Respir Res. 2024 Jun 19;25(1):249. doi: 10.1186/s12931-024-02875-2.

ABSTRACT

BACKGROUND: Our study examined whether prevalent and incident comorbidities are increased in idiopathic pulmonary fibrosis (IPF) patients when compared to matched chronic obstructive pulmonary disease (COPD) patients and control subjects without IPF or COPD.

METHODS: IPF and age, gender and smoking matched COPD patients, diagnosed between 01/01/1997 and 01/01/2019 were identified from the Clinical Practice Research Datalink GOLD database multiple registrations cohort at the first date an ICD-10 or read code mentioned IPF/COPD. A control cohort comprised age, gender and pack-year smoking matched subjects without IPF or COPD. Prevalent (prior to IPF/COPD diagnosis) and incident (after IPF/COPD diagnosis) comorbidities were examined. Group differences were estimated using a t-test. Mortality relationships were examined using multivariable Cox proportional hazards adjusted for patient age, gender and smoking status.

RESULTS: Across 3055 IPF patients, 38% had 3 or more prevalent comorbidities versus 32% of COPD patients and 21% of matched control subjects. Survival time reduced as the number of comorbidities in an individual increased (p < 0.0001). In IPF, prevalent heart failure (Hazard ratio [HR] = 1.62, 95% Confidence Interval [CI]: 1.43-1.84, p < 0.001), chronic kidney disease (HR = 1.27, 95%CI: 1.10-1.47, p = 0.001), cerebrovascular disease (HR = 1.18, 95%CI: 1.02-1.35, p = 0.02), abdominal and peripheral vascular disease (HR = 1.29, 95%CI: 1.09-1.50, p = 0.003) independently associated with reduced survival. Key comorbidities showed increased incidence in IPF (versus COPD) 7-10 years prior to IPF diagnosis.

INTERPRETATION: The mortality impact of excessive prevalent comorbidities in IPF versus COPD and smoking matched controls suggests that multiorgan mechanisms of injury need elucidation in patients that develop IPF.

PMID:38898447 | DOI:10.1186/s12931-024-02875-2

Sci Adv. 2024 Jun 21;10(25):eadm9817. doi: 10.1126/sciadv.adm9817. Epub 2024 Jun 19.

ABSTRACT

Precision management of fibrotic lung diseases is challenging due to their diverse clinical trajectories and lack of reliable biomarkers for risk stratification and therapeutic monitoring. Here, we validated the accuracy of CMKLR1 as an imaging biomarker of the lung inflammation-fibrosis axis. By analyzing single-cell RNA sequencing datasets, we demonstrated CMKLR1 expression as a transient signature of monocyte-derived macrophages (MDMφ) enriched in patients with idiopathic pulmonary fibrosis (IPF). Consistently, we identified MDMφ as the major driver of the uptake of CMKLR1-targeting peptides in a murine model of bleomycin-induced lung fibrosis. Furthermore, CMKLR1-targeted positron emission tomography in the murine model enabled quantification and spatial mapping of inflamed lung regions infiltrated by CMKLR1-expressing macrophages and emerged as a robust predictor of subsequent lung fibrosis. Last, high CMKLR1 expression by bronchoalveolar lavage cells identified an inflammatory endotype of IPF with poor survival. Our investigation supports the potential of CMKLR1 as an imaging biomarker for endotyping and risk stratification of fibrotic lung diseases.

PMID:38896611 | DOI:10.1126/sciadv.adm9817

Cells. 2024 May 30;13(11):946. doi: 10.3390/cells13110946.

ABSTRACT

Pulmonary fibrosis is a chronic, progressive, irreversible lung disease characterized by fibrotic scarring in the lung parenchyma. This condition involves the excessive accumulation of extracellular matrix (ECM) due to the aberrant activation of myofibroblasts in the alveolar environment. Transforming growth factor beta (TGF-β) signaling is a crucial driver of fibrogenesis because it promotes excessive ECM deposition, thereby leading to scar formation and lung damage. A primary target of TGF-β signaling in fibrosis is Collagen Triple Helix Repeat Containing 1 (CTHRC1), a secreted glycoprotein that plays a pivotal role in ECM deposition and wound repair. TGF-β transcriptionally regulates CTHRC1 in response to tissue injury and controls the wound healing response through functional activity. CTHRC1 may also play an essential role in re-establishing and maintaining tissue homeostasis after wound closure by modulating both the TGF-β and canonical Wnt signaling pathways. This dual function suggests that CTHRC1 regulates tissue remodeling and homeostasis. However, deregulated CTHRC1 expression in pathogenic fibroblasts has recently emerged as a hallmark of fibrosis in multiple organs and tissues. This review highlights recent studies suggesting that CTHRC1 can serve as a diagnostic and prognostic biomarker for fibrosis in idiopathic pulmonary fibrosis, systemic sclerosis, and post-COVID-19 lung fibrosis. Notably, CTHRC1 expression is responsive to antifibrotic drugs that target the TGF-β pathway, such as pirfenidone and bexotegrast, indicating its potential as a biomarker of treatment success. These findings suggest that CTHRC1 may present new opportunities for diagnosing and treating patients with lung fibrosis.

