Am J Respir Crit Care Med. 2024 Jul 30. doi: 10.1164/rccm.202406-1194ED. Online ahead of print.

NO ABSTRACT

PMID:39078173 | DOI:10.1164/rccm.202406-1194ED

Cureus. 2024 Jun 29;16(6):e63467. doi: 10.7759/cureus.63467. eCollection 2024 Jun.

ABSTRACT

A 72-year-old man with idiopathic pulmonary fibrosis (IPF) was on home oxygen therapy at 1 L/min. He fell approximately 3 m onto a concrete surface while painting the roof of his home and was emergently transported to a local hospital due to pain in his lower back and right lower limb. His initial Krebs von den Lungen level decreased with medical treatments but has shown an increasing trend over the past three respiratory outpatient visits. His other medical conditions, including dyslipidemia, lumbar pain, and allergic rhinitis, were treated with several drugs prescribed by a nearby clinic. At the previous hospital, an increased oxygen demand of around 5 L via mask was noted, although other vital signs were stable. A plain whole-body computed tomography (CT) scan revealed pulmonary edema, a fracture of the right femoral neck, and a fracture of the third lumbar vertebral body. During transfer to our hospital for surgery, crossing the Amagi Pass at an elevation of approximately 830 m, the patient's respiratory condition rapidly deteriorated. Upon arrival, the cardiac wall movement was hyperdynamic, and PaO2 was 29 mmHg under supplemental oxygen at 15 L/min, necessitating oral endotracheal intubation and initiation of mechanical ventilation. A chest CT scan showed worsening diffuse ground-glass opacities in both lungs compared to the previous CT scan at the referring hospital. Despite positive pressure ventilation with the mechanical ventilator, the patient's condition did not improve, and he died in the emergency room. Acute respiratory distress syndrome (ARDS) can occur following severe trauma but the onset of ARDS due to moderate trauma is extremely rare. Considering the possibility of an acute exacerbation of IPF prior to the injury, this report discusses the possibility of developing ARDS due to trauma-induced cytokines and lung damage from damage-associated molecular patterns, the possibility of inhaling dust while working on the roof, pneumonia caused by prescribed medication, viral infections, exposure to pollen and/or high altitude while passing through the mountain pass, and hypoxemia-inducing pulmonary edema.

PMID:39077261 | PMC:PMC11285813 | DOI:10.7759/cureus.63467

Res Diagn Interv Imaging. 2022 Oct 29;4:100017. doi: 10.1016/j.redii.2022.100017. eCollection 2022 Dec.

ABSTRACT

OBJECTIVES: To develop an imaging prognostic model for idiopathic pulmonary fibrosis (IPF) patients using hybrid auto-segmentation radiomics analysis, and compare the predictive ability between the radiomics analysis and conventional visual score methods.

METHODS: Data from 72 IPF patients who had undergone CT were analyzed. In the radiomics analysis, quantitative CT analysis was performed using the semi-auto-segmentation method. In the visual method, the extent of radiologic abnormalities was evaluated and the overall percentage of lung involvement was calculated by averaging values for six lung zones. Using a training cohort of 50 cases, we generated a radiomics model and a visual score model. Subsequently, we investigated the predictive ability of these models in a testing cohort of 22 cases.

RESULTS: Three significant prognostic factors such as contrast, Idn, and cluster shade were selected by LASSO Cox regression analysis. In the visual method, multivariate Cox regression analysis revealed that honeycombing and reticulation were significant prognostic factors. Subsequently, a predictive nomogram for prognosis in IPF patients was established using these factors. In the testing cohort, the c-index of the visual and radiomics nomograms were 0.68 and 0.74, respectively. When dividing the cohort into high-risk and low-risk groups using the median nomogram score, significant differences in overall survival (OS) in the visual and radiomics models were observed (P=0.000 and P=0.0003, respectively).

CONCLUSIONS: The prediction model with hybrid radiomics analysis had a better ability to predict OS in IPF patients than that of the visual method.

PMID:39076611 | PMC:PMC11265392 | DOI:10.1016/j.redii.2022.100017

ERJ Open Res. 2024 Jul 29;10(4):00666-2023. doi: 10.1183/23120541.00666-2023. eCollection 2024 Jul.

