Cell Commun Signal. 2024 Nov 13;22(1):542. doi: 10.1186/s12964-024-01925-y.

ABSTRACT

Despite the tremendous advancements in the knowledge of the pathophysiology and clinical aspects of SARS-CoV-2 infection, still many issues remain unanswered, especially in the long-term effects. Mounting evidence suggests that pulmonary fibrosis (PF) is one of the most severe complications associated with COVID-19. Therefore, understanding the molecular mechanisms behind its development is helpful to develop successful therapeutic strategies. Epithelial to mesenchymal transition (EMT) and its cell specific variants endothelial to mesenchymal transition (EndMT) and mesothelial to mesenchymal transition (MMT) are physio-pathologic cellular reprogramming processes induced by several infectious, inflammatory and biomechanical stimuli. Cells undergoing EMT acquire invasive, profibrogenic and proinflammatory activities by secreting several extracellular mediators. Their activity has been implicated in the pathogenesis of PF in a variety of lung disorders, including idiopathic pulmonary fibrosis (IPF) and COVID-19. Aim of this article is to provide an updated survey of the cellular and molecular mechanisms, with emphasis on EMT-related processes, implicated in the genesis of PF in IFP and COVID-19.

PMID:39538298 | DOI:10.1186/s12964-024-01925-y

Eur Respir Rev. 2024 Nov 13;33(174):240129. doi: 10.1183/16000617.0129-2024. Print 2024 Oct.

ABSTRACT

Air pollution is one of the leading causes of early deaths worldwide, with particulate matter (PM) as an emerging factor contributing to this trend. PM is classified based on its physical size, which ranges from PM10 (diameter ≤10 μm) to PM2.5 (≤2.5 μm) and PM0.5 (≤0.5 μm). Smaller-sized PM can move freely through the air and readily infiltrate deep into the lungs, intensifying existing health issues and exacerbating complications. Lung complications are the most common issues arising from PM exposure due to the primary site of deposition in the respiratory system. Conditions such as asthma, COPD, idiopathic pulmonary fibrosis, lung cancer and various lung infections are all susceptible to worsening due to PM exposure. PM can epigenetically modify specific target sites, further complicating its impact on these conditions. Understanding these epigenetic mechanisms holds promise for addressing these complications in cases of PM exposure. This involves studying the effect of PM on different gene expressions and regulation through epigenetic modifications, including DNA methylation, histone modifications and microRNAs. Targeting and manipulating these epigenetic modifications and their mechanisms could be promising strategies for future treatments of lung complications. This review mainly focuses on different epigenetic modifications due to PM2.5 exposure in the various lung complications mentioned above.

PMID:39537244 | DOI:10.1183/16000617.0129-2024

Chron Respir Dis. 2024 Jan-Dec;21:14799731241299443. doi: 10.1177/14799731241299443.

ABSTRACT

OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive fibrosis of the lung parenchyma, resulting in respiratory failure. This study analysed differences in patient characteristics and antifibrotic treatment strategies during the first years after IPF diagnosis.

METHODS: Data from patients with IPF was extracted from the Swedish IPF registry. Patients were defined as treated (either as fully- or reduced treated) or non-treated with antifibrotic drugs. Differences in clinical parameters and side effects were defined.

RESULTS: Among 532 patients, 371 received treatment with antifibrotic drugs. Treated patients were younger, had worse lung function, higher body mass index (BMI), higher Gender-Age-Physiology stage, and were more often on oxygen treatment. Non-treated patients displayed a stable BMI, whereas patients treated with antifibrotics declined in BMI during follow-up. More than half (56%) of treated patients had reduced antifibrotic treatment. Sixty per cent reported side effects, with diarrhoea, nausea, and skin rash as the most common.

CONCLUSIONS: Patients prescribed antifibrotic treatment had more advanced disease compared to patients not prescribed antifibrotics. A considerable proportion of the patients had reduced treatment, probably due to more side effects in this group. This indicates that individuals starting treatment at IPF diagnosis are considered to be in greater need of antifibrotic drug treatment by the prescriber, compared to individuals with less severe disease.

PMID:39532288 | DOI:10.1177/14799731241299443

Ann Am Thorac Soc. 2024 Nov 12. doi: 10.1513/AnnalsATS.202404-382OC. Online ahead of print.