PMID:38891078 | DOI:10.3390/cells13110946

Cells. 2024 May 22;13(11):893. doi: 10.3390/cells13110893.

ABSTRACT

Fibrosing interstitial lung diseases (FILDs), e.g., due to idiopathic pulmonary fibrosis (IPF), are chronic progressive diseases with a poor prognosis. The management of these diseases is challenging and focuses mainly on the suppression of progression with anti-fibrotic drugs. Therefore, novel FILD treatments are needed. In recent years, cell-based therapy with various stem cells has been investigated for FILD, and the use of mesenchymal stem cells (MSCs) has been widely reported and clinical studies are also ongoing. Induced pluripotent stem cells (iPSCs) have also been reported to have an anti-fibrotic effect in FILD; however, these have not been as well studied as MSCs in terms of the mechanisms and side effects. While MSCs show a potent anti-fibrotic effect, the possibility of quality differences between donors and a stable supply in the case of donor shortage or reduced proliferative capacity after cell passaging needs to be considered. The application of iPSC-derived cells has the potential to overcome these problems and may lead to consistent quality of the cell product and stable product supply. This review provides an overview of iPSCs and FILD, followed by the current status of cell-based therapy for FILD, and then discusses the possibilities and perspectives of FILD therapy with iPSC-derived cells.

PMID:38891026 | DOI:10.3390/cells13110893

Respir Res. 2024 Jun 18;25(1):247. doi: 10.1186/s12931-024-02871-6.

ABSTRACT

INTRODUCTION: Sleep-disordered breathing (SDB) is a major comorbidity in idiopathic pulmonary fibrosis (IPF) and is associated with a poor outcome. There is a lack of knowledge regarding the impact of SDB treatment on IPF. We assessed at one year: (1) the effect of CPAP and/or nocturnal oxygen therapy on IPF regarding lung function, blood mediators, and quality of life; (2) adherence to SDB treatment and SDB changes.

METHODOLOGY: This is a prospective study of consecutive newly diagnosed IPF patients initiating anti-fibrotic treatment. Lung function, polysomnography, blood tests and quality of life questionnaires were performed at inclusion and after one year. Patients were classified as obstructive sleep apnoea (OSA), central sleep apnoea (CSA), and sleep-sustained hypoxemia (SSH). SDB therapy (CPAP and/or nocturnal oxygen therapy) was initiated if needed.

RESULTS: Fifty patients were enrolled (36% had OSA, 22% CSA, and 12% SSH). CPAP was started in 54% of patients and nocturnal oxygen therapy in 16%. At one-year, polysomnography found improved parameters, though 17% of patients had to add nocturnal oxygen therapy or CPAP, while 33% presented SDB onset at this second polysomnography. CPAP compliance at one year was 6.74 h/night (SD 0.74). After one year, matrix metalloproteinase-1 decreased in OSA and CSA (p = 0.029; p = 0.027), C-reactive protein in OSA (p = 0.045), and surfactant protein D in CSA group (p = 0.074). There was no significant change in lung function.

CONCLUSIONS: Treatment of SBD with CPAP and NOT can be well tolerated with a high compliance. IPF patients may exhibit SDB progression and require periodic re-assessment. Further studies to evaluate the impact of SDB treatment on lung function and serological mediators are needed.

PMID:38890648 | DOI:10.1186/s12931-024-02871-6

Am J Respir Crit Care Med. 2024 Jun 18. doi: 10.1164/rccm.202404-0767RL. Online ahead of print.

NO ABSTRACT

PMID:38889351 | DOI:10.1164/rccm.202404-0767RL

Curr Opin Pulm Med. 2024 Jun 19. doi: 10.1097/MCP.0000000000001086. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: To discuss the most recent applications of radiological imaging, from conventional to quantitative, in the setting of idiopathic pulmonary fibrosis (IPF) diagnosis.