ABSTRACT

BACKGROUND: The Gender, Age and Physiology (GAP) model is a simple mortality prediction tool in patients with idiopathic pulmonary fibrosis that uses demographic and physiological variables available at initial evaluation. White blood cell variables may have associations with idiopathic pulmonary fibrosis outcomes. We evaluated whether incorporating blood cell counts in modified GAP (cGAP) models would improve outcome prediction in patients with idiopathic pulmonary fibrosis.

PATIENTS AND METHODS: This retrospective analysis included pooled data from phase 3 randomised trials of pirfenidone in idiopathic pulmonary fibrosis (ASCEND, CAPACITY 004, CAPACITY 006). Study outcomes (disease progression, all-cause mortality, all-cause hospitalisation, respiratory-related hospitalisation) were evaluated during the initial 1-year period. Shared frailty models were used to evaluate associations between continuous and categorical baseline white and red blood cell parameters and study outcomes in a bivariate context, and to evaluate the impact of adding continuous monocyte count (cGAP1) or white and red blood cell parameters (cGAP2) to traditional GAP variables in a multivariable context based on C-statistics changes.

RESULTS: Data were pooled from 1247 patients (pirfenidone, n=623; placebo, n=624). Significant associations (bivariate analyses) were idiopathic pulmonary fibrosis progression with neutrophil and eosinophil counts; all-cause mortality with monocyte and neutrophil counts; all-cause hospitalisation with monocyte count, neutrophil count and haemoglobin level; and respiratory-related hospitalisation with monocyte count, neutrophil count and haemoglobin level. In multivariate analyses, C-statistics were highest for the cGAP2 model for each of the outcomes.

CONCLUSION: Modified GAP models incorporating monocyte counts alone or plus other white and red blood cell variables may be useful to improve prediction of outcomes in patients with idiopathic pulmonary fibrosis.

PMID:39076530 | PMC:PMC11284599 | DOI:10.1183/23120541.00666-2023

Respir Med. 2024 Jul 27:107748. doi: 10.1016/j.rmed.2024.107748. Online ahead of print.

ABSTRACT

BACKGROUND: In patients with interstitial lung disease (ILD), exercise-induced desaturation during the six-minute walk test (6MWT), specifically nadir oxygen saturation (nSpO2) of ≤88% is a negative prognostic marker. As the 6MWT is often impractical for ILD patients, the aim of this study is to compare the 1-minute sit-to-stand test (1minSTS) with the 6MWT to detect exercise-induced desaturation.

METHODS: Participants were recruited from a tertiary referral clinic with both tests performed on the same day. Utilising Bland-Altman analysis, the relationship between nSpO2 on 1minSTS and 6MWT was determined. An area under the receiver operating characteristic curve (AUC) determined the ability of nSpO2 on 1minSTS test to predict SpO2 ≤88% on 6MWT.

RESULTS: Fifty participants completed the study (idiopathic pulmonary fibrosis n=24,48%; connective tissue disease associated ILD n=20,40%; other ILD n=6,12%). Mean (SD) FVC%pred was 73±16%, mean DLCO%pred 57±16% and resting SpO2 99±1%. The 1minSTS resulted in less exercise-induced oxygen desaturation, with a median IQR nSpO2 of 95% (89-98) and 93% (85-96) respectively (p<0.001). Moderate agreement was determined between the nSpO2 on both tests, with a mean difference of 3.2% [-14 to +3.0%]. The 1minSTS test accurately identified participants with nSpO2 ≤88% on 6MWT (AUC 0.96). Oxygen desaturation ≤ 94% during the 1minSTS test provided 100% sensitivity and 87% specificity for oxygen desaturation ≤88% at 6MWT.

CONCLUSION: This study demonstrates that exercise-induced oxygen desaturation during the 1minSTS test correlates with oxygen desaturation on 6MWT. The 1minSTS may be a practical screening tool for ILD patients who would benefit from further exercise testing.

PMID:39074595 | DOI:10.1016/j.rmed.2024.107748

Pulm Ther. 2024 Jul 29. doi: 10.1007/s41030-024-00267-x. Online ahead of print.

