ERJ Open Res. 2024 Dec 9;10(6):00411-2024. doi: 10.1183/23120541.00411-2024. eCollection 2024 Nov.

ABSTRACT

INTRODUCTION: Exertion-induced desaturation (EID) is a common complication of numerous pulmonary disorders and often treated with supplementary oxygen during exertion. We performed a systematic review and meta-analysis of randomised clinical trials (RCTs) to evaluate the efficacy of supplementary oxygen for EID in pulmonary disorders.

MATERIAL AND METHODS: Medline and Embase were systematically searched from July 2022 to June 2023 following PRISMA guidelines. RCTs that met predefined inclusion criteria were included. Means and standard deviations were extracted and standardised mean differences (SMDs), the difference in means between groups divided by the standard deviation, and 95% confidence intervals were calculated. Exercise capacity was the primary outcome; exercise dyspnoea, baseline dyspnoea and quality of life were secondary objectives. The immediate, post-rehabilitation, short-term and ambulatory effects of oxygen supplementation were evaluated.

RESULTS: We included 15 studies in our analysis. Oxygen supplementation to treat adult EID had been investigated for COPD and idiopathic pulmonary fibrosis (IPF) only. Oxygen supplementation was superior to placebo for its immediate effect on exercise capacity for COPD (SMD 0.42, 95% CI 0.15-0.69, I2=3%) and IPF (SMD 0.41, 95% CI 0.08-0.75, I2=57%) and exercise dyspnoea for COPD (SMD -0.40, 95% CI -0.76--0.04, I2=31%). Sensitivity analysis revealed similar results.

CONCLUSIONS: Our study revealed the efficacy of supplemental oxygen for EID and only a positive immediate effect on exercise capacity and dyspnoea, but no improvement in other short-term or long-term measures.

PMID:39655174 | PMC:PMC11626617 | DOI:10.1183/23120541.00411-2024

ERJ Open Res. 2024 Dec 9;10(6):00553-2024. doi: 10.1183/23120541.00553-2024. eCollection 2024 Nov.

ABSTRACT

INTRODUCTION: Progressive pulmonary fibrosis (PPF) corresponds to any fibrotic interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis (IPF) that presents clinical, physiological and/or radiological evidence of disease progression similar to IPF. Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of pulmonary fibrosis and are associated with disease progression and reduced survival in IPF and other fibrotic ILDs. This study aimed to investigate the role of serum levels of MMP-1 and MMP-7 in patients with fibrotic non-IPF ILD as possible biomarkers of patients at risk of developing PPF.

METHODS: Newly diagnosed patients with fibrotic non-IPF ILD were included in this study. Serum levels of MMP-1 and MMP-7 were quantified at baseline and disease progression was monitored. PPF was defined according to the recent European Respiratory Society, American Thoracic Society, Japanese Respiratory Society and the Latin American Thoracic Society Clinical Practice Guidelines.

RESULTS: 79 patients with fibrotic non-IPF ILDs were included and classified as having PPF or non-PPF. Significantly higher levels of MMP-7, but not MMP-1, were detected in the PPF group (p=0.01). MMP-7 was independently associated with PPF (adjusted OR 1.263, 95% CI 1.029-1.551; p=0.026) after adjustment for sex, age and smoking history. A cut-off value of 3.53 ng·mL-1 for serum MMP-7 levels had a sensitivity of 61% and a specificity of 74% for predicting PPF in non-IPF ILDs.

CONCLUSIONS: In patients with fibrotic non-IPF ILDs, serum MMP-7 levels were significantly greater in the subgroup of patients meeting the PPF criteria at follow-up. This can be considered and further investigated as a possible biomarker to identify fibrotic ILD patients at risk of PPF.

PMID:39655167 | PMC:PMC11626614 | DOI:10.1183/23120541.00553-2024

Bioorg Chem. 2024 Dec 7;154:108017. doi: 10.1016/j.bioorg.2024.108017. Online ahead of print.