ABSTRACT

RATIONALE: While exposure to air pollution is a known risk factor for adverse pulmonary outcomes, its impact in individuals with idiopathic pulmonary fibrosis (IPF) is less well understood.

OBJECTIVE: To investigate the effects of long-term exposure to air pollution on disease severity and progression in patients with IPF and to determine whether genomic factors, such as MUC5B promoter polymorphism or telomere length, modify these associations.

METHODS: We performed analyses at enrollment and after one year of follow-up in the IPF-PRO Registry, a prospective observational registry that enrolled individuals with IPF at 46 US sites from June 2014 to October 2018. Five-year average pollution exposures (PM2.5, NO2, O3) prior to enrollment date were estimated at participants' residential addresses with validated national spatio-temporal models. Multivariable regression models estimated associations between pollution exposure and physiologic measurements (FVC, DLCO, supplemental oxygen use at rest) and quality of life measurements (St. George's Respiratory Questionnaire [SGRQ], EuroQoL, Cough and Sputum Assessment Questionnaire) at enrollment. Cox proportional hazard models estimated associations between pollutants and a composite outcome of death, lung transplant, or >10% absolute decline in FVC % predicted in the year after enrollment. Models were adjusted for individual-level and spatial confounders, including proxies for disease onset. Gene-environment interactions with MUC5B and telomere length were assessed.

RESULTS: Of 835 participants, 94% were non-Hispanic Whites, 76% were male, mean (SD) age was 70 (7.7) years. In fully adjusted analyses, higher PM2.5 exposure was associated with worse quality of life per SGRQ activity score (3.48 [95% confidence interval (CI) 0.64, 6.32] per 2µg/m3 PM2.5) and EuroQoL scores (-0.04 [95%CI -0.06, -0.01] per 2µg/m3 PM2.5), and lower FVC % predicted and lower DLCO% predicted at enrollment. Each 3 parts per billion difference in O3 exposure was associated with a 1.57% [95% CI 0.15, 2.98] higher FVC % predicted at enrollment, although this effect was attenuated in multi-pollutant models. There was no association between NO2 and enrollment measures, between pollution exposure and one-year outcomes, or evidence for gene-environment interactions.

CONCLUSION: In the IPF-PRO Registry, long-term exposure to PM2.5 was associated with worse quality of life and lung function at enrollment, but not with short-term disease progression or mortality. There was no evidence of effect modification by interaction of genomic factors with pollution. The reason for the unexpected relationship between O3 exposure and higher FVC is unclear.

PMID:39531618 | DOI:10.1513/AnnalsATS.202404-382OC

Adv Mater. 2024 Nov 12:e2407661. doi: 10.1002/adma.202407661. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is exacerbated by injurious mechanical forces that destabilize the pulmonary mechanical microenvironment homeostasis, leading to alveolar dysfunction and exacerbating disease severity. However, given the inherent mechanosensitivity of fibrotic lungs, where type II alveolar epithelial cells (AEC IIs) are subjected to persistent stretching and overactivated myofibroblasts experience malignant interactions during mechanotransduction, it becomes imperative to develop effective strategies to modulate the pulmonary mechanical microenvironment. Herein, cyclo (RGDfC) peptide-decorated zeolitic imidazolate framework-8 nanoparticles (named ZDFPR NPs) are constructed to target and repair the aberrant mechanical force levels in pathological lungs. Specifically, reduces mechanical tension in AEC IIs by pH-responsive ZDFPR NPs that release zinc ions and 7, 8-dihydroxyflavone to promote alveolar repair and differentiation. Meanwhile, malignant interactions between myofibroblast contractility and extracellular matrix stiffness during mechanotransduction are disrupted by the fasudil inhibition ROCK signaling pathway. The results show that ZDFPR NPs successfully restored pulmonary mechanical homeostasis and terminated the fibrosis process in bleomycin-induced fibrotic mice. This study not only presents a promising strategy for modulating pulmonary mechanical microenvironment but also pioneers a novel avenue for IPF treatment.

PMID:39529565 | DOI:10.1002/adma.202407661

Respir Res. 2024 Nov 11;25(1):405. doi: 10.1186/s12931-024-03014-7.

