Front Med (Lausanne). 2024 Sep 25;11:1415278. doi: 10.3389/fmed.2024.1415278. eCollection 2024.

ABSTRACT

Pulmonary fibrosis (PF) is a highly complex and challenging disease affecting the respiratory system. Patients with PF usually have an abbreviated survival period and a consequential high mortality rate after the diagnosis is confirmed, posing serious threats to human health. In clinical practice, PF is typically treated by antifibrotic agents, such as Pirfenidone and Nintedanib. However, these agents have been reported to correlate with substantial adverse effects, escalating costs, and insufficient efficacy. Moreover, it remains unclarified about the multifactorial pathology of PF. Therefore, there is an urgent demand for elucidating these underlying mechanisms and identifying safe, efficient, and targeted therapeutic strategies for PF treatment. The crucial role of the transforming growth factor-β (TGF-β) signaling pathway in PF development has been explored in many studies. MicroRNAs (miRNAs), which function as post-transcriptional regulators of gene expression, can significantly affect the development of PF by modulating TGF-β signaling. In turn, TGF-β signaling can regulate the expression and biogenesis of miRNAs, thereby substantially affecting the progression of PF. Hence, the therapeutic strategies that focus on the drug-targeted regulation of miRNAs, either by augmenting down-regulated miRNAs or inhibiting overexpressed miRNAs, may hinder the pathways related to TGF-β signaling. These strategies may contribute to the prevention and suppression of PF progression and may provide novel insights into the treatment of this disease.

PMID:39386739 | PMC:PMC11461268 | DOI:10.3389/fmed.2024.1415278

Front Immunol. 2024 Sep 25;15:1466901. doi: 10.3389/fimmu.2024.1466901. eCollection 2024.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is the most common and severe form of pulmonary fibrosis, characterized by scar formation in the lung interstitium. Transforming growth factor beta (TGF-β) is known as a key mediator in the fibrotic process, acting on fibroblasts and mediating their proliferation and differentiation into myofibroblasts. Although the immune system is not considered responsible for the initiation of IPF, markers of tolerogenic immunity define the pro-fibrotic microenvironment in the lungs. In homeostatic conditions, regulatory T cells (Tregs) constitute the main lymphoid population responsible for maintaining peripheral tolerance. Similar to Tregs, regulatory B cells (Bregs) represent a recently described subset of B lymphocytes with immunosuppressive functions. In the context of IPF, numerous studies have suggested a role for Tregs in enhancing fibrosis, mainly via the secretion of TGF-β. In humans, most studies show increased percentages of Tregs associated with the severity of IPF, although their exact role remains unclear. In mice, the most commonly used model involves triggering acute lung inflammation with bleomycin, leading to a subsequent fibrotic process. Consequently, data are still conflicting, as Tregs may play a protective role during the inflammatory phase and a deleterious role during the fibrotic phase. Bregs have been less studied in the context of IPF, but their role appears to be protective in experimental models of lung fibrosis. This review presents the latest updates on studies exploring the implication of regulatory lymphoid cells in IPF and compares the different approaches to better understand the origins of conflicting findings.

PMID:39386201 | PMC:PMC11461235 | DOI:10.3389/fimmu.2024.1466901

Respir Res. 2024 Oct 9;25(1):364. doi: 10.1186/s12931-024-02995-9.

ABSTRACT

BACKGROUND: For patients with interstitial lung diseases (ILDs) presenting with a progressive pulmonary fibrosis (PPF) phenotype, current knowledge of disease characteristics at diagnosis, patient journey, and treatment is limited. This study aimed to describe demographics and clinical experiences of patients presenting with PPF in a European real-world setting.

METHODS: Data were analysed from the Adelphi Real World PPF-ILD Disease Specific Programme™, a cross-sectional survey of pulmonologists and rheumatologists in five European countries (France, Germany, Italy, Spain, United Kingdom) and internal medicine specialists (France) from April to October 2022. Physicians provided data for up to 12 consecutive patients with physician-confirmed ILD with a progressive phenotype other than idiopathic pulmonary fibrosis. Analyses were descriptive.