ABSTRACT

INTRODUCTION: Clinical practice guidelines recommend autoimmune serological testing in patients newly diagnosed with interstitial lung disease of apparently unknown cause who may have idiopathic pulmonary fibrosis (IPF), in order to exclude connective tissue disease (CTD). Autoantibody positivity has been associated with unique patient profiles and prognosis in patients with IPF who otherwise lack a CTD diagnosis.

METHODS: This post-hoc analysis of patients with IPF from the Phase III ASCEND trial (NCT01366209) evaluated the association of antinuclear antibodies (ANA), rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) status with baseline disease characteristics, disease progression [percent predicted forced vital capacity (%FVC), forced vital capacity (FVC) volume and progression-free survival (PFS)], and treatment outcomes with pirfenidone and placebo (%FVC, FVC and PFS).

RESULTS: Of 555 participants, 244/514 (47.5%) were ANA positive (ANA+), 83/514 (16.1%) had high ANA+ (ANA titre ≥ 1:160 or positive nucleolar- or centromere-staining patterns), 60/555 (10.8%) were RF positive (RF+) and/or anti-CCP positive (anti-CCP+) and 270/514 (52.5%) were autoantibody negative (AAb-). Baseline demographics and characteristics were generally comparable between autoantibody subgroups. Although not statistically significant, more placebo-treated participants with ANA+ or high ANA+ had a decline from baseline to Week 52 of ≥ 10% in %FVC or death (48.7% and 55.9%, respectively) or in FVC volume or death (48.7% and 47.1%, respectively) compared with the AAb- group (%FVC or death: 42.0%; FVC volume or death: 42.0%). The RF+ and/or anti-CCP+ group was similar to AAb-. No differences were observed in PFS. A treatment benefit for pirfenidone versus placebo was observed regardless of autoantibody status [PFS: ANA+ HR (95% CI): 0.56 (0.37 to 0.86), P = 0.007; AAb- HR (95% CI): 0.50 (0.32 to 0.78), P = 0.002].

CONCLUSION: IPF disease course did not differ by autoantibody status in ASCEND. Pirfenidone had a treatment benefit regardless of the presence of ANA.

TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01366209.

PMID:39073523 | DOI:10.1007/s41030-024-00267-x

Chem Biodivers. 2024 Jul 29:e202401030. doi: 10.1002/cbdv.202401030. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial disease leading to pulmonary damage and respiratory failure. We aimed to investigate the effect of prickly pear molasses (PPM) on an experimental model of pulmonary fibrosis induced by bleomycin (BLM) in Wistar rat. Animals were divided into 5 groups: the control group (G1), the BLM group (G2) and three groups (G3, G4, G5) receiving a single intra-tracheal injection of BLM (4 mg/kg) and PPM (at 2, 4.5 and10 %) that was introduced into the diet one week before BLM injection and continued for 3 weeks. Our phytochemical results revealed significant polyphenol and flavonoid content. LCMS analysis revealed the presence of Sinapinic acid, t-ferulic acid, t-cinnamic acid, Caffeic acid, gallic acid and vallinic acid among others. Our histological study revealed significant decrease in collagen deposition in the groups of rats treated with 4.5% and 10% molasses compared to BLM group. Oxidative stress in pulmonary tissues was investigated using catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA) assays. Treatment with PPM normalized the disturbance in the level of these oxidative markers in G3,G4, G5 compared to G2. In conclusion, PPM exhibit antifibrotic and antioxidant activities in BLM model of lung fibrosis.

PMID:39073317 | DOI:10.1002/cbdv.202401030

Tissue Barriers. 2024 Jul 29:2386183. doi: 10.1080/21688370.2024.2386183. Online ahead of print.

ABSTRACT

Diabetes Mellitus presents a formidable challenge as one of the most prevalent and complex chronic diseases, exerting significant strain on both patients and the world economy. It is recognized as a common comorbidity among severely ill individuals, often leading to a myriad of micro- and macro-vascular complications. Despite extensive research dissecting the pathophysiology and molecular mechanisms underlying vascular complications of diabetes, relatively little attention has been paid to potential lung-related complications. This review aims to illuminate the impact of diabetes on prevalent respiratory diseases, including chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), tuberculosis (TB), pneumonia infections, and asthma, and compare the vascular complications with other vascular beds. Additionally, we explore the primary mechanistic pathways contributing to these complications, such as the expression modulation of blood-tissue-barrier proteins, resulting in increased paracellular and transcellular permeability, and compromised immune responses rendering diabetes patients more susceptible to infections. The activation of inflammatory pathways leading to cellular injury and hastening the onset of these respiratory complications is also discussed.