ABSTRACT

BACKGROUND: The receptor for advanced glycation end product (RAGE) is a transmembrane receptor accelerating a pro-inflammatory signal. RAGE signalling is promoted by decreased soluble isoform of RAGE (sRAGE), which is a decoy receptor for RAGE ligands, and RAGE SNP rs2070600 minor allele. In Caucasian and Japanese cohorts, low circulatory sRAGE levels and presence of the minor allele are associated with poor survival of idiopathic pulmonary fibrosis (IPF) and increased disease susceptibility to interstitial lung disease, respectively. However, whether sRAGE and RAGE SNP rs2070600 are associated with acute exacerbation of IPF (AE-IPF) is unclear.

METHODS: This retrospective cohort study evaluated the association between the onset of AE-IPF and serum sRAGE levels in 69 German and 102 Japanese patients with IPF. The association of AE-IPF with RAGE SNP rs2070600 in 51 German and 84 Japanese patients, whose DNA samples were stored, was also investigated.

RESULTS: In each cohort, the incidence of AE-IPF was significantly and reproducibly higher in the patients with sRAGE < 467.1 pg/mL. In a pooled exploratory analysis, the incidence of AE-IPF was lowest in the patients with higher sRAGE levels and rs2070600 minor allele, although no significant difference in the incidence was observed between the patients with and without the rs2070600 minor allele.

CONCLUSIONS: Low sRAGE levels were associated with increased incidence of AE-IPF in two independent cohorts of different ethnicities. The combination of rs2070600 and sRAGE levels may stratify patients with IPF for the risk of AE.

PMID:39529063 | DOI:10.1186/s12931-024-03014-7

Signal Transduct Target Ther. 2024 Nov 11;9(1):306. doi: 10.1038/s41392-024-02011-y.

ABSTRACT

Fibroblast activation plays an important role in the occurrence and development of idiopathic pulmonary fibrosis (IPF), which is a progressive, incurable, and fibrotic lung disease. However, the underlying mechanism of fibroblast activation in IPF remains elusive. Here, we showed that the expression levels of STX11 and SNAP25 were downregulated in the lung tissues from patients with IPF and mice with bleomycin (BLM)-induced lung fibrosis as well as in the activated fibroblasts. Upregulation of STX11 or SNAP25 suppressed TGF-β1-induced activation of human lung fibroblasts (HLFs) via promoting autophagy. However, they failed to suppress fibroblast actviation when autophagy was blocked with the use of chloroquine (CQ). In addition, STX11 or SNAP25 could inhibit TGF-β1-induced fibroblast proliferation and migration. In vivo, overexpression of STX11 exerted its protective role in the mice with BLM-induced lung fibrosis. STX11 and SNAP25 mutually promoted expression of each other. Co-IP assay indicated that STX11 has an interaction with SNAP25. Mechanistically, STX11-SNAP25 interaction activated fibroblast autophagy and further inhibited fibroblast activation via blocking the PI3K/AKT/mTOR pathway. Overall, the results suggested that STX11-SNAP25 interaction significantly inhibited lung fibrosis by promoting fibroblast autophagy and suppressing fibroblast activation via blocking the PI3K/ATK/mTOR signaling pathway. Therefore, STX11 serves as a promising therapeutic target in IPF.

PMID:39523374 | DOI:10.1038/s41392-024-02011-y

Respir Res. 2024 Nov 10;25(1):404. doi: 10.1186/s12931-024-03032-5.

ABSTRACT

BACKGROUND: Little is known about whether central airway morphological changes beyond traction bronchiectasis develop and affect clinical outcomes in patients with idiopathic pulmonary fibrosis (IPF). This study aimed to compare central airway structure comprehensively between patients with IPF, subjects with interstitial lung abnormality (ILA), and those without ILA (control) using computed tomography (CT). We further examined the prognostic impact of IPF-specific CT airway parameters in patients with IPF.

METHODS: This retrospective study included male patients with IPF, and male health checkup subjects divided into those with ILA and control based on lung cancer screening CT. Using an artificial intelligence-based segmentation technique, the extent of fibrotic regions in the lung was quantified. After airway tree segmentation, CT parameters for central airway morphology, including the lumen area of the extrapulmonary airways (LAextra), wall and lumen area of the segmental/subsegmental intrapulmonary airways (WAintra and LAintra), tracheal distortion (tortuosity and curvature) and bifurcation angle of the main carina, were calculated.