RESULTS: Overall, 265 physicians reported on 1,335 patients. Mean (standard deviation) age at survey date was 60.4 (11.6) years, 91.2% were white, 58.1% female, 44.0% non-smokers. Most patients (63.3%) first consulted a primary care physician. There was a mean delay of 7.8 (22.7) months between first ILD symptom and healthcare professional visit, and another 7.7 (12.8) months to ILD diagnosis. At survey date, 47.7% of patients had physician-reported moderate ILD, 42.3% had mild ILD and 10.0% had severe ILD. Disease progression was reported in the 12 months prior to the survey for 19.5% of patients; of these, progression was based on worsening symptom in 27.3% and lung function decline in 25.8%. For patients experiencing symptoms prior to ILD diagnosis (72.8%), the most common symptoms were dyspnoea on exertion (80.5%) and cough (57.8%). Overall, 17.4% of patients were misdiagnosed prior to ILD diagnosis, with chronic obstructive pulmonary disease suspected in 39.2% of them. The most frequent comorbidities were anxiety (16.9%) and gastroesophageal reflux (15.5%). Although 77.8% of patients were receiving treatment for ILD at survey date, 15.6% of patients had never been prescribed treatment for ILD.

CONCLUSIONS: This real-world study expands our understanding of patients, diagnostic delays and treatment gaps experienced by patients diagnosed with PPF in Europe. There was a mean delay of 15.5 months between first ILD symptoms and ILD diagnosis. Given the progressive nature of PPF, diagnostic delay may lead to poor outcomes, including shorter survival.

TRIAL REGISTRATION: N/a.

PMID:39385232 | PMC:PMC11465623 | DOI:10.1186/s12931-024-02995-9

BMC Pulm Med. 2024 Oct 9;24(1):499. doi: 10.1186/s12890-024-03317-x.

ABSTRACT

BACKGROUND: Lung transplantation (LTx) remains the only efficient treatment for selected patients with end-stage pulmonary disease. The age limit for the acceptance of donor organs in LTx is still a matter of debate. We here analyze the impact of donor organ age and the underlying pulmonary disease on short- and long-term outcome and survival after LTx.

METHODS: Donor and recipient characteristics of LTx recipients at our institution between 03/2003 and 12/2021 were analyzed. Statistical analysis was performed using SPSS and GraphPad software.

RESULTS: In 230 patients analyzed, donor age ≥ 55 years was associated with a higher incidence of severe primary graft dysfunction (PGD2/3) (46% vs. 31%, p = 0.03) and reduced long-term survival after LTx (1-, 5- and 10-year survival: 75%, 54%, 37% vs. 84%, 76%, 69%, p = 0.006). Notably, this was only significant in recipients with idiopathic pulmonary fibrosis (IPF) (PGD: 65%, vs. 37%, p = 0.016; 1-, 5-, and 10-year survival: 62%, 38%, 16% vs. 80%, 76%, 70%, p = 0.0002 respectively). In patients with chronic obstructive pulmonary disease (COPD), donor age had no impact on the incidence of PGD2/3 or survival (21% vs. 27%, p = 0.60 and 68% vs. 72%; p = 0.90 respectively). Moreover, we found higher Torque-teno virus (TTV)-DNA levels after LTx in patients with IPF compared to COPD (X2 = 4.57, p = 0.033). Donor age ≥ 55 is an independent risk factor for reduced survival in the whole cohort and patients with IPF specifically.

CONCLUSIONS: In recipients with IPF, donor organ age ≥ 55 years was associated with a higher incidence of PGD2/3 and reduced survival after LTx. The underlying pulmonary disease may thus be a relevant factor for postoperative graft function and survival.

TRIAL REGISTRATION NUMBER DKRS: DRKS00033312.

PMID:39385110 | PMC:PMC11465681 | DOI:10.1186/s12890-024-03317-x

Sci Rep. 2024 Oct 10;14(1):23653. doi: 10.1038/s41598-024-71770-z.