PMID:39072526 | DOI:10.1080/21688370.2024.2386183

bioRxiv [Preprint]. 2024 Jul 19:2024.07.17.603936. doi: 10.1101/2024.07.17.603936.

ABSTRACT

Immune-mediated diseases are characterized by aberrant immune responses, posing significant challenges to global health. In both inflammatory and autoimmune diseases, dysregulated immune reactions mediated by tissue-residing immune and non-immune cells precipitate chronic inflammation and tissue damage that is amplified by peripheral immune cell extravasation into the tissue. Chemokine receptors are pivotal in orchestrating immune cell migration, yet deciphering the signaling code across cell types, diseases and tissues remains an open challenge. To delineate disease-specific cell-cell communications involved in immune cell migration, we conducted a meta-analysis of publicly available single-cell RNA sequencing (scRNA-seq) data across diverse immune diseases and tissues. Our comprehensive analysis spanned multiple immune disorders affecting major organs: atopic dermatitis and psoriasis (skin), chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis (lung), ulcerative colitis (colon), IgA nephropathy and lupus nephritis (kidney). By interrogating ligand-receptor (L-R) interactions, alterations in cell proportions, and differential gene expression, we unveiled intricate disease- specific and common immune cell chemoattraction and extravasation patterns. Our findings delineate disease-specific L-R networks and shed light on shared immune responses across tissues and diseases. Insights gleaned from this analysis hold promise for the development of targeted therapeutics aimed at modulating immune cell migration to mitigate inflammation and tissue damage. This nuanced understanding of immune cell dynamics at the single-cell resolution opens avenues for precision medicine in immune disease management.

PMID:39071425 | PMC:PMC11275869 | DOI:10.1101/2024.07.17.603936

Eur J Pharmacol. 2024 Jul 26:176843. doi: 10.1016/j.ejphar.2024.176843. Online ahead of print.

ABSTRACT

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a fatal progressive condition often requiring lung transplantation. Accelerated senescence of type II alveolar epithelial cells (AECII) plays a crucial role in pulmonary fibrosis progression through the secretion of the senescence-associated secretory phenotype (SASP). Low-dose carbon monoxide (CO) possesses anti-inflammatory, anti-oxidative, and anti-aging properties. This study aims to explore the preventive effects of CO-releasing molecule 2 (CORM2) in a bleomycin-induced pulmonary fibrosis model.

METHODS: We established an pulmonary fibrosis model in C57BL/6J mice and evaluated the impact of CORM2 on fibrosis pathology using Masson's trichrome staining, fluorescence staining, and pulmonary function tests. Fibrogenic marker expression and SASP secretion in tissues and AECII cells were analyzed using qRT-PCR, Western blot, and ELISA assays both in vivo and in vitro. Additionally, we investigated DNA damage and cellular senescence through immunofluorescence and SA-β-gal staining.

RESULTS: CORM2 showed a preventive effect on bleomycin-induced lung fibrosis by improving pulmonary function and reducing the expression of fibrosis-related genes, such as TGF-β, α-SMA, Collagen I/III. CORM2 decreased the DNA damage response by inhibiting γ-H2AX, p53, and p21. We identified PAI-1 as a new target gene that was downregulated by CORM2, and which was associated with cellular senescence and fibrosis. CORM2 effectively inhibited cellular senescence and delayed EMT occurrence in AECII cells.

CONCLUSION: Our study highlights the potential of CORM2 in preventing DNA damage-induced cellular senescence in bleomycin-induced pulmonary fibrosis through modulation of the p53/PAI-1 signaling pathway. These findings underscore the promising prospects of CORM2 in targeting cellular senescence and the p53/PAI-1 pathway as a potential preventive strategy for IPF.