RESULTS: There were 106 patients with IPF, 53 subjects with ILA, and 1295 controls. Multivariable models adjusted for age, height and smoking history revealed that LAintra and WAintra were larger in both ILA and IPF, and that tracheal tortuosity and curvature were higher in IPF, but not in ILA, than in the control, whereas the bifurcation angle did not differ between the 3 groups. According to multivariable Cox proportional hazards models including only patients with IPF, increased WAintra was significantly associated with greater mortality (standardized hazard ratio [95% confidence interval] = 1.58 [1.17, 2.14]), independent of the volume of fibrotic regions, normal-appearing regions, or the whole airway tree in the lung.

CONCLUSION: Increased lumen area and wall thickening of the central airways may be involved in the pathogenesis of ILA and IPF, and wall thickening may affect the prognosis of patients with IPF.

PMID:39523300 | DOI:10.1186/s12931-024-03032-5

Chest. 2024 Nov 7:S0012-3692(24)05452-7. doi: 10.1016/j.chest.2024.10.042. Online ahead of print.

ABSTRACT

TOPIC IMPORTANCE: Interstitial lung diseases (ILDs) represent a broad group of heterogeneous parenchymal lung diseases. Some ILDs progress, causing architectural distortion and pulmonary fibrosis, thus are called fibrotic ILDs. Recent studies have shown a beneficial effect of antifibrotic therapy in fibrotic ILDs other than Idiopathic Pulmonary Fibrosis (IPF) that manifest progressive pulmonary fibrosis (PPF). However, it is still challenging to predict which patients with fibrotic ILDs will manifest PPF. Precision medicine approaches could identify patients at risk for progression and guide treatment in patients with IPF or PPF.

REVIEW FINDINGS: Multiple biomarkers able to highlight disease susceptibility risk, provide an accurate diagnosis, prognosticate or assess treatment response have been identified. Advances in precision medicine led to the identification of endotypes that could discriminate patients with different fibrotic ILDs or patients with different disease course. Importantly, recent studies have shown that particular compounds were efficacious only in particular endotypes. The aforementioned findings are promising. However, implementation in clinical practice is still an unmet need.

SUMMARY: Substantial progress has been observed in the context of precision medicine approaches in fibrotic ILDs during the last years. Nonetheless, there are still infrastructure, financial, regulatory and ethical challenges to overcome for the implementation of precision medicine in the clinical practice. Overcoming such barriers and moving from ''one-size fits all'' approach to a patient-centered care could substantially improve patient's quality of life and survival.

PMID:39521375 | DOI:10.1016/j.chest.2024.10.042

Clin Biochem. 2024 Nov 7:110836. doi: 10.1016/j.clinbiochem.2024.110836. Online ahead of print.

NO ABSTRACT

PMID:39521318 | DOI:10.1016/j.clinbiochem.2024.110836

Clin Biochem. 2024 Nov 7;135:110837. doi: 10.1016/j.clinbiochem.2024.110837. Online ahead of print.

NO ABSTRACT

PMID:39521317 | DOI:10.1016/j.clinbiochem.2024.110837

Molecules. 2024 Oct 29;29(21):5106. doi: 10.3390/molecules29215106.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and age-related lung disease that has few treatment options. Reactive oxygen species (ROS) play an important role in the introduction and development of IPF. In the present study, we developed multifunctional Cobalt (Co)-Manganese (Mn) complex oxide nanoparticles (Co-MnNPs), which can scavenge multiple types of ROS. Benefiting from ROS scavenging activities and good biosafety, Co-MnNPs can suppress canonical and non-canonical TGF-β pathways and, thus, inhibit the activation of fibroblasts and the productions of extracellular matrix. Furthermore, the scavenging of ROS by Co-MnNPs reduce the LPS-induced expressions of pro-inflammatory factors in macrophages, by suppressing NF-κB signaling pathway. Therefore, Co-MnNPs can reduce the excessive extracellular matrix deposition and inflammatory responses in lungs and, thus, alleviate pulmonary fibrosis induced by bleomycin (BLM) in mice. Taken together, this work offers an anti-fibrotic agent for treatment of IPF and other ROS-related diseases.

PMID:39519747 | DOI:10.3390/molecules29215106

Int J Mol Sci. 2024 Nov 4;25(21):11827. doi: 10.3390/ijms252111827.