ABSTRACT

The accumulation of monocyte-derived macrophages in the lung tissue during inflammation is important for the pathogenesis of fibrotic lung disease. Deficiencies in chemokine receptors CCR2 and CCR5 and their ligands, which mediate monocyte/macrophage migration, ameliorate bleomycin (BLM)-induced lung fibrosis. Disulfiram (DSF), which is used to treat alcoholism because of its aldehyde dehydrogenase (ALDH)-inhibiting effect, inhibits monocyte/macrophage migration by inhibiting FROUNT, an intracellular regulator of CCR2/CCR5 signalling. Here, we investigated the antifibrotic effect of oral DSF administration in a mouse model of BLM-induced lung fibrosis, focusing on macrophage response and fibrosis progression. The direct inhibitory activity of DSF on monocyte migration was measured using the Boyden chamber assay and compared with that of DSF-related inhibitors with different FROUNT-inhibition activities. Quantitative PCR was used to determine the expression of fibrosis-promoting genes in the lung tissue. DSF significantly suppressed macrophage infiltration into lung tissues and attenuated BLM-induced lung fibrosis. DSF and its metabolites, diethyldithiocarbamate (DDC) and copper diethyldithiocarbamate (Cu(DDC)2), inhibited monocyte migration toward the culture supernatant of primary mouse lung cells mainly comprising CCL2, whereas cyanamide, another ALDH inhibitor, did not. DSF, with higher inhibitory activity against FROUNT than DDC and Cu(DDC)2, inhibited monocyte migration most strongly. In BLM-induced fibrotic lung tissues, profibrotic factors were highly expressed but were reduced by DSF treatment. These results suggest DSF inhibits macrophage infiltration, which might be attributed to its inhibitory effect on FROUNT, and attenuates BLM-induced lung fibrosis. In addition, multiplex immunofluorescence imaging revealed reduced infiltration of S100A4+ macrophages into the lungs in DSF-treated mice and high expression of FROUNT in S100A4+ macrophages in idiopathic pulmonary fibrosis (IPF). These findings underscore the potential of macrophage-targeted therapy with DSF as a promising drug repositioning approach for treating fibrotic lung diseases, including IPF.

PMID:39384840 | PMC:PMC11464646 | DOI:10.1038/s41598-024-71770-z

NPJ Prim Care Respir Med. 2024 Oct 9;34(1):27. doi: 10.1038/s41533-024-00387-6.

ABSTRACT

The benefits of pulmonary rehabilitation (PR) and palliative care (PC) as non-pharmacological therapies for people with idiopathic pulmonary fibrosis (IPF) are increasingly being recognised but in the UK the proportion of people with this life-limiting condition who are referred to such services is thought to be low. This retrospective cohort study aimed to describe trends in referrals to PR and PC services among people with IPF over a 10-year period and to identify factors associated with non-referral. Our study cohort was drawn from the UK's pseudonymised Clinical Practice Research Datalink (CPRD) Aurum primary care database and comprised 17,071 individuals diagnosed with IPF between 2010 and 2019. While 12.0% of IPF patients were offered a referral to PR, less than 2% completed a PR programme. Around a fifth (19.4%) received a referral to generic PC support services; however, this is well below reported PC referral rates for lung cancer patients. Moreover, the majority of PC referrals occurred late; among those who died, 31% were referred within a month and 70% within 6 months of death. Referrals to PR and PC had however increased (by around 2-fold and 4-fold, respectively) over the course of the study period. Factors associated with non-referral to PR included female sex, older age and co-diagnosis of dementia; barriers to PC referral included being female or of Asian or Black ethnicity. We also found evidence of regional differences in referrals. These findings confirm that PR and PC service provision for people with IPF across England is suboptimal.

PMID:39384815 | PMC:PMC11464758 | DOI:10.1038/s41533-024-00387-6

Eur Respir Rev. 2024 Oct 9;33(174):230265. doi: 10.1183/16000617.0265-2023. Print 2024 Oct.

ABSTRACT

BACKGROUND: People living with serious respiratory illness experience a high burden of distressing symptoms. Although opioids are prescribed for symptom management, they generate adverse events, and their benefits are unclear.

METHODS: We examined the efficacy and safety of opioids for symptom management in people with serious respiratory illness. Embase, MEDLINE and the Cochrane Central Register of Controlled Trials were searched up to 11 July 2022. Reports of randomised controlled trials administering opioids to treat symptoms in people with serious respiratory illness were included. Key exclusion criteria included <80% of participants having a nonmalignant lung disease. Data were extracted regarding study characteristics, outcomes of breathlessness, cough, health-related quality of life (HRQoL) and adverse events. Treatment effects were pooled using a generic inverse variance model with random effects. Risk of bias was assessed using the Cochrane Risk of Bias tool version 1.