ABSTRACT

Tyrosine kinase inhibitors (TKIs) represent a pivotal class of targeted therapies in oncology, with multiple generations developed to address diverse molecular targets. Imatinib is the first TKI developed to target the BCR-ABL1 chimeric protein, which is the key driver oncogene implicated in Philadelphia chromosome-positive chronic myeloid leukemia (CML). Several second-generation tyrosine kinase inhibitors (2GTKIs), such as nilotinib, dasatinib, bosutinib, and radotinib (RTB), followed the groundbreaking introduction of imatinib. RTB occupies the unique position of being the least explored member of this class. While nilotinib, dasatinib, and bosutinib have garnered significant attention and extensive research focus, RTB remains relatively uncharted in comparison to its counterparts. Fundamental drug characteristics, such as the pharmacokinetic and pharmacodynamic properties of RTB, remain unavailable in existing sources. Compared to other 2GTKIs, RTB has been less utilized in combinatorial drug studies, and no investigations have been reported on its effects on solid tumors to date. However, the effects of RTB have been studied in acute myeloid leukemia (AML), multiple myeloma (MM), Parkinson's disease, and idiopathic pulmonary fibrosis (IPF). Although RTB has been investigated in some conditions, these studies are still in their preliminary stages and are comparatively lesser than studies on other 2GTKIs. This review is the first attempt that extensively presents a compilation of data on RTB and describes its therapeutic potential against blood and solid tumors. Further investigations on RTB could expand its chemotherapeutic usage in various solid tumors and enhance the possibility of drug repurposing in cancer therapy.

PMID:39647393 | DOI:10.1016/j.bioorg.2024.108017

Respir Investig. 2024 Dec 7;63(1):81-85. doi: 10.1016/j.resinv.2024.11.018. Online ahead of print.

ABSTRACT

BACKGROUND: Surgical lung biopsy (SLB) is recommended for diagnosing idiopathic pulmonary fibrosis in patients with interstitial lung disease (ILD). The safety of SLB is controversial, as the reported mortality and mobility vary according to the patient's background. This study aimed to assess SLB safety using eligibility criteria that excluded patients at the risk of postoperative complications, including acute exacerbations.

METHODS: We retrospectively reviewed 94 patients with ILD who underwent SLB at our institution between 2010 and 2021. Two peripheral lung locations were resected using 3-port video-assisted thoracoscopic surgery. Complications within 30 and 90 days after surgery were evaluated based on the Clavien-Dindo classification. Preoperative high-resolution computed tomography findings were evaluated according to the guidelines of the American Thoracic Society, 2018. Patients with a radiological usual interstitial pneumonia (UIP) pattern, preoperative oxygen dependence, or organ failure incompatible with general anesthesia were excluded from the study.

RESULTS: The median age of the patients was 66 years. The median vital capacity percentage was 81.0%. The following radiological patterns were observed: UIP, 0%; probable UIP, 30%; indeterminate UIP, 14%; and alternative diagnoses, 56%. The median operative time was 45 min. The 30- and 90-day mortality rates were both 0%. One patient (1%) developed an acute exacerbation of ILD on postoperative day 66. Other grade ≥ III complications were observed in 4 cases (4%), 3 of which were associated with air leakage. Home oxygen therapy was not initiated.

CONCLUSIONS: By excluding patients with poor SLB indications, our criteria are suggested to be valid for safe SLB.

PMID:39647322 | DOI:10.1016/j.resinv.2024.11.018

Eur Radiol. 2024 Dec 8. doi: 10.1007/s00330-024-11209-1. Online ahead of print.

ABSTRACT

OBJECTIVES: Recent studies suggest the existence of an idiopathic pulmonary arterial hypertension (IPAH) phenotype affecting mostly patients with a smoking history, characterised by low diffusion capacity for carbon monoxide (DLCO) without clinically significant emphysema. This study's objective was to test the hypothesis of a loss of pulmonary capillaries as an underlying mechanism by comparison to other patient groups with and without pulmonary hypertension (PH).

MATERIALS AND METHODS: Between March 2019 and June 2023, patients of four groups were recruited for this observational study: IPAH with preserved (1) and low DLCO (2), combined pulmonary fibrosis and emphysema with PH (3), and emphysema without PH (4). Patients underwent clinical CT and 129Xe MRI including dissolved-phase imaging yielding the ratio of 129Xe in red blood cells and membrane tissues (RBC-M), chemical shift saturation recovery for determining RBC fraction η and diffusion-weighted imaging yielding surface-volume ratio. Kruskal-Wallis tests were used for statistical analysis.