ABSTRACT

The persistent challenge of idiopathic pulmonary fibrosis (IPF), characterized by disease progression and high mortality, underscores the urgent need for innovative therapeutic strategies. We have developed a novel small molecule-catechin derivative ABI-171-selectively targeting dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) and proviral integration site for Moloney murine leukemia virus 1 (PIM1) kinases, crucial in the pathogenesis of fibrotic processes. We employed the Bleomycin-induced (intratracheal) mouse model of pulmonary fibrosis (PF) to evaluate the therapeutic efficacy of ABI-171. Mice with induced PF were treated QD with ABI-171, either prophylactically or therapeutically, using oral and intranasal routes. Pirfenidone (100 mg/kg, TID) and Epigallocatechin gallate (EGCG, 100 mg/kg, QD), a natural catechin currently in a Phase 1 clinical trial, were used as reference compounds. ABI-171, administered prophylactically, led to a significant reduction in hydroxyproline levels and fibrotic tissue formation compared to the control group. Treatment with ABI-171 improved body weight, indicating mitigation of disease-related weight loss. Additionally, ABI-171 demonstrated anti-inflammatory activity, reducing lymphocyte and neutrophil infiltration. In the therapeutic setting, ABI-171, administered 7 days post-induction, reduced mortality rates (p = 0.04) compared with the bleomycin and EGCG control groups. ABI-171 also ameliorated the severity of lung injuries assessed by improved Masson's trichrome scores when administered both orally and intranasally. ABI-171 significantly decreases bleomycin-induced PF and improves survival in mice, showcasing promising therapeutic potential beyond current medications like pirfenidone and EGCG for patients with IPF. Based on these results, further studies with ABI-171 are ongoing in preclinical studies.

PMID:39519378 | DOI:10.3390/ijms252111827

Int J Mol Sci. 2024 Nov 1;25(21):11751. doi: 10.3390/ijms252111751.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a lethal disorder characterized by relentless progression of lung fibrosis that causes respiratory failure and early death. Currently, no curative treatments are available, and existing therapies include a limited selection of antifibrotic agents that only slow disease progression. The development of novel therapeutics has been hindered by a limited understanding of the disease's etiology and pathogenesis. A significant challenge in developing new treatments and understanding IPF is the lack of in vitro models that accurately replicate crucial microenvironments. In response, three-dimensional (3D) in vitro models have emerged as powerful tools for replicating organ-level microenvironments seen in vivo. This review summarizes the state of the art in advanced 3D lung models that mimic many physiological and pathological processes observed in IPF. We begin with a brief overview of conventional models, such as 2D cell cultures and animal models, and then explore more advanced 3D models, focusing on lung-on-a-chip systems. We discuss the current challenges and future research opportunities in this field, aiming to advance the understanding of the disease and the development of novel devices to assess the effectiveness of new IPF treatments.

PMID:39519302 | DOI:10.3390/ijms252111751

Int J Mol Sci. 2024 Oct 30;25(21):11669. doi: 10.3390/ijms252111669.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with limited effective therapies. Interstitial macrophages (IMs), especially those derived from monocytes, play an unknown role in IPF pathogenesis. By using single-cell RNA sequencing (scRNA-seq), bleomycin (BLM)-induced pulmonary fibrosis mouse lungs were analyzed to characterize the cellular landscape and heterogeneity of macrophages in this model. scRNA-seq was used to identify distinct interstitial macrophage subpopulations in fibrotic lungs, with monocyte-derived macrophages exhibiting a pro-fibrotic gene expression profile enriched in wound healing, extracellular matrix (ECM) remodeling, and pro-fibrotic cytokine production functions. A pseudotime analysis revealed that IMs originated from monocytes and differentiated along a specific trajectory. A cell-cell communication analysis demonstrated strong interactions between monocyte-derived interstitial macrophages (Mo-IMs) and fibroblasts through the transforming growth factor beta (TGFβ), secreted phosphoprotein 1 (SPP1), and platelet-derived growth factor (PDGF) signaling pathways. Flow cytometry validated the presence and expansion of Mo-IMs subpopulations in BLM-treated mice. This study reveals the cellular heterogeneity and developmental trajectory of lung macrophages in early BLM-induced pulmonary fibrosis, highlighting the crucial role of Mo-IMs with a pro-fibrotic phenotype in IPF pathogenesis via interactions with fibroblasts. Targeting these specific macrophage subpopulations and associated signaling pathways may provide novel therapeutic strategies for IPF.