RESULTS: Out of 17 included trials, six were laboratory-based exercise trials (n=70), 10 were home studies measuring breathlessness in daily life (n=788) and one (n=18) was conducted in both settings. Overall certainty of evidence was "very low" to "low". Opioids reduced breathlessness intensity during laboratory exercise testing (standardised mean difference (SMD) -0.37, 95% CI -0.67- -0.07), but not breathlessness measured in daily life (SMD -0.10, 95% CI -0.64-0.44). No effects on HRQoL (SMD -0.42, 95% CI -0.98-0.13) or cough (SMD -1.42, 95% CI -3.99-1.16) were detected. In at-home studies, opioids led to increased frequency of nausea/vomiting (OR 3.32, 95% CI 1.70-6.51), constipation (OR 3.08, 95% CI 1.69-5.61) and drowsiness (OR 1.37, 95% CI 1.01-1.86), with serious adverse events including hospitalisation and death identified.

CONCLUSIONS: Opioids improved exertional breathlessness in laboratory exercise studies, but did not improve breathlessness, cough or HRQoL measured in daily life at home. There were significant adverse events, which may outweigh any benefits.

PMID:39384304 | PMC:PMC11462312 | DOI:10.1183/16000617.0265-2023

Ther Adv Respir Dis. 2024 Jan-Dec;18:17534666241282538. doi: 10.1177/17534666241282538.

ABSTRACT

The review summarizes the applications of CT and AI algorithms for prognostic models in IPF and procedures of model construction. It reveals the current limitations and prospects of AI-aid models, and helps clinicians to recognize the AI algorithms and apply them to more clinical work.

PMID:39382448 | DOI:10.1177/17534666241282538

Microbiol Spectr. 2024 Oct 8:e0053024. doi: 10.1128/spectrum.00530-24. Online ahead of print.

ABSTRACT

Diffuse panbronchiolitis (DPB) is a rare, idiopathic inflammatory disease primarily diagnosed in East Asian populations. DPB is characterized by diffuse pulmonary lesions, inflammation of the respiratory bronchioles, and bacterial infections of the airway. Historically, sputum cultures reveal Pseudomonas aeruginosa in 22% of DPB patients, increasing to 60% after 4 years from disease onset. Although DPB patients have a known susceptibility to respiratory P. aeruginosa infections, as is observed in other chronic lung diseases such as cystic fibrosis (CF), the characterization of DPB P. aeruginosa strains is limited. In this study, we characterized 24 strains obtained from a cohort of DPB patients for traits previously associated with virulence, including growth, motility, antibiotic susceptibility, lipopolysaccharide structure, and genomic diversity. Our cohort of DPB P. aeruginosa strains exhibits considerable genomic variability when compared with isolates from people with cystic fibrosis chronically colonized with P. aeruginosa and acute P. aeruginosa infection isolates. Similar to CF, DPB P. aeruginosa strains produce a diverse array of modified lipid A structures. Antibiotic susceptibility testing revealed increased resistance to erythromycin, a representative agent of the macrolide antibiotics used to manage DPB patients. Differences in the O-antigen type among P. aeruginosa strains collected from these different backgrounds were also observed. Ultimately, the characterization of DPB P. aeruginosa strains highlights several unique qualities of P. aeruginosa strains collected from chronically diseased airways, underscoring the challenges in treating DPB, CF, and other obstructive respiratory disease patients with P. aeruginosa infections.

IMPORTANCE: Diffuse panbronchiolitis (DPB), a chronic lung disease characterized by persistent P. aeruginosa infection, serves as an informative comparator to more common chronic lung diseases, such as cystic fibrosis (CF). This study aimed to better address the interplay between P. aeruginosa and chronically compromised airway environments through the examination of DPB P. aeruginosa strains, as existing literature regarding DPB is limited to case reports, case series, and clinical treatment guidelines. The evaluation of these features in the context of DPB, in tandem with prevailing knowledge of P. aeruginosa strains collected from more common chronic lung diseases (e.g., CF), can aid in the development of more effective strategies to combat respiratory P. aeruginosa infections in patients with chronic lung diseases.

PMID:39377602 | DOI:10.1128/spectrum.00530-24

BMC Pulm Med. 2024 Oct 7;24(1):488. doi: 10.1186/s12890-024-03289-y.