RESULTS: Twenty-nine participants were recruited, of which 22 (age 64 ± 10, 11 male, 5/5/7/5 for the individual groups) could be included in the analysis. RBC-M and η were reduced in IPAH with low versus preserved DLCO and emphysema groups (p ≤ 0.01). CT low-attenuation area percentage was not increased in IPAH with low DLCO compared to any group. 129Xe MRI-derived surface-volume ratio was reduced in IPAH with low versus preserved DLCO (p = 0.04).

CONCLUSION: Results are consistent with a loss of pulmonary capillaries in patients with IPAH and low DLCO along with destruction of alveolar tissue, likely due to early diffuse emphysema.

KEY POINTS: Question A loss of pulmonary capillaries has been suggested in patients with IPAH and low diffusion capacity without clinically significant emphysema on CT. Findings 129Xe uptake in red blood cells and lung surface-volume ratio were reduced in IPAH patients with low compared to preserved diffusion capacity. Clinical relevance This study furthers the understanding of the underlying pathological mechanisms in IPAH with low diffusion capacity, providing evidence that loss of pulmonary capillaries is accompanied by alveolar tissue destruction despite near-normal CT.

PMID:39645621 | DOI:10.1007/s00330-024-11209-1

Exp Lung Res. 2024;50(1):278-289. doi: 10.1080/01902148.2024.2437377. Epub 2024 Dec 7.

ABSTRACT

Purpose/Aim: Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia. Multiple genetic factors, environmental exposures, micro-aspirations secondary to gastroesophageal reflux, age, sex, smoking habit, and infections contribute to its etiology; consequently, its pathogenesis remains unclear. The homeostasis of gut microbiota, including bacteria, archaea, and fungi, can influence the functions of both the intestine and remote organs. There are still many unknowns regarding the effects and mechanisms of gut microbiota dysbiosis on the development of IPF. In this study, we aimed to characterize the gut microbiota of patients with IPF compared with that of healthy controls. Furthermore, we assessed the effects of antifibrotic drugs on gut dysbiosis. Materials and Methods: This study involved 12 patients with IPF receiving antifibrotic drug therapy, 12 patients with IPF not receiving antifibrotic drug therapy, and 8 healthy controls. The clinical parameters of the patients were recorded, and DNA extracted from stool samples was subjected to 16S ribosomal RNA gene sequencing of the V1-V9 hypervariable regions. Results: Campylobacterota species were detected in the patient groups but not in the control group. Staphylococcales and Gemellaceae species were not detected in the IPF groups; however, a significant relationship was observed in the control group. In the IPF groups, Actinobacteria, Bifidobacteriales, Burkholderiales, Bacteroidaceae, Dorea, Fusicatenibacter, and Ruminococcus -gauvreauii abundance was low and Enterobacterales, Erysipelotrichaceae, Holdemanella, and Alloprevotella abundance was high compared with those in the control group. When the IPF group using antifibrotic drugs and that not using antifibrotic drugs were compared, only Lachnospiraceae UCG 004 abundance was found to be lower in the patient group receiving antifibrotic drugs. Conclusions: Patients with IPF exhibit higher or lower abundance of certain taxa compared to healthy controls, providing novel perspectives on the pathogenesis and treatment of various illnesses. Examining changes in intestinal microbiota during treatment may guide the clinical strategy for managing adverse effects.