PMID:39519222 | DOI:10.3390/ijms252111669

J Clin Med. 2024 Oct 22;13(21):6304. doi: 10.3390/jcm13216304.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal lung disease most commonly encountered in older individuals. Several decades of research have contributed to a better understanding of its pathogenesis, though only two drugs thus far have shown treatment efficacy, i.e., by slowing the decline of lung function. The pathogenesis of IPF remains incompletely understood and involves multiple complex interactions and mechanisms working in tandem or separately to result in unchecked deposition of extracellular matrix components and collagen characteristic of the disease. These mechanisms include aberrant response to injury in the alveolar epithelium, inappropriate communication between epithelial cells and mesenchymal cells, imbalances between oxidative injury and tissue repair, recruitment of inflammatory pathways that induce fibrosis, and cell senescence leading to sustained activation and proliferation of fibroblasts and myofibroblasts. Targeted approaches to each of these mechanistic pathways have led to recent clinical studies evaluating the safety and efficacy of several agents. This review highlights selected concepts in the pathogenesis of IPF as a rationale for understanding current or future therapeutic approaches, followed by a review of several selected agents and their recent or active clinical studies. Current novel therapies include approaches to attenuating or modifying specific cellular or signaling processes in the fibrotic pathway, modifying inflammatory and metabolic derangements, and minimizing inappropriate cell senescence.

PMID:39518443 | DOI:10.3390/jcm13216304

Biochem Pharmacol. 2024 Nov 6:116613. doi: 10.1016/j.bcp.2024.116613. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disorder characterized by the accumulation of extracellular matrix and collagen, resulting in significant parenchymal scarring and respiratory failure that leads to mortality. Yohimbine (YBH) is an α-2 adrenergic receptor antagonist with anti-oxidant and anti-inflammatory properties. In the current study, we aimed to investigate the anti-inflammatory, anti-oxidant and anti-fibrotic activity of YBH against LPS/TGF-β-induced differentiation in BEAS-2B/LL29 cells and bleomycin (BLMN) induced pulmonary fibrosis model in rats. Network pharmacology, gene expression, Western-blot analysis, immune-cytochemistry/immunohistochemistry, lung function and histology techniques were used to assess the fibrotic marker expression/levels in cells or rat lung tissues. YBH treatment significantly attenuated the LPS-induced pro-inflammatory (identified through a network-pharmacology approach) and oxidative stress markers expression in lung epithelial cells. TGF-β stimulation significantly elevated the fibrotic cascade of markers and treatment with YBH attenuated these markers' expression/levels. Intra-tracheal administration of BLMN caused a significant elevation of various inflammatory/oxidative stress and fibrotic markers expression in lung tissues and treatment with YBH significantly mitigated the same. Ashcroft score analysis revealed that BLMN exhibited severe distortion of the lungs, elevation of thickness of the alveolar walls and accumulation of collagen in tissues, further treatment with YBH significantly suppressed these events and improved the lung architecture. Lung functional parameters demonstrated that BLMN-induced stiffness and resistance were reduced considerably upon YBH treatment and restored lung function dose-dependently. Overall, this study reveals that YBH treatment significantly attenuated the BLMN-induced fibrosis by regulating the MAPK pathway and provided insightful information for progressing towards translational outcomes.

PMID:39515589 | DOI:10.1016/j.bcp.2024.116613

Int Immunopharmacol. 2024 Nov 7;143(Pt 3):113572. doi: 10.1016/j.intimp.2024.113572. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic pulmonary disease with unknown pathogenesis and poor prognosis. PANoptosis, a newly identified form of inflammatory programmed cell death, has been implicated in various inflammatory lung diseases. This study aimed to identify differentially expressed PANoptosis-related genes (PRDEGs) associated with immune infiltration and prognosis in IPF, while also establishing a novel prognostic prediction model. A total of 63 PRDEGs were identified from GSE110147 dataset, with 31 exhibiting consistent expression trends in GSE213001. Enrichment analysis indicated that the majority of these PRDEGs were enriched in inflammatory and immune-related pathways. Three key PRDEGs-NLRP3, ATM, and VEGFA-were selected through univariate and multivariable Cox regression analyses. The prognostic prediction model developed from these key PRDEGs demonstrated robust predictive performance. Furthermore, the expression of most PRDEGs was positively correlated with pro-inflammatory immune cells, including macrophages, neutrophils, and CD4+ T cells. Validation of the expression levels of these key PRDEGs was conducted in fibrotic mouse lung tissue. This study suggests that PANoptosis plays a role in IPF, potentially linked to the infiltration of pro-inflammatory immune cells, and may influence disease progression through the regulation of inflammatory immune signaling pathway. A new prognostic prediction model for IPF based on PRDEGs was successfully developed.