ABSTRACT

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is a fatal disease with scarce therapeutic alternatives, which imposes a significant economic burden on society. The identification of novel drug targets is thus critically essential. Plasma proteins with discernible causal evidence hold promise as viable drug targets for this condition.

METHODS: We performed a proteome-wide Mendelian randomization (MR) analysis to assess the causal effects of 4,907 circulating proteins from the deCODE study on the risk of IPF from the Finngen Database (2,018 cases vs. 373,064 controls). We further replicated the MR analysis in 1426 proteins from the ARIC study and IPF from the UK Biobank (1,369 cases vs. 435,866 controls). Then a series of analyses including Bayesian colocalization, Steiger filtering, and phenotype scanning were conducted to validate the credibility of the MR results. Subsequently, protein-protein interaction (PPI) analysis, pathway enrichment analysis, and druggability assessment were executed to elucidate the underlying mechanisms. Finally, the findings were corroborated using a bleomycin-induced pulmonary fibrosis mouse model.

RESULTS: The MR analysis bolstered by robust evidence of colocalization, indicated a significant positive association between Prothrombin and increased IPF risk (OR = 3.26,95%CI 1.75-6.07). Conversely, Bone Sialoprotein (IBSP) demonstrated an inverse association with IPF susceptibility (OR = 0.27,95%CI 0.14-0.55).

CONCLUSIONS: The integrative analysis suggests that Prothrombin and IBSP are promising candidates as potential drug targets for IPF. Additional clinical investigations are warranted to substantiate these findings.

PMID:39375737 | PMC:PMC11459707 | DOI:10.1186/s12890-024-03289-y

J Transl Med. 2024 Oct 7;22(1):910. doi: 10.1186/s12967-024-05655-0.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and lethal lung disorder for which effective treatments remain limited. Recent investigations revealed a potential link between altered glucose metabolism and the activation of fibroblasts, the key cells responsible for generating and depositing extracellular matrix proteins within the lung interstitium during IPF development.

METHOD: In this study, we aimed to investigate the potential therapeutic impact of albendazole on fibroblast to myofibroblast transition in IPF. We assess albendazole's effectiveness in attenuating the activation of fibroblasts. We focused on elucidating the mechanism underlying albendazole's impact on TGF-β1-induced aerobic glycolysis in both lung tissues and fibroblasts obtained from patients with IPF and other lung fibrosis types. Furthermore, the antifibrotic effects of oral administration of albendazole were investigated in mouse models of pulmonary fibrosis induced by BLM or SiO2. Human precision-cut lung slices were employed to evaluate the impact of albendazole following TGF-β1 stimulation.

RESULT: In this work, we demonstrated that albendazole, a first-line broad-spectrum anthelmintic drug, effectively attenuated fibroblast to myofibroblast transition through alleviating TGF-β1-induced aerobic glycolysis dependent on the LRRN3/PFKFB3 signaling pathway. Additionally, LRRN3 expression was downregulated in both lung tissues and fibroblasts from patients with IPF and other types of lung fibrosis. Importantly, the levels of LRRN3 correlated with the progression of the disease. Notably, oral administration of albendazole exerted potent antifibrotic effects in mouse models of pulmonary fibrosis induced by BLM or SiO2, and in human precision-cut lung slices after TGF-β1 stimulation, as evidenced by improvements in lung morphology, reduced myofibroblast formation, and downregulation of α-SMA, collagen type 1 and Fibronectin expression in the lungs.

CONCLUSION: Our study implies that albendazole can act as a potent agonist of LRRN3 during fibroblast to myofibroblast differentiation and its oral administration shows potential as a viable therapeutic approach for managing IPF.

PMID:39375691 | PMC:PMC11459805 | DOI:10.1186/s12967-024-05655-0

World J Clin Cases. 2024 Oct 6;12(28):6247-6249. doi: 10.12998/wjcc.v12.i28.6247.

ABSTRACT

This editorial comments on the study by Lei et al investigating the efficacy of early treatment with pirfenidone on the lung function of patients with idiopathic pulmonary fibrosis (IPF) published. This study evaluates the efficacy of early treatment with pirfenidone on lung function in patients with IPF. The early and advanced stages of IPF are defined, highlighting the drug's benefits. While prior research indicates pirfenidone's effectiveness in advanced IPF, this study focuses on its advantages in early stages. The study emphasizes the importance of computed tomography imaging alongside biochemical data and lung function tests for a comprehensive analysis of symptom relief. Results show that early intervention with pirfenidone significantly reduces disease progression and preserves lung function, underscoring its potential as a critical treatment strategy in early IPF.