PMID:39644491 | DOI:10.1080/01902148.2024.2437377

Int Immunopharmacol. 2024 Dec 5;145:113688. doi: 10.1016/j.intimp.2024.113688. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a prevalent chronic lung condition of unknown etiology characterized by fibrosis and inflammation. Lung scarring progresses owing to cytokines and immune cells that promote inflammation and fibrosis in idiopathic pulmonary fibrosis (IPF). The anti-inflammatory and anti-fibrotic properties of the ethyl acetate extract of Clerodendrum phlomidis (CPEA), derived from the Indian plant "agnimantha," are recognized in traditional Ayurvedic medicine. This study investigated the potential protective mechanisms of Clerodendrum phlomidis (CPEA), which have not been previously examined, and demonstrated how CPEA affects bleomycin (BLM)-induced lung fibrosis. Phytometabolomic analysis of Clerodendrum phlomidis was performed using UPLC-ESI-Q/TOF-MS. Free radical scavenging assays were also used to evaluate the antioxidant capacity of the plants using ABTS, DPPH, FRAP, and NO assays. Using ELISA and Griess reagent assays, we assessed the anti-inflammatory effects of CPEA in LPS-induced Jurkat, THP-1, and LL-29 cell lines. This study compared intratracheal injection of BLM-induced IPF in Wistar rats with oral administration of CPEA extract for its anti-fibrotic and anti-inflammatory properties. Multiple techniques were employed, including enzyme-linked immunosorbent assay (ELISA), hydroxyproline, histopathological, biochemical, antioxidant enzyme profiling, and hematological analyses. Polyphenolic compounds were identified using qualitative CPEA. Plant extracts demonstrated free radical-scavenging activity in vitro and exhibited antioxidant properties. CPEA extract reduced TNF-α, IL-1β, and NO levels in LPS-stimulated Jurkat, THP-1, and LL-29 cells. In response to BLM-induced lung and serum conditions in Wistar rats, the CPEA extract significantly reduced (p < 0.05) markers of inflammation and fibrosis (ALP, LDH, TNF-α, CXCL8-MIP2, MMP7, SP-A, SP-D, NO, TBARS, and MPO) and significantly restored antioxidant enzymes (p < 0.05) (GSH, GPx, and GST) and anti-inflammatory cytokines (IL10). Oral CPEA extract attenuates fibrosis, inflammation, oxidative stress, nitrosative stress, and lipid peroxidation in BLM-induced idiopathic pulmonary fibrosis (IPF). CPEA extract improved lung function and increased survival rates. Clinical trials are necessary, as this study indicated that the dietary flavonoid-rich component of CPEA extracts possesses anti-inflammatory and antioxidant properties. CPEA extract restored antioxidant enzyme levels and exerted anti-fibrotic and anti-inflammatory effects in rats with idiopathic lung fibrosis induced by BLM. CPEAs protect against lipopolysaccharide (LPS)-induced inflammation in vitro and bleomycin-induced idiopathic pulmonary fibrosis (IPF) in vivo. The findings of our investigation indicate that CPEA demonstrates therapeutic potential for IPF in human subjects, as evidenced by its capacity to enhance antioxidant, anti-inflammatory, and anti-fibrotic markers in preclinical disease models.

PMID:39642567 | DOI:10.1016/j.intimp.2024.113688

Am J Respir Cell Mol Biol. 2024 Dec 6. doi: 10.1165/rcmb.2024-0372TR. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) and lung fibrosis secondary to infections such as influenza A and COVID-19 have limited treatment options outside of supportive therapy and lung transplantation. Multiple lung stem cell populations have been implicated in the pathogenesis of lung fibrosis, and more progenitor cell populations continue to be discovered and characterized. In this review, we summarize the functions and differentiation pathways of various cells that comprise the lung epithelium. We then focus on two subpopulations of KRT5+ or KRT8+ transitional cells that both originate from alveolar type II cells but experience different cell fates and play important roles in lung regeneration and repair. We address these transitional cells' potential role in fibrosis and bronchiolization of the alveoli, as they are correlated to aggregate near fibrotic foci in both in vivo models and in human fibrotic lung disease. We conclude by discussing recent advances in cell and organoid therapy to replace aberrant transitional cells and treat lung fibrosis. Namely, we focus on strategies to minimize immune clearance of transplanted cells and to optimize engraftment by transplanting cells pre-cultured as 3D organoids.

PMID:39642382 | DOI:10.1165/rcmb.2024-0372TR

Am J Respir Cell Mol Biol. 2024 Dec 6. doi: 10.1165/rcmb.2024-0255OC. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is characterized by the sustained activation of interstitial fibroblasts leading to excessive collagen deposition and progressive organ failure. Epigenetic and metabolic abnormalities have been shown to contribute to the persistent activated state of scar-forming fibroblasts. However, how epigenetic changes regulate fibroblast metabolic responses to promote fibroblast activation and progressive fibrosis remains largely unknown. Here we show that the epigenetic regulator chromobox protein homolog 5 (CBX5) is critical to the transition of quiescent fibroblasts to activated collagen-producing fibroblasts in response to bleomycin induced lung injury. Loss of mesenchymal CBX5 attenuated fibrosis development, and this effect was accompanied by the downregulation of pathogenic fibroblast genes, including Cthrc1, Col1a1, and Spp1, and by the upregulation of metabolic genes with anti-fibrotic activity such as Ppara and Pparg. scRNA-seq and immunohistochemistry analyses revealed that CBX5 expression was enriched in pathogenic fibroblasts and fibroblastic foci of IPF lungs. Bulk RNA-seq analysis combined with metabolic assessments demonstrated that CBX5 silencing in IPF fibroblasts potently inhibited TGFβ-stimulated glycolysis while enhancing AMPK signaling and mitochondrial metabolism. Finally, interruption of the CBX5 pathway in IPF fibroblasts in vitro and in IPF lung explants ex vivo synergistically potentiated metformin-induced AMPK activation and inhibited collagen secretion. Collectively, our findings identify CBX5 as an epigenetic regulator linking metabolic maladaptation to the persistent activated state of lung fibroblasts during IPF progression.

