibrosis. It was shown that they increased cell proliferation and the expression of drug resistance-related genes in LCOs with fibrosis. In addition, changes in resistance to sensitizing targeted anti-cancer drugs in LCOs with fibrosis were significantly greater in LudECM than in that Matrigel. Therefore, assessment of drug responsiveness in vascularized lung cancer models that recapitulate lung fibrosis can help determine the appropriate therapy for lung cancer patients accompanied by fibrosis. Furthermore, it is expected that this approach could be utilized for the development of targeted therapies or the identification of biomarkers for lung cancer patients accompanied by fibrosis.

PMID:37236168 | DOI:10.1088/1758-5090/acd95f

Sci Adv. 2023 May 26;9(21):eadf0133. doi: 10.1126/sciadv.adf0133. Epub 2023 May 26.

ABSTRACT

Idiopathic pulmonary fibrosis is a progressive fibrotic disease characterized by excessive deposition of (myo)fibroblast produced collagen fibrils in alveolar areas of the lung. Lysyl oxidases (LOXs) have been proposed to be the central enzymes that catalyze the cross-linking of collagen fibers. Here, we report that, while its expression is increased in fibrotic lungs, genetic ablation of LOXL2 only leads to a modest reduction of pathological collagen cross-linking but not fibrosis in the lung. On the other hand, loss of another LOX family member, LOXL4, markedly disrupts pathological collagen cross-linking and fibrosis in the lung. Furthermore, knockout of both Loxl2 and Loxl4 does not offer any additive antifibrotic effects when compared to Loxl4 deletion only, as LOXL4 deficiency decreases the expression of other LOX family members including Loxl2. On the basis of these results, we propose that LOXL4 is the main LOX activity underlying pathological collagen cross-linking and lung fibrosis.

PMID:37235663 | DOI:10.1126/sciadv.adf0133

Altern Ther Health Med. 2023 May 26:AT8195. Online ahead of print.

ABSTRACT

OBJECTIVE: To summarize the use of Chinese Herbal Medicines (CHMs) for Idiopathic Pulmonary Fibrosis (IPF) and provide high-level evidence for clinical decisions.

METHODS: We analyzed systematic reviews (SRs). Two English-language and three Chinese-language electronic databases were searched from inception to July 1, 2019. Published SRs and meta-analyses evaluating CHM use in IPF and reporting clinically-relevant outcomes such as lung function, PO2, and quality of life were eligible for inclusion in this overview. The methodological qualities of the included SRs were assessed by AMSTAR and ROBIS tools.

RESULTS: All reviews were published from 2008 to 2019. 15SRs were published in Chinese-language while 2 were in English. A total of 15550 participants were included. All intervention arms received CHM with or without conventional treatment and were compared with control arms with conventional treatment alone, or hormone therapy. Twelve SRs were assessed with low risk of bias while five were assessed high risk by ROBIS. The quality of evidence was assessed to be "moderate" or "low" or "very low" using GRADE.

CONCLUSIONS: CHM has potential benefits for patients with IPF especially in improving lung function (forced vital capacity (FVC), total lung capacity (TLC), and diffusing capacity of the lungs for carbon monoxide (DLCO)), PO2 level, and the quality of life of patients. Due to the low methodological quality of reviews, our findings should be interpreted with caution.

PMID:37235494

Aging Cell. 2023 May 26:e13874. doi: 10.1111/acel.13874. Online ahead of print.

ABSTRACT

Emerging evidence has shown that leukocyte telomere length (LTL) is associated with various health-related outcomes, while the causality of these associations remains unclear. We performed a systematic review and meta-analysis of current evidence from Mendelian randomization (MR) studies on the association between LTL and health-related outcomes. We searched PubMed, Embase, and Web of Science up to April 2022 to identify eligible MR studies. We graded the evidence level of each MR association based on the results of the main analysis and four sensitive MR methods, MR-Egger, weighted median, MR-PRESSO, and multivariate MR. Meta-analyses of published MR studies were also performed. A total of 62 studies with 310 outcomes and 396 MR associations were included. Robust evidence level was observed for the association between longer LTL and increased risk of 24 neoplasms (the strongest magnitude for osteosarcoma, GBM, glioma, thyroid cancer, and non-GBM glioma), six genitourinary and digestive system outcomes of excessive or abnormal growth, hypertension, metabolic syndrome, multiple sclerosis, and clonal hematopoiesis of indeterminate potential. Robust inverse association was observed for coronary heart disease, chronic kidney disease, rheumatoid arthritis, juvenile idiopathic arthritis, idiopathic pulmonary fibrosis, and facial aging. Meta-analyses of MR studies suggested that genetically determined LTL was associated with 12 neoplasms and 9 nonneoplasm outcomes. Evidence from published MR studies supports that LTL plays a causal role in various neoplastic and nonneoplastic diseases. Further research is required to elucidate the underlying mechanisms and to bring insight into the potential prediction, prevention, and therapeutic applications of telomere length.

PMID:37232505 | DOI:10.1111/acel.13874