PMID:39371563 | PMC:PMC11362896 | DOI:10.12998/wjcc.v12.i28.6247

FASEB J. 2024 Oct 15;38(19):e70077. doi: 10.1096/fj.202302405RR.

ABSTRACT

In idiopathic pulmonary fibrosis (IPF), epithelial abnormalities are present including bronchiolization and alveolar cell dysfunction. We hypothesized that the IPF microenvironment disrupts normal epithelial growth and differentiation. We mimicked the soluble factors within an IPF microenvironment using an IPF cocktail (IPFc), composed of nine factors which are increased in IPF lungs (CCL2, IL-1β, IL-4, IL-8, IL-13, IL-33, TGF-β, TNFα, and TSLP). Using IPFc, we asked whether the soluble factor milieu in IPF affects epithelial growth and differentiation and how IPFc compares to TGF-β alone. Epithelial growth and differentiation were studied using mouse lung organoids (primary Epcam+ epithelial cells co-cultured with CCL206 fibroblasts). Organoids exposed to IPFc and TGF-β were re-sorted into epithelial and fibroblast fractions and subjected to RNA sequencing. IPFc did not affect the number of organoids formed. However, pro-surfactant protein C expression was decreased. On these parameters, TGF-β alone had similar effects. However, RNA sequencing of re-sorted organoids revealed that IPFc and TGF-β had distinct effects on both epithelial cells and fibroblasts. IPFc upregulated goblet cell markers, whereas these were inhibited by TGF-β. Although both IPFc and TGF-β increased extracellular matrix gene expression, only TGF-β increased myofibroblast markers. VEGF-C and Wnt signaling were among the most differentially regulated signaling pathways by IPFc versus TGF-β. Interestingly, Wnt pathway activation rescued Sftpc downregulation induced by IPFc. In conclusion, IPFc alters epithelial differentiation in a way that is distinct from TGF-β. Alterations in Wnt signaling contribute to these effects. IPFc may be a more comprehensive representation of the soluble factor microenvironment in IPF.

PMID:39370849 | DOI:10.1096/fj.202302405RR

Small Methods. 2024 Oct 6:e2400980. doi: 10.1002/smtd.202400980. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by sustained fibrotic lesions. Orally administered drugs usually fail to efficiently penetrate the interstitial tissue and reach the lesions, resulting in low treatment efficiency. Luteolin (Lut) is a natural flavonoid, active metabolites of which possess antioxidant, anti-inflammatory, anti-fibrotic, and anti-apoptotic properties. In this study, a nano-formulation is developed by loading Lut into hyaluronidase nanoparticles (Lut@HAase). These Lut@HAase nanoparticles (NPs) exhibit small size and good stability, suitable for noninvasive inhalation and accumulation in the lungs, and hyaluronidase at the site of lesions can degrade hyaluronic acid in the interstitial tissue, enabling efficient penetration of Lut. Lut's therapeutic effect, when administered via NPs, is studied both in vitro (using MRC5 cells) and in vivo (using IPF mice models), and its anti-fibrotic properties are found to inhibit inflammation and eliminate reactive oxygen species. Conclusively, this study demonstrates that Lut@HAase can improve lung function and enhance survival rates while reducing lung damage with few abnormalities during IPF treatment.

PMID:39370583 | DOI:10.1002/smtd.202400980

JNMA J Nepal Med Assoc. 2024 Jul 31;62(276):511-515. doi: 10.31729/jnma.8706.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis is the most prevalent form of interstitial lung disease, which presents as usual interstitial pneumonia on histopathology and imaging. It leads to significant lung scarring, damage, and fibrosis and is associated with a high degree of mortality, repeated hospital admissions, and oxygen dependence. Many complications are associated with idiopathic pulmonary fibrosis, which further increases the morbidity of patients. High-resolution computed tomography chest is the imaging modality of choice for usual interstitial pneumonia tracking its progression, evaluating treatment response, and detecting potential complications.