PMID:39642371 | DOI:10.1165/rcmb.2024-0255OC

Am J Respir Crit Care Med. 2024 Dec 6. doi: 10.1164/rccm.202410-1975ED. Online ahead of print.

NO ABSTRACT

PMID:39642358 | DOI:10.1164/rccm.202410-1975ED

Biomark Insights. 2024 Dec 4;19:11772719241297171. doi: 10.1177/11772719241297171. eCollection 2024.

ABSTRACT

BACKGROUND: Rheumatoid arthritis (RA) is complicated with interstitial lung disease (ILD). Gastroesophageal reflux disease is prevented by Helicobacter pylori infection and is a predisposing factor for idiopathic pulmonary fibrosis. However, the prevalence of H. pylori infection in RA patients with ILD has not been sufficiently investigated.

OBJECTIVE: In this study, we analyzed anti-H. pylori antibodies in RA patients with ILD.

DESIGN: Case-control observational study.

METHODS: Anti-H. pylori antibodies were analyzed in the sera of RA patients using a commercially available enzyme-linked immunosorbent assay kit.

RESULTS: The positivity of anti-H. pylori antibodies in RA with ILD (n = 30 [18.0%], P = .0227), usual interstitial pneumonia (n = 10 [14.3%], P = .0212), and airway disease (n = 30 [18.0%], P = .0227) was significantly lower than that of RA without chronic lung disease (n = 78 [27.5%]). The positivity of anti-H. pylori antibodies was also lower in RA with chronic lung disease (n = 68 [18.2%], P = .0059). Multiple logistic regression analyses showed that the presence of anti-H. pylori antibodies was independently and protectively associated with chronic lung disease in RA.

CONCLUSION: The seroprevalence of H. pylori was lower in RA with ILD. H. pylori infection prevented ILD in patients with RA by protecting them from gastroesophageal reflux disease.

PMID:39640205 | PMC:PMC11618895 | DOI:10.1177/11772719241297171

Cell Commun Signal. 2024 Dec 5;22(1):586. doi: 10.1186/s12964-024-01966-3.

ABSTRACT

Pyroptosis, an inflammatory regulated cell death (RCD) mechanism, is characterized by cellular swelling, membrane rupture, and subsequent discharge of cellular contents, exerting robust proinflammatory effects. Recent studies have significantly advanced our understanding of pyroptosis, revealing that it can be triggered through inflammasome- and caspase-independent pathways, and interacts intricately with other RCD pathways (e.g., pyroptosis, necroptosis, ferroptosis, and cuproptosis). The pathogenesis of pulmonary fibrosis (PF), including idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases, involves a multifaceted interplay of factors such as pathogen infections, environmental pollutants, genetic variations, and immune dysfunction. This chronic and progressive interstitial lung disease is characterized by persistent inflammation, extracellular matrix (ECM) accumulation, and fibrotic alveolar wall thickening, which potentially contribute to deteriorated lung function. Despite recent advances in understanding pyroptosis, the mechanisms by which it regulates PF are not entirely elucidated, and effective strategies to improve clinical outcomes remain unclear. This review strives to deliver a comprehensive overview of the biological functions and molecular mechanisms of pyroptosis, exploring its roles in the pathogenesis of PF. Furthermore, it examines potential biomarkers and therapeutic agents for anti-fibrotic treatments.