PMID:39068977 | DOI:10.1016/j.ejphar.2024.176843

Drug Metab Pharmacokinet. 2024 Jun 10;57:101025. doi: 10.1016/j.dmpk.2024.101025. Online ahead of print.

ABSTRACT

Nintedanib is used to treat idiopathic pulmonary fibrosis, systemic sclerosis, interstitial lung disease, and progressive fibrotic interstitial lung disease. It is primarily cleared via hepatic metabolism, hydrolysis, and glucuronidation. In addition, formation of the iminium ion, a possible reactive metabolite, was predicted based on the chemical structure of nintedanib. To obtain a hint which may help to clarify the cause of nintedanib-induced liver injury, we investigated whether iminium ions were formed in the human liver. To detect unstable iminium ions using liquid chromatography-tandem mass spectrometry (LC-MS/MS), potassium cyanide was added to the reaction mixture as a trapping agent. Human liver and intestinal microsomes were incubated with nintedanib in the presence of NADPH to form two iminium ion metabolites on the piperazine ring. Their formation is strongly inhibited by ketoconazole, a potent cytochrome P450 (CYP) 3A4 inhibitor. Among the recombinant P450s, only CYP3A4 formed cyanide adducts. The role of CYP3A4 was supported by the positive correlation between CYP3A4 protein abundance, as determined by LC-MS-based proteomics, and the formation of cyanide adducts in 25 individual human liver microsomes. In conclusion, we have demonstrated that iminium ion metabolites are formed from nintedanib by CYP3A4 as potential reactive metabolites.

PMID:39068856 | DOI:10.1016/j.dmpk.2024.101025

Clin Exp Med. 2024 Jul 28;24(1):172. doi: 10.1007/s10238-024-01447-4.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a diagnosis of exclusion, requiring that potential etiologies of interstitial lung disease be ruled out. Antinuclear antibody (ANA) testing is commonly performed in individuals with IPF, but the clinical significance of ANA positivity remains uncertain. A retrospective search identified 161 patients diagnosed with IPF between May 2010 and January 2021. Data on ANA titers at the time of diagnosis were available in all cases. Mean age of the patients was 66.4 ± 9.6 years; 70.8% were male. ANA titers were high (≥ 1:160) in 25.4% of the cohort. Baseline characteristics were comparable between those with high and low ANA titers. During follow-up (median 28 months), 93 patients (57%) died. On Cox proportional-hazards analysis with lung transplantation entered as a competing risk and adjusting for potential confounders (age, sex, and baseline forced vital capacity and diffusing lung capacity for carbon monoxide), ANA ≥ 1:160, as a dichotomized variable, was significantly associated with case-specific mortality (HR 2.25, 95% CI 1.14-4.42, P = 0.02) and older age (for each 10-year increment, HR 1.55, 95% CI 1.07-2.25, P = 0.02). High ANA titers appear to be associated with increased mortality in IPF. This finding emphasizes the potential prognostic value of ANA testing. Further studies are needed to validate these findings and explore their implications for patient management.

PMID:39068615 | DOI:10.1007/s10238-024-01447-4

Hum Reprod Update. 2024 Jul 27:dmae023. doi: 10.1093/humupd/dmae023. Online ahead of print.

ABSTRACT

BACKGROUND: Fibrosis is an important pathological feature of endometriotic lesions of all subtypes. Fibrosis is present in and around endometriotic lesions, and a central role in its development is played by myofibroblasts, which are cells derived mainly after epithelial-to-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT). Transforming growth factor-β (TGF-β) has a key role in this myofibroblastic differentiation. Myofibroblasts deposit extracellular matrix (ECM) and have contracting abilities, leading to a stiff micro-environment. These aspects are hypothesized to be involved in the origin of endometriosis-associated pain. Additionally, similarities between endometriosis-related fibrosis and other fibrotic diseases, such as systemic sclerosis or lung fibrosis, indicate that targeting fibrosis could be a potential therapeutic strategy for non-hormonal therapy for endometriosis.

OBJECTIVE AND RATIONALE: This review aims to summarize the current knowledge and to highlight the knowledge gaps about the role of fibrosis in endometriosis. A comprehensive literature overview about the role of fibrosis in endometriosis can improve the efficiency of fibrosis-oriented research in endometriosis.