METHODS: This descriptive cross-sectional study was approved by the Institutional Ethics Committee (Reference number: IEC-INT/2023/Study-1256). Departmental computed tomography report database from November, 2017 to June, 2018 was reviewed and scans with imaging features consistent with the 'usual interstitial pneumonia' pattern were identified. Total sampling method was used and two independent radiologists, blinded to the patient's clinical information, reviewed the high-resolution computed tomography chest scans to assess for imaging features of usual interstitial pneumonia and associated complications. Data was collected and analyzed using Microsoft Excel.

RESULTS: There were 65 patients reported as unusual interstitial pneumonia pattern. Emphysema and pneumothorax were identified in 4 (6.15%) and 1 (1.53%) scans, respectively. Two (3.08%) scans showed features of pulmonary arterial hypertension. Ten (15.38%) scans exhibited findings consistent with co-existent or superimposed pulmonary infection. Additionally, features of lung malignancy were identified in high-resolution computed tomography scans of 5 (7.69%) patients.

CONCLUSIONS: Patients with UIP often experience severe lung scarring, and frequent complications, and require regular chest CT scans to monitor disease progression and identify potential complications.

PMID:39369401 | PMC:PMC11455644 | DOI:10.31729/jnma.8706

Respir Res. 2024 Oct 5;25(1):359. doi: 10.1186/s12931-024-02970-4.

ABSTRACT

INTRODUCTION: The usual interstitial pneumonia (UIP) pattern, hallmark of idiopathic pulmonary fibrosis (IPF), may induce harmful local overdistension during mechanical ventilation given the juxtaposition of different tissue elasticities. Mechanotransduction, linking mechanical stress and strain to molecular pro-fibrotic pathways, likely contributes to fibrosis progression. Understanding the mechanical forces and aeration patterns in the lungs of IPF patients is crucial for unraveling potential mechanisms of disease progression. Quantitative lung computed tomography (CT) can accurately assess the air content of lung regions, thus informing on zonal distension. This study aims to investigate radiological evidence of lung over aeration in spontaneously breathing UIP patients compared to healthy controls during maximal inspiration.

METHODS: Patients with IPF diagnosis referred to the Center for Rare Lung Diseases of the University Hospital of Modena (Italy) in the period 2020-2023 who underwent High Resolution Computed Tomography (HRCT) scans at residual volume (RV) and total lung capacity (TLC) using standardized protocols were retrospectively considered eligible. Patients with no signs of lung disease at HRCT performed with the same image acquisition protocol nor at pulmonary function test (PFTs) served as controls. Lung segmentation and quantitative analysis were performed using 3D Slicer software. Lung volumes were measured, and specific density thresholds defined over aerated and fibrotic regions. Comparison between over aerated lung at RV and TLC in the two groups and according to lung lobes was sought. Further, the correlation between aerated lung and the extent of fibrosis was assessed and compared at RV and TLC.

RESULTS: IPF patients (N = 20) exhibited higher over aerated lung proportions than controls (N = 15) both at RV and TLC (4.5% vs. 0.7%, p < 0.0001 and 13.8% vs. 7%, p < 0.0001 respectively). Over aeration increased significantly from RV to TLC in both groups, with no intergroup difference (p = 0.67). Sensitivity analysis revealed significant variations in over aerated lung areas among lobes when passing from RV to TLC with no difference within lobes (p = 0.28). Correlation between over aeration and fibrosis extent was moderate at RV (r = 0.62, p < 0.0001) and weak at TLC (r = 0.27, p = 0.01), being the two significantly different at interpolation analysis (p < 0.0001).

CONCLUSIONS: This study provides the first evidence of radiological signs of lung over aeration in patients with UIP-pattern patients when passing from RV to TLC. These findings offer new insights into the complex interplay between mechanical forces, lung structure, and fibrosis and warrant larger and longitudinal investigations.

PMID:39369240 | PMC:PMC11453093 | DOI:10.1186/s12931-024-02970-4

Respir Res. 2024 Oct 5;25(1):362. doi: 10.1186/s12931-024-02989-7.

ABSTRACT

BACKGROUND: The prevalence of non-small cell lung cancer (NSCLC) is notably elevated in individuals diagnosed with idiopathic pulmonary fibrosis (IPF). Secreted phosphoprotein 1 (SPP1), known for its involvement in diverse physiological processes, including oncogenesis and organ fibrosis, has an ambiguous role at the intersection of IPF and NSCLC. Our study sought to elucidate the function of SPP1 within the pathogenesis of IPF and its subsequent impact on NSCLC progression.