PMID:39639365 | DOI:10.1186/s12964-024-01966-3

Nat Commun. 2024 Dec 5;15(1):10624. doi: 10.1038/s41467-024-54997-2.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive respiratory scarring disease arising from the maladaptive differentiation of lung stem cells into bronchial epithelial cells rather than into alveolar type 1 (AT1) cells, which are responsible for gas exchange. Here, we report that healthy lungs maintain their stem cells through tonic Hippo and β-catenin signaling, which promote Yap/Taz degradation and allow for low-level expression of the Wnt target gene Myc. Inactivation of upstream activators of the Hippo pathway in lung stem cells inhibits this tonic β-catenin signaling and Myc expression and promotes their Taz-mediated differentiation into AT1 cells. Vice versa, increased Myc in collaboration with Yap promotes the differentiation of lung stem cells along the basal and myoepithelial-like lineages allowing them to invade and bronchiolize the lung parenchyma in a process reminiscent of submucosal gland development. Our findings indicate that stem cells exhibiting the highest Myc levels become supercompetitors that drive remodeling, whereas loser cells with lower Myc levels terminally differentiate into AT1 cells.

PMID:39639058 | DOI:10.1038/s41467-024-54997-2

Am J Respir Crit Care Med. 2024 Dec 5. doi: 10.1164/rccm.202311-2021OC. Online ahead of print.

ABSTRACT

RATIONALE: Idiopathic Pulmonary Fibrosis (IPF) is a lethal disease with limited therapeutic options. FGF21, an endocrine fibroblast growth factor that acts through the FGFR1/KLB pathway, mitigates liver fibrosis.

OBJECTIVES: We hypothesized that FGF21 could exert anti-fibrotic properties in the lung.

METHODS: The concentrations of FGF21 and KLB in the plasma of IPF patients and control subjects were assessed. Pulmonary fibrosis development was assessed in Fgf21-deficient mice as compared to Wild Type littermates, at Day 14 after intra-tracheal injection of bleomycin. We determined the effect of repeated subcutaneous injections of a PEGylated FGF21 analog (PEG-FGF21) at D7, 10, 14 and 17 after bleomycin on the development of pulmonary fibrosis. Mice were sacrificed at D21. The effects of FGF21, alone or with KLB, on apoptosis in MLE15 cells and on the phenotype of human lung fibroblasts were assessed in vitro.

RESULTS: In the plasma of IPF patients, FGF21 concentration was increased, while KLB levels were decreased. Fgf21 deficient mice presented an increased sensitivity to bleomycin, in comparison to their Wild Type littermate. Treatment with PEGylated FGF21 mitigated lung fibrogenesis, as evidenced by a lower injury score, decreased fibrosis markers and pro-fibrotic mediators expression as compared to the control group receiving the diluent. In MLE15 cells, stimulation with FGF21 and KLB inhibited apoptosis, through the decrease of BAX and BIM. Fibroblastic phenotype remained unaltered.

CONCLUSION: Our data indicate a possible anti-fibrotic effect of FGF21 in the lung achieved through the inhibition of alveolar type 2 cells apoptosis.

PMID:39637324 | DOI:10.1164/rccm.202311-2021OC

Proc Natl Acad Sci U S A. 2024 Dec 10;121(50):e2401899121. doi: 10.1073/pnas.2401899121. Epub 2024 Dec 5.

ABSTRACT

Fibrosis drives end-organ damage in many diseases. However, clinical trials targeting individual upstream activators of fibroblasts, such as TGFβ, have largely failed. Here, we target the leukemia inhibitory factor receptor (LIFR) as an "autocrine master amplifier" of multiple upstream activators of lung fibroblasts. In idiopathic pulmonary fibrosis (IPF), the most common fibrotic lung disease, we found that lung myofibroblasts had high LIF expression, and the fibroblasts in fibroblastic foci coexpressed LIF and LIFR. In IPF, fibroblastic foci are the "leading edge" of fibrosis and a key site of disease pathogenesis. TGFβ1, one of the principal drivers of fibrosis, up-regulated LIF expression in IPF fibroblasts. We found that TGFβ1, IL-4, and IL-13 stimulations of fibroblasts require the LIF-LIFR axis to evoke a strong fibrogenic effector response in fibroblasts. In vitro antibody blockade of LIFR on IPF lung fibroblasts reduced the induction of profibrotic genes after TGFβ1 stimulation. Silencing LIF and LIFR reduced profibrotic fibroblast activation following TGFβ1, IL-4, and IL-13 stimulations. We also demonstrated that LIFR amplified profibrotic stimuli in precision-cut lung slices from IPF patients. These LIFR signals were transduced via JAK2, and STAT1 in IPF lung fibroblasts. Together, we find that LIFR drives an autocrine circuit that amplifies and sustains pathogenic activation of IPF fibroblasts. Targeting a single, downstream master amplifier on fibroblasts, like LIFR, is an alternative therapeutic strategy that simultaneously attenuates the profibrotic effects of multiple upstream stimuli.