RECENT FINDINGS: In this article, current concepts on radiological diagnosis of IPF, from high-resolution computed tomography (CT) to other imaging modalities, are reviewed. In a separate section, advances in quantitative CT and development of novel imaging biomarkers, as well as current limitations and future research trends, are described.

SUMMARY: Radiological imaging in IPF, particularly quantitative CT, is an evolving field which holds promise in the future to allow for an increasingly accurate disease assessment and prognostication of IPF patients. However, further standardization and validation studies of alternative imaging applications and quantitative biomarkers are needed.

PMID:38888028 | DOI:10.1097/MCP.0000000000001086

J Cell Mol Med. 2024 Jun;28(12):e18499. doi: 10.1111/jcmm.18499.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a common, chronic, and progressive lung disease that severely impacts human health and survival. However, the intricate molecular underpinnings of IPF remains elusive. This study aims to delve into the nuanced molecular interplay of cellular interactions in IPF, thereby laying the groundwork for innovative therapeutic approaches in the clinical field of IPF. Sophisticated bioinformatics methods were employed to identify crucial biomarkers essential for the progression of IPF. The GSE122960 single-cell dataset was obtained from the Gene Expression Omnibus (GEO) compendium, and intercellular communication potentialities were scrutinized via CellChat. The random survival forest paradigm was established using the GSE70866 dataset. Quintessential genes were selected through Kaplan-Meier (KM) curves, while immune infiltration examinations, functional enrichment critiques and nomogram paradigms were inaugurated. Analysis of intercellular communication revealed an intimate potential connections between macrophages and various cell types, pinpointing five cardinal genes influencing the trajectory and prognosis of IPF. The nomogram paradigm, sculpted from these seminal genes, exhibits superior predictive prowess. Our research meticulously identified five critical genes, confirming their intimate association with the prognosis, immune infiltration and transcriptional governance of IPF. Interestingly, we discerned these genes' engagement with the EPITHELIAL_MESENCHYMAL_TRANSITION signalling pathway, which may enhance our understanding of the molecular complexity of IPF.

PMID:38887981 | DOI:10.1111/jcmm.18499

Stem Cell Res Ther. 2024 Jun 18;15(1):170. doi: 10.1186/s13287-024-03782-5.

ABSTRACT

Fibrosis is a pathological process, that could result in permanent scarring and impairment of the physiological function of the affected organ; this condition which is categorized under the term organ failure could affect various organs in different situations. The involvement of the major organs, such as the lungs, liver, kidney, heart, and skin, is associated with a high rate of morbidity and mortality across the world. Fibrotic disorders encompass a broad range of complications and could be traced to various illnesses and impairments; these could range from simple skin scars with beauty issues to severe rheumatologic or inflammatory disorders such as systemic sclerosis as well as idiopathic pulmonary fibrosis. Besides, the overactivation of immune responses during any inflammatory condition causing tissue damage could contribute to the pathogenic fibrotic events accompanying the healing response; for instance, the inflammation resulting from tissue engraftment could cause the formation of fibrotic scars in the grafted tissue, even in cases where the immune system deals with hard to clear infections, fibrotic scars could follow and cause severe adverse effects. A good example of such a complication is post-Covid19 lung fibrosis which could impair the life of the affected individuals with extensive lung involvement. However, effective therapies that halt or slow down the progression of fibrosis are missing in the current clinical settings. Considering the immunomodulatory and regenerative potential of distinct stem cell types, their application as an anti-fibrotic agent, capable of attenuating tissue fibrosis has been investigated by many researchers. Although the majority of the studies addressing the anti-fibrotic effects of stem cells indicated their potent capabilities, the underlying mechanisms, and pathways by which these cells could impact fibrotic processes remain poorly understood. Here, we first, review the properties of various stem cell types utilized so far as anti-fibrotic treatments and discuss the challenges and limitations associated with their applications in clinical settings; then, we will summarize the general and organ-specific mechanisms and pathways contributing to tissue fibrosis; finally, we will describe the mechanisms and pathways considered to be employed by distinct stem cell types for exerting anti-fibrotic events.