SEARCH METHODS: A systematic literature search was performed in three biomedical databases using search terms for 'endometriosis', 'fibrosis', 'myofibroblasts', 'collagen', and 'α-smooth muscle actin'. Original studies were included if they reported about fibrosis and endometriosis. Both preclinical in vitro and animal studies, as well as research concerning human subjects were included.

OUTCOMES: Our search yielded 3441 results, of which 142 studies were included in this review. Most studies scored a high to moderate risk of bias according to the bias assessment tools. The studies were divided in three categories: human observational studies, experimental studies with human-derived material, and animal studies. The observational studies showed details about the histologic appearance of fibrosis in endometriosis and the co-occurrence of nerves and immune cells in lesions. The in vitro studies identified several pro-fibrotic pathways in relation to endometriosis. The animal studies mainly assessed the effect of potential therapeutic strategies to halt or regress fibrosis, for example targeting platelets or mast cells.

WIDER IMPLICATIONS: This review shows the central role of fibrosis and its main cellular driver, the myofibroblast, in endometriosis. Platelets and TGF-β have a pivotal role in pro-fibrotic signaling. The presence of nerves and neuropeptides is closely associated with fibrosis in endometriotic lesions, and is likely a cause of endometriosis-associated pain. The process of fibrotic development after EMT and FMT shares characteristics with other fibrotic diseases, so exploring similarities in endometriosis with known processes in diseases like systemic sclerosis, idiopathic pulmonary fibrosis or liver cirrhosis is relevant and a promising direction to explore new treatment strategies. The close relationship with nerves appears rather unique for endometriosis-related fibrosis and is not observed in other fibrotic diseases.

REGISTRATION NUMBER: N/A.

PMID:39067455 | DOI:10.1093/humupd/dmae023

Int Immunopharmacol. 2024 Jul 26;139:112766. doi: 10.1016/j.intimp.2024.112766. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable lung disease characterized by unknown etiology. This study employs robust ranking aggregation to identify consistent differential genes across multiple datasets, aiming to enhance prognostic evaluation and facilitate the development of more effective immunotherapy strategies for IPF. Using the GSE10667, GSE110147, and GSE24206 datasets, the analysis identifies 92 robust differentially expressed genes (DEGs), including SPP1, IGF1, ASPN, and KLHL13, highlighted as potential biomarkers through machine learning and experimental validation. Additionally, significant differences in immune cell types between IPF samples and controls, such as Plasma cells, Macrophages M0, Mast cells resting, T cells CD8, and NK cells resting, inform the construction of diagnostic and survival prediction models, demonstrating good applicability. These findings provide insights into IPF pathophysiology and suggest potential therapeutic targets.

PMID:39067403 | DOI:10.1016/j.intimp.2024.112766

BMC Pulm Med. 2024 Jul 27;24(1):362. doi: 10.1186/s12890-024-03167-7.

ABSTRACT

The lung is a highly mechanical organ as it is exposed to approximately 109 strain cycles, (where strain is the length change of tissue structure per unit initial length), with an approximately 4% amplitude change during quiet tidal breathing or 107 strain cycles at a 25% amplitude during heavy exercises, sighs, and deep inspirations. These mechanical indices have been reported to become aberrant in lung diseases such as acute respiratory distress syndrome (ARDS), pulmonary hypertension, bronchopulmonary dysplasia (BPD), idiopathic pulmonary fibrosis (IPF), and asthma. Through recent innovations, various in vitro systems/bioreactors used to mimic the lung's mechanical strain have been developed. Among these, the Flexcell tension system which is composed of bioreactors that utilize a variety of programs in vitro to apply static and cyclic strain on different cell-types established as 2D monolayer cultures or cell-embedded 3D hydrogel models, has enabled the assessment of the response of different cells such as fibroblasts to the lung's mechanical strain in health and disease. Fibroblasts are the main effector cells responsible for the production of extracellular matrix (ECM) proteins to repair and maintain tissue homeostasis and are implicated in the excessive deposition of matrix proteins that leads to lung fibrosis. In this review, we summarise, studies that have used the Flexcell tension bioreactor to assess effects of the mechanical lung on the structure, function, and phenotype of lung fibroblasts in homeostatic conditions and abnormal environments associated with lung injury and disease. We show that these studies have revealed that different strain conditions regulate fibroblast proliferation, ECM protein production, and inflammation in normal repair and the diseased lung.