PMID:39636853 | DOI:10.1073/pnas.2401899121

J Cell Mol Med. 2024 Dec;28(23):e70252. doi: 10.1111/jcmm.70252.

ABSTRACT

Acute Interstitial Pneumonia (AIP) represents a severe form of diffuse lung injury within the idiopathic interstitial pneumonia spectrum. Given the limited understanding of its molecular basis, this study aims to elucidate AIP's genomic and transcriptomic profiles to uncover its pathophysiological underpinnings and identify potential therapeutic targets. We conducted a comprehensive analysis of genomic and transcriptomic data from lung tissues of 15 AIP patients. This included assessing differentially expressed genes (DEGs) and identifying mutations in exonic coding variants, as well as analysing expression quantitative trait loci (eQTL) profiles to link non-coding SNP genotypes with gene expression levels. Transcriptomic analysis revealed a significant upregulation of genes linked to the Type I interferon receptor and keratin filament, and a downregulation of genes related to focal adhesion and endothelial integrity, compared to healthy individuals. These patterns were distinct from those observed in idiopathic pulmonary fibrosis (IPF) and non-IPF interstitial lung diseases (ILDs). Genomic analysis highlighted mutations in genes associated with keratin and the extracellular matrix. Additionally, eQTL profiling provided insights into the genetic regulation of gene expression in AIP. Our findings reveals AIP's unique molecular landscape, differentiating it from other ILDs and laying the groundwork for future diagnostic and therapeutic research.

PMID:39636205 | DOI:10.1111/jcmm.70252

Cureus. 2024 Nov 4;16(11):e73008. doi: 10.7759/cureus.73008. eCollection 2024 Nov.

ABSTRACT

Background and objective Fibrotic Hypersensitivity Pneumonitis (FHP) and idiopathic pulmonary fibrosis (IPF) are interstitial lung diseases (ILDs) that are challenging to differentiate with prognostic and therapeutic implications. Clinical observations suggest that patients with FHP may have a lower baseline ratio of forced vital capacity (FVC) to the diffusing capacity of the lung for carbon monoxide (DLCO), or FVC/DLCO (F/D) ratio, than patients with IPF. In light of this, we aimed to determine whether patients with FHP have a significantly lower baseline F/D ratio than patients with IPF. Methods A retrospective chart review was performed at a single academic ILD center. Patients with a probable or definite diagnosis of FHP or IPF were considered for inclusion, while patients with poor-quality pulmonary function tests (PFTs) were excluded. The data collected included demographics, diagnosis modality, FVC and DLCO values within six months of diagnosis, as well as hemoglobin levels within three months of PFTs. Baseline F/D ratios were calculated using each patient's FVC percentage of predicted value divided by the DLCO percentage of predicted value adjusted for hemoglobin when available. One-tailed independent two-sample T-tests were performed. Results Eighty-nine patients met the inclusion criteria: 39 (44%) with FHP and 50 (56%) with IPF. The mean baseline F/D ratio was significantly lower for patients with FHP (M = 1.24, 95% CI: 1.14, 1.33) than for patients with IPF (M = 1.44, 95% CI: 1.31, 1.57, T(87) = 2.23, p = 0.014). A secondary analysis excluding patients with pulmonary hypertension and resting hypoxemia was performed, yielding 72 patients: 32 (44%) with FHP and 40 (56%) with IPF. The mean baseline F/D ratio was significantly lower for patients with FHP (M = 1.22, 95% CI: 1.12, 1.31) compared to patients with IPF (M = 1.37, 95% CI: 1.27, 1.46, T (70) = 2.37, p = 0.01). Conclusions In patients with probable to definite FHP versus IPF, the baseline F/D ratio was significantly lower in patients with FHP, even after excluding patients with coexisting pulmonary hypertension and resting hypoxemia. A lower baseline F/D ratio may be a novel, clinic-ready index to heighten clinical suspicion for FHP compared to IPF. Further larger prospective studies are needed to validate our findings.