PMID:38886859 | DOI:10.1186/s13287-024-03782-5

Respir Res. 2024 Jun 17;25(1):245. doi: 10.1186/s12931-024-02878-z.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) represents a chronic and progressive pulmonary disorder distinguished by a notable mortality rate. Despite the elusive nature of the pathogenic mechanisms, several signaling pathways have been elucidated for their pivotal roles in the progression of this ailment. This manuscript aims to comprehensively review the existing literature on the signaling pathways linked to the pathogenesis of IPF, both within national and international contexts. The objective is to enhance the comprehension of the pathogenic mechanisms underlying IPF and offer a scholarly foundation for the advancement of more efficacious therapeutic strategies, thereby fostering research and clinical practices within this domain.

PMID:38886743 | DOI:10.1186/s12931-024-02878-z

J Thorac Dis. 2024 May 31;16(5):3371-3380. doi: 10.21037/jtd-24-45. Epub 2024 May 21.

ABSTRACT

In patients with non-small cell lung cancer (NSCLC), pre-existing interstitial lung disease (ILD) is a risk factor for the development of pneumonitis induced by immune checkpoint inhibitors (ICIs). Anti-fibrotic agents, including nintedanib, reduce the potential for acute exacerbation of idiopathic pulmonary fibrosis (IPF). However, whether nintedanib can reduce the potential for ICI-induced pneumonitis is unknown. From among 140 patients with NSCLC treated with atezolizumab monotherapy at our institution, we retrospectively investigated 4 patients with pre-existing ILD treated concurrently with nintedanib. On computed tomography (CT), a usual interstitial pneumonia (UIP) pattern was present in one patient, probable UIP pattern in one patient, and indeterminate for UIP pattern in two patients. Of those four patients with pre-existing ILD, two achieved a partial response to ICI treatment, with response durations of 8.1 and 7.6 months. The other two patients experienced progressive disease. Notable adverse events included the development of non-symptomatic grade 1 pneumonitis in the patient with a probable UIP pattern and grade 3 lower gastrointestinal hemorrhage in another patient. None of the patients experienced a worsening of respiratory symptoms. In patients with NSCLC and pre-existing ILD, nintedanib might reduce the potential for ICI-induced pneumonitis and enhance the antitumor effect.

PMID:38883641 | PMC:PMC11170387 | DOI:10.21037/jtd-24-45

Front Physiol. 2024 May 31;15:1243629. doi: 10.3389/fphys.2024.1243629. eCollection 2024.

ABSTRACT

Cu is an essential micronutrient for various physiological processes in almost all human cell types. Given the critical role of Cu in a wide range of cellular processes, the local concentrations of Cu and the cellular distribution of Cu transporter proteins in the lung are essential for maintaining a steady-state internal environment. Dysfunctional Cu metabolism or regulatory pathways can lead to an imbalance in Cu homeostasis in the lungs, affecting both acute and chronic pathological processes. Recent studies have identified a new form of Cu-dependent cell death called cuproptosis, which has generated renewed interest in the role of Cu homeostasis in diseases. Cuproptosis differs from other known cell death pathways. This occurs through the direct binding of Cu ions to lipoylated components of the tricarboxylic acid cycle during mitochondrial respiration, leading to the aggregation of lipoylated proteins and the subsequent downregulation of Fe-S cluster proteins, which causes toxic stress to the proteins and ultimately leads to cell death. Here, we discuss the impact of dysregulated Cu homeostasis on the pathogenesis of various respiratory diseases, including asthma, chronic obstructive pulmonary disease, idiopathic interstitial fibrosis, and lung cancer. We also discuss the therapeutic potential of targeting Cu. This study highlights the intricate interplay between copper, cellular processes, and respiratory health. Copper, while essential, must be carefully regulated to maintain the delicate balance between necessity and toxicity in living organisms. This review highlights the need to further investigate the precise mechanisms of copper interactions with infections and immune inflammation in the context of respiratory diseases and explore the potential of therapeutic strategies for copper, cuproptosis, and other related effects.

PMID:38883186 | PMC:PMC11176810 | DOI:10.3389/fphys.2024.1243629

Heliyon. 2024 May 29;10(11):e32118. doi: 10.1016/j.heliyon.2024.e32118. eCollection 2024 Jun 15.

ABSTRACT

PURPOSE: Cytokines can help predict prognosis in interstitial lung disease (ILD) and to differentiate between ILD subtypes. The objectives of our study were to evaluate association of baseline cytokine levels with time to ILD progression and to compare baseline cytokine levels between ILD subtypes.

METHODS: We quantified 27 cytokines using a multiplex assay in peripheral blood samples from 77 patients. Cox proportional hazards regression analysis was performed to evaluate cytokine impact on the time to progression in the total cohort and within each ILD type. We evaluated for significant differences in cytokine levels between ILD types using ANOVA, Wilcoxon signed-rank test and Tukey method.