PMID:39068387 | DOI:10.1186/s12890-024-03167-7

Pharmaceuticals (Basel). 2024 Jul 11;17(7):930. doi: 10.3390/ph17070930.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a rare and progressive interstitial lung disease characterized by irreversible distortion of lung architecture and subsequent loss of pulmonary function. Pirfenidone is an antifibrotic agent associated with increased progression-free survival and overall survival rates, but it carries multiple side effects. The aim of the study was to examine the efficacy and safety profile of pirfenidone in a real-life context, with a focus on the concomitant use of antithrombotic and/or anticoagulant treatments. The clinical and functional data (forced vital capacity [FVC], forced expiratory volume in 1 s [FEV1], diffusing lung capacity for carbon monoxide [DLCO], and 6 min walking test distance [6MWD]) of all IPF patients treated with pirfenidone and referred to our two centers between 2019 and 2022 were retrospectively analyzed at baseline, 6 and 12 months after the start of treatment. A total of 55 IPF subjects undergoing pirfenidone treatment were included in the analysis (45.5% females, median [IQR] age at disease onset 68.0 [10.0] years, median [IQR] age at baseline 69.0 [10.8] years). Compared to baseline, at 12 months, FVC (86.0% vs. 80.0%; p = 0.023) and DLCO (44.0% vs. 40.0%; p = 0.002) were significantly reduced, while FEV1 (p = 0.304) and 6MWD (p = 0.276) remained stable; no significant change was recorded at 6 months. Most of the reported adverse events were mild or moderate. Gastrointestinal intolerance (9.1%) was the main cause of treatment discontinuation. A total of 5% of patients reported at least one minor bleeding event, although all episodes occurred in those receiving concomitant antithrombotic or anticoagulant. Overall, this real-life experience confirms the efficacy and safety profile of pirfenidone in the case of the concomitant use of antithrombotic and/or anticoagulant drugs.

PMID:39065780 | DOI:10.3390/ph17070930

J Clin Med. 2024 Jul 15;13(14):4127. doi: 10.3390/jcm13144127.

ABSTRACT

N-acetyl-L-cysteine (NAC) was initially introduced as a treatment for mucus reduction and widely used for chronic respiratory conditions associated with mucus overproduction. However, the mechanism of action for NAC extends beyond its mucolytic activity and is complex and multifaceted. Contrary to other mucoactive drugs, NAC has been found to exhibit antioxidant, anti-infective, and anti-inflammatory activity in pre-clinical and clinical reports. These properties have sparked interest in its potential for treating chronic lung diseases, including chronic obstructive pulmonary disease (COPD), bronchiectasis (BE), cystic fibrosis (CF), and idiopathic pulmonary fibrosis (IPF), which are associated with oxidative stress, increased levels of glutathione and inflammation. NAC's anti-inflammatory activity is noteworthy, and it is not solely secondary to its antioxidant capabilities. In ex vivo models of COPD exacerbation, the anti-inflammatory effects have been observed even at very low doses, especially with prolonged treatment. The mechanism involves the inhibition of the activation of NF-kB and neurokinin A production, resulting in a reduction in interleukin-6 production, a cytokine abundantly present in the sputum and breath condensate of patients with COPD and correlates with the number of exacerbations. The unique combination of mucolytic, antioxidant, anti-infective, and anti-inflammatory properties positions NAC as a safe, cost-effective, and efficacious therapy for a plethora of respiratory conditions.

PMID:39064168 | DOI:10.3390/jcm13144127

Life (Basel). 2024 Jul 19;14(7):897. doi: 10.3390/life14070897.