PMID:39634966 | PMC:PMC11617056 | DOI:10.7759/cureus.73008

Respir Res. 2024 Dec 4;25(1):426. doi: 10.1186/s12931-024-03041-4.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a high-mortality lung disease with unclear pathogenesis. Convincing evidence suggests that an imbalance in mitochondrial homeostasis resulting from repeated injury to alveolar epithelial type 2 cells (AEC2) underlies IPF. Non-receptor protein tyrosine phosphatase 21 (PTPN21) performs various functions in cancer; however, its role in IPF has not been studied. This study aimed to investigate the role of PTPN21 in lung fibrosis. The experimental results showed that loss of PTPN21 exacerbated lung fibrosis by increasing cell numbers in bronchoalveolar lavage fluid, lung hydroxyproline content, and extracellular matrix protein expression of fibronectin and α-smooth muscle actin (α-SMA) in bleomycin-challenged mouse lungs. In A549 cells (AEC2), knockdown of PTPN21 suppressed focal adhesion and migration, reduced mitochondrial fission and increased fusion, increased the level of mitochondrial superoxide, decreased mitochondrial membrane potential and ATP levels. Simultaneously, knockdown of PTPN21 impaired autophagy, and increased intracellular reactive oxygen species levels. Treatment of fibroblasts (MRC-5) and primary human lung fibroblasts (PHLF)) with the supernatant from PTPN21-knockdown A549 cells increased the expression of fibronectin, collagen 1 and α-SMA. Conversely, overexpression of PTPN21 in A549 cells produced opposite effects. However, treatment of MRC-5 and PHLF with the supernatant from PTPN21-overexpressing A549 cells only slightly reduced the expression of fibronectin, collagen 1 in MRC-5 cells, but did not change the expression of α-SMA. In summary, this study revealed that the loss of PTPN21 in epithelial cells disrupted mitochondrial metabolic homeostasis, leading to epithelial cell inactivation and increased the deposition of extracellular matrix proteins in fibroblasts, thereby exacerbating experimental pulmonary fibrosis.

PMID:39633451 | DOI:10.1186/s12931-024-03041-4

J Transl Med. 2024 Dec 4;22(1):1106. doi: 10.1186/s12967-024-05914-0.

NO ABSTRACT

PMID:39633377 | DOI:10.1186/s12967-024-05914-0

BMC Pulm Med. 2024 Dec 4;24(1):602. doi: 10.1186/s12890-024-03430-x.

ABSTRACT

BACKGROUND: The prevalence of invasive pulmonary aspergillosis (IPA) among patients with interstitial lung disease (ILD) is steadily increasing, leading to high mortality. The purpose of this study is to analyze the clinical features and risk factors of IPA in patients with ILD.

METHODS: 353 hospitalized ILD patients admitted in Nanjing Drum Tower Hospital from March 2023 and April 2024 were enrolled. The enrolled patients were divided into the IPA group (proven and probable IPA) and non-IPA group, and the clinical characteristics and prognosis were compared between the two groups.

RESULTS: Among 353 patients with ILD, 58 who suffered from IPA were identified. Among them, 2 (3.4%) episodes of proven IPA and 56 (96.6%) of probable IPA were diagnosed. The median age was 68.4 ± 8.6 years, and 35 patients were men. The forms of ILD included idiopathic pulmonary fibrosis (n = 21), interstitial pneumonia with autoimmune features (n = 13), rheumatoid arthritis related interstitial pneumonia (n = 11) and Sjögren's syndrome (n = 4). The clinical features of IPA in ILD were cough (100.0%), dyspnea (93.1%) and fever (55.2%). Chest CT images showed reticulation (87.9%), traction bronchiectasis (84.5%), GGO (77.6%), honeycombing (69.0%), consolidation (44.8%) and pleural effusion (24.1%). The incidence of honeycombing and consolidation were higher in ILD patients with IPA compared to control group (P < 0.05). The main pathogens were A. fumigatus (50.0%) and A. flavus (29.3%). Following the diagnosis of IPA, all patients were treated with antifungal drugs. The overall survival rate after 90 days was 74.1%. Multivariate conditional Logistic regression analysis showed that lymphopenia (OR = 2.745, 95% CI 1.344-5.607) and honeycombing (OR = 2.915, 95% CI 1.429-5.949) were the risk factors of ILD with IPA (P < 0.05).

CONCLUSION: IPA is one of the major complications of ILD and its prognosis is poor. Lymphopenia and honeycombing increased the risk of IPA in ILD patients.

PMID:39633326 | DOI:10.1186/s12890-024-03430-x