RESULTS: Higher IL-13 level was associated with longer time to progression (hazard ratio 0.52 [0.33-0.81], p-value 0.004). FGF-β, GM-CSF, and IL-17 levels differed significantly between fibrotic and inflammatory ILD subgroups.

CONCLUSION: IL-13 may be a useful biomarker predicting ILD stability.

PMID:38882341 | PMC:PMC11176841 | DOI:10.1016/j.heliyon.2024.e32118

Lancet Respir Med. 2024 Jun 13:S2213-2600(24)00177-2. doi: 10.1016/S2213-2600(24)00177-2. Online ahead of print.

NO ABSTRACT

PMID:38880115 | DOI:10.1016/S2213-2600(24)00177-2

Expert Rev Respir Med. 2024 Jun 15. doi: 10.1080/17476348.2024.2369253. Online ahead of print.

ABSTRACT

BACKGROUND: Previous observational studies have shown that past infection of herpes simplex virus (HSV) is associated with idiopathic pulmonary fibrosis (IPF). The present study aims to identify the causal link between HSV infection (exposure factor) and IPF (outcome factor).

RESEARCH DESIGN AND METHODS: To date, the largest publicly available genome-wide association study (GWAS) for HSV infection (1,595 cases and 211,856 controls from Finnish ancestry) and for IPF (1,028 cases and 196,986 controls from Finnish ancestry) were used to perform this two-sample Mendelian randomization (MR) study.

RESULTS: We found no significant pleiotropy or heterogeneity of all selected nine HSV infection-associated genetic instrumental variants (IVs) in IPF GWAS dataset. Interestingly, we found that as HSV infection genetically increased, IPF risk increased based on an inverse-variance weighted (IVW) analysis (odds ratio [OR] = 1.280, 95% confidence interval [CI]: 1.048-1.563; p = 0.015) and weighted median (OR = 1.321, 95% CI: 1.032-1.692; p = 0.027).

CONCLUSIONS: Our analysis suggests a causal effect of genetically increased HSV infection on IPF risk. Thus, HSV infection may be a potential risk factor for IPF.

PMID:38878268 | DOI:10.1080/17476348.2024.2369253

Sci Rep. 2024 Jun 14;14(1):13774. doi: 10.1038/s41598-024-64548-w.

ABSTRACT

Assessment of lung function is an important clinical tool for the diagnosis and monitoring of chronic lung diseases, including idiopathic pulmonary fibrosis (IPF). In mice, lung function maneuvers use algorithm-based ventilation strategies including forced oscillation technique (FOT), negative pressure-driven forced expiratory (NPFE) and pressure-volume (PV) maneuvers via the FlexiVent system. This lung function test (LFT) is usually performed as end-point measurement only, requiring several mice for each time point to be analyzed. Repetitive lung function maneuvers would allow monitoring of a disease process within the same individual while reducing the numbers of laboratory animals. However, its feasibility in mice and impact on developing lung fibrosis has not been studied so far. Using orotracheal cannulation without surgical exposure of the trachea, we examined the tolerability to repetitive lung function maneuvers (up to four times) in one and the same mouse, both under healthy conditions and in a model of AdTGF-β1 induced lung fibrosis. In essence, we found that repetitive invasive lung function maneuvers were well tolerated and did not accentuate experimental lung fibrosis in mice. This study contributes to the 3R principle aiming to reduce the numbers of experimental animals used in biomedical research.

PMID:38877042 | DOI:10.1038/s41598-024-64548-w

Acta Histochem. 2024 Jun 13:152168. doi: 10.1016/j.acthis.2024.152168. Online ahead of print.

NO ABSTRACT

PMID:38876928 | DOI:10.1016/j.acthis.2024.152168

Acad Radiol. 2024 Jun 13:S1076-6332(24)00286-1. doi: 10.1016/j.acra.2024.05.005. Online ahead of print.

ABSTRACT

RATIONALE AND OBJECTIVES: To establish a quantitative CT threshold for radiological disease progression of progressive pulmonary fibrosis (PPF) and evaluate its feasibility in patients with connective tissue disease-related interstitial lung disease (CTD-ILD).