ABSTRACT

Background: Idiopathic pulmonary fibrosis (IPF) has the potential to cause fatal pulmonary toxicity after radiotherapy and can increase the morbidity and mortality of non-small-cell lung cancer (NSCLC) patients. In this context, we aimed to develop imaging complexity biomarkers to predict the incidence of severe pulmonary toxicity in patients with NSCLC who have underlying IPF and are treated with radiotherapy. Methods: We retrospectively reviewed the medical records of 19 patients with NSCLC who had underlying IPF and were treated with radiotherapy at the Korea University Guro Hospital between March 2018 and December 2022. To quantify the morphometric complexity of the lung parenchyma, box-counting fractal dimensions and lacunarity analyses were performed on pre-radiotherapy simulation chest computed tomography scans. Results: Of the 19 patients, the incidence of grade 3 or higher radiation pneumonitis was observed in 8 (42.1%). After adjusting for age, sex, smoking status, histology, and diffusing capacity of the lung for carbon monoxide, eight patients with a lower fractal dimension showed a significantly higher hazard ratio of 7.755 (1.168-51.51) for grade 3 or higher pneumonitis than those with a higher fractal dimension. Patients with lower lacunarity exhibited significantly lower hazards in all models, both with and without adjustments. The lower-than-median lacunarity group also showed significantly lower incidence curves for all models built in this study. Conclusions: We devised a technique for quantifying morphometric complexity in NSCLC patients with IPF on radiotherapy and discovered lacunarity as a potential imaging biomarker for grade 3 or higher pneumonitis.

PMID:39063650 | DOI:10.3390/life14070897

Int J Mol Sci. 2024 Jul 18;25(14):7867. doi: 10.3390/ijms25147867.

ABSTRACT

Currently, the global lifespan has increased, resulting in a higher proportion of the population over 65 years. Changes that occur in the lung during aging increase the risk of developing acute and chronic lung diseases, such as acute respiratory distress syndrome, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and lung cancer. During normal tissue homeostasis, cell proliferation and apoptosis create a dynamic balance that constitutes the physiological cell turnover. In basal conditions, the lungs have a low rate of cell turnover compared to other organs. During aging, changes in the rate of cell turnover in the lung are observed. In this work, we review the literature that evaluates the role of molecules involved in cell proliferation and apoptosis in lung aging and in the development of age-related lung diseases. The list of molecules that regulate cell proliferation, apoptosis, or both processes in lung aging includes TNC, FOXM1, DNA-PKcs, MicroRNAs, BCL-W, BCL-XL, TCF21, p16, NOX4, NRF2, MDM4, RPIA, DHEA, and MMP28. However, despite the studies carried out to date, the complete signaling pathways that regulate cell turnover in lung aging are still unknown. More research is needed to understand the changes that lead to the development of age-related lung diseases.

PMID:39063108 | DOI:10.3390/ijms25147867

Int J Mol Sci. 2024 Jul 15;25(14):7754. doi: 10.3390/ijms25147754.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a long-term condition with an unidentified cause, and currently there are no specific treatment options available. Alveolar epithelial type II cells (AT2) constitute a heterogeneous population crucial for secreting and regenerative functions in the alveolus, essential for maintaining lung homeostasis. However, a comprehensive investigation into their cellular diversity, molecular features, and clinical implications is currently lacking. In this study, we conducted a comprehensive examination of single-cell RNA sequencing data from both normal and fibrotic lung tissues. We analyzed alterations in cellular composition between IPF and normal tissue and investigated differentially expressed genes across each cell population. This analysis revealed the presence of two distinct subpopulations of IPF-related alveolar epithelial type II cells (IR_AT2). Subsequently, three unique gene co-expression modules associated with the IR_AT2 subtype were identified through the use of hdWGCNA. Furthermore, we refined and identified IPF-related AT2-related gene (IARG) signatures using various machine learning algorithms. Our analysis demonstrated a significant association between high IARG scores in IPF patients and shorter survival times (p-value < 0.01). Additionally, we observed a negative correlation between the percent predicted diffusing capacity for lung carbon monoxide (% DLCO) and increased IARG scores (cor = -0.44, p-value < 0.05). The cross-validation findings demonstrated a high level of accuracy (AUC > 0.85, p-value < 0.01) in the prognostication of patients with IPF utilizing the identified IARG signatures. Our study has identified distinct molecular and biological features among AT2 subpopulations, specifically highlighting the unique characteristics of IPF-related AT2 cells. Importantly, our findings underscore the prognostic relevance of specific genes associated with IPF-related AT2 cells, offering valuable insights into the advancement of IPF.

PMID:39062997 | DOI:10.3390/ijms25147754