PMID:39515041 | DOI:10.1016/j.intimp.2024.113572

Turk Gogus Kalp Damar Cerrahisi Derg. 2024 Jul 23;32(3):325-332. doi: 10.5606/tgkdc.dergisi.2024.26403. eCollection 2024 Jul.

ABSTRACT

BACKGROUND: The aim of this study was to evaluate the role of radiological and clinical findings in determining lobectomy decision in undiagnosed resectable lung lesions.

METHODS: Between January 2014 and April 2023, a total of 135 patients (114 males, 21 females; mean age: 60.8±11.5 years; range, 17 to 84 years) who underwent lobectomy or wedge resection based on clinical and radiological data were retrospectively analyzed. Patients with undiagnosed lung lesions, whose diagnosis could not be confirmed through transthoracic fine needle aspiration biopsy or bronchoscopic endobronchial ultrasound, were included in the study. Clinical data including age, sex, smoking status, history of extrapulmonary cancer, family history of lung cancer, and presence of chronic obstructive pulmonary disease/idiopathic pulmonary fibrosis were noted. Radiological data including lesion size, margin characteristics, internal structure of the lesion, relationship of the lesion with surrounding tissues, and nuclear imaging results were also recorded.

RESULTS: Malignant lesions were detected in 74 patients, while benign lesions were detected in 61 patients. Comparing benign and malignant lesions, age, lesion size, lesion localization, presence of pleural retraction, and moderate-to-high maximum standardized uptake value (SUVmax) on positron emission tomography-computed tomography were found to be correlated with malignancy.

CONCLUSION: The accurate assessment of lung lesions and prompt identification of possible malignancy are of paramount importance for implementing appropriate treatment strategies.

PMID:39513164 | PMC:PMC11538939 | DOI:10.5606/tgkdc.dergisi.2024.26403

Ther Adv Respir Dis. 2024 Jan-Dec;18:17534666241292507. doi: 10.1177/17534666241292507.

ABSTRACT

BACKGROUND: Pirfenidone (PFD) is commonly applied for antifibrotic treatment in patients with idiopathic pulmonary fibrosis but has rarely been studied in cases with connective tissue disease-associated interstitial lung diseases (CTD-ILDs).

OBJECTIVES: We aimed to examine the efficacy of PFD in patients with CTD-ILD based on real-world data.

DESIGN: A retrospective cohort study.

METHODS: This study assessed the clinical features of CTD-ILD patients with or without a 6-month PFD treatment. A linear mixed effects model was employed to evaluate the effectiveness of PFD in alleviating lung function changes. Differences in response to PFD were analyzed based on CTD subtype, imaging classification, and pattern of pulmonary function at baseline.

RESULTS: A total of 289 patients with CTD-ILD were included, with 155 (53.6%) receiving PFD treatment and the remaining constituting the control group. Patients with the usual interstitial pneumonia (UIP) pattern were more likely to receive PFD treatment, and a relatively lower proportion of cases in the PFD group received immunosuppressive therapies compared to the control group (p < 0.05). At the 6-month follow-up, patients in the PFD group demonstrated a more significant improvement in forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLCO) (ΔFVC%: 2.9% vs 0.45%, p = 0.009; ΔDLCO%: 1.9% vs -1.1%, p = 0.004). In the linear mixed model analysis, there was a statistically significant group-time interaction between FVC% and DLCO% changes over time (FVC%: β = 4.52, p < 0.001; DLCO%: β = 4.13, p = 0.003). Furthermore, subgroup analysis indicated that pirfenidone may have superior therapeutic effects in patients with systemic sclerosis (SSc)-associated ILD, non-UIP pattern, and restrictive pattern of lung function at baseline.

CONCLUSION: This study provided real-world data demonstrating the effectiveness of PFD in terms of lung function improvement in patients with CTD-ILD.

PMID:39512192 | DOI:10.1177/17534666241292507