MATERIALS AND METHODS: Between April 2007 and October 2022, patients diagnosed with CTD-ILD retrospectively evaluated. CT quantification was conducted using a commercial software by summing the percentages of ground-glass opacity, consolidation, reticular opacity, and honeycombing. The quantitative threshold for radiological progression was determined based on the highest discrimination on overall survival (OS). Two thoracic radiologists independently evaluated visual radiological progression, and the senior radiologist's assessment was used as the final result. Cox regression was used to assess prognosis of PPF based on the visual assessment and quantitative threshold.

RESULTS: 97 patients were included and followed up for a median of 30.3 months (range, 4.7-198.1 months). For defining radiological disease progression, the optimal quantitative CT threshold was 4%. Using this threshold, 12 patients were diagnosed with PPF, while 14 patients were diagnosed with PPF based on the visual assessment, with an agreement rate of 97.9% (95/97). Worsening respiratory symptoms (hazard ratio [HR], 12.73; P < .001), PPF based on the visual assessment (HR, 8.86; P = .002) and based on the quantitative threshold (HR, 6.72; P = .009) were independent risk factors for poor OS.

CONCLUSION: The quantitative CT threshold for radiological disease progression (4%) was feasible in defining PPF in terms of its agreement with PPF grouping and prognostic performance when compared to visual assessment.

PMID:38876844 | DOI:10.1016/j.acra.2024.05.005

Biomed Pharmacother. 2024 Jun 13;176:116896. doi: 10.1016/j.biopha.2024.116896. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a severe disability due to progressive lung dysfunction. IPF has long been viewed as a non-immune form of pulmonary fibrosis, but nowadays it is accepted that a chronic inflammatory response can exacerbate fibrotic patterns. IL-1-like cytokines and ATP are highly detected in the lung and broncho-alveolar lavage fluid of IPF patients. Because ATP binds the purinergic receptor P2RX7 involved in the release of IL-1-like cytokines, we aimed to understand the role of P2RX7 in IPF. PBMCs from IPF patients were treated with nintedanib or pirfenidone in the presence of ATP. Under these conditions, PBMCs still released IL-1-like cytokines and the pro-fibrotic TGFβ. Bulk and scRNAseq demonstrated that lung tissues of IPF patients had higher levels of P2RX7, especially on macrophages, which were correlated to T cell activity and inflammatory response with a TGFBI and IL-10 signature. A subcluster of macrophages in IPF lung tissues had 2055 genes that were not in common with the other subclusters, and that were involved in metabolic and PDGF, FGF and VEGF associated pathways. These data confirmed what observed on circulating cells that, although treated with anti-fibrotic agents, nintedanib or pirfenidone, they were still able to release IL-1 cytokines and the fibrogenic TGFβ. In conclusion, these data imply that because nintedanib and pirfenidone do not block ATP-induced IL-1-like cytokines and TGFβ induced during P2RX7 activation, it is plausible to consider P2RX7 on circulating cells and/or tissue biopsies as potential pharmacological tool for IPF patients.

PMID:38876049 | DOI:10.1016/j.biopha.2024.116896

Fibrosis (Hong Kong). 2023 Dec;1(2):10007. doi: 10.35534/fibrosis.2023.10007. Epub 2023 Nov 28.

ABSTRACT

The composition of extracellular matrix (ECM) is altered during pathologic scarring in damaged organs including the lung. One major change in the ECM involves the cross-linking of collagen, which promotes fibroblast to myofibroblast differentiation. We examined the role of lysyl oxidase (LOX)-like 2 in lung progenitors and fibroblasts cultured from normal or IPF lung samples and in a humanized mouse model of IPF using a monoclonal antibody (Simtuzumab). Primary lung fibroblasts from normal donor lungs and IPF lung explants were examined for expression of LOXL2. Targeting LOXL2 with Simtuzumab on normal and IPF fibroblasts was examined both in vitro and in vivo for synthetic, functional, and profibrotic properties. LOXL2 was increased at transcript and protein level in IPF compared with normal lung samples. In a dose-dependent manner, Simtuzumab enhanced differentiation of fibroblasts into myofibroblasts. Inhibition of LOXL2 also enhanced fibroblast invasion and accelerated the outgrowth of fibroblasts from dissociated human lung cell preparations. Finally, preventative or delayed delivery of Simtuzumab enhanced lung fibrosis in a humanized mouse model of pulmonary fibrosis. Consistent with its failure in a Phase 2 clinical trial, Simtuzumab exhibited no therapeutic efficacy in translational in vitro and in vivo assays.

PMID:38873180 | PMC:PMC11175361 | DOI:10.35534/fibrosis.2023.10007