METHODS: Four GEO datasets was analyzed for common differential genes and TCGA database was used to analyze the prognosis. The immune infiltration was analyzed by TIMER database. SPP1 expression was examined in human lung tissues, the IPF fibroblasts and the BLM-induced mouse lung fibrosis model. Combined with SPP1 gene gain- and loss-of-function, qRT-PCR, Western blot, EdU and CCK-8 experiments were performed to evaluate the effects and mechanisms of SPP1 in IPF progression. Effect of SPP1 on NSCLC was detected by co-cultured IPF fibroblasts and NSCLC cells.

RESULTS: Through bioinformatics analysis, we observed a significant overexpression of SPP1 in both IPF and NSCLC patient datasets, correlating with enhanced immune infiltration of cancer-associated fibroblasts in NSCLC. Elevated levels of SPP1 were detected in lung tissue samples from IPF patients and bleomycin-induced mouse models, with partial colocalization observed with α-smooth muscle actin. Knockdown of SPP1 inhibits TGF-β1-induced differentiation of fibroblasts to myofibroblasts and the proliferation of IPF fibroblasts. Conversely, SPP1 overexpression promoted IPF fibroblast proliferation via PI3K/Akt/mTOR pathway. Furthermore, IPF fibroblasts promoted NSCLC cell proliferation and activated the PI3K/Akt/mTOR pathway; these effects were attenuated by SPP1 knockdown in IPF fibroblasts.

CONCLUSIONS: Our findings suggest that SPP1 functions as a molecule promoting both fibrosis and tumorigenesis, positioning it as a prospective therapeutic target for managing the co-occurrence of IPF and NSCLC.

PMID:39369217 | PMC:PMC11456247 | DOI:10.1186/s12931-024-02989-7

BMJ Open Respir Res. 2024 Oct 4;11(1):e002538. doi: 10.1136/bmjresp-2024-002538.

ABSTRACT

BACKGROUNDS: The management of lung complications, especially fibrosis, after COVID-19 pneumonia, is an important issue in the COVID-19 post-pandemic era. We aimed to investigate risk factors for pulmonary fibrosis development in patients with severe COVID-19 pneumonia.

METHODS: Clinical and radiological data were prospectively collected from 64 patients who required mechanical ventilation due to COVID-19 pneumonia and were enrolled from eight hospitals in South Korea. Fibrotic changes on chest CT were evaluated by visual assessment, and extent of fibrosis (mixed disease score) was measured using automatic quantification system.

RESULTS: 64 patients were enrolled, and their mean age was 58.2 years (64.1% were males). On chest CT (median interval: 60 days [IQR; 41-78 days] from enrolment), 35 (54.7%) patients showed ≥3 fibrotic lesions. The most frequent fibrotic change was traction bronchiectasis (47 patients, 73.4 %). Median extent of fibrosis measured by automatic quantification was 10.6% (IQR, 3.8-40.7%). In a multivariable Cox proportional hazard model, which included nine variables with a p value of <0.10 in an unadjusted analysis as well as age, sex and Body Mass Index, male sex (HR, 3.01; 95% CI, 1.27 to 7.11) and higher initial Sequential Organ Failure Assessment (SOFA) score (HR, 1.18; 95% CI, 1.02 to 1.37) were independently associated with pulmonary fibrosis (≥3 fibrotic lesions).

CONCLUSION: Our data suggests that male gender and higher SOFA score at intensive care unit admission were associated with pulmonary fibrosis in patients with severe COVID-19 pneumonia requiring mechanical ventilation.

PMID:39366721 | DOI:10.1136/bmjresp-2024-002538

Heliyon. 2024 Sep 20;10(18):e38173. doi: 10.1016/j.heliyon.2024.e38173. eCollection 2024 Sep 30.

ABSTRACT

OBJECTIVE: Jinbei oral liquid (JBOL), which is derived from a traditional hospital preparation, is frequently utilized to treat idiopathic pulmonary fibrosis (IPF) and has shown efficacy in clinical therapy. However, there are now several obstacles facing the mechanism inquiry, including target proteins, active components, and the binding affinity between crucial compounds and target proteins. To gain additional insight into the mechanisms underlying JBOL in anti-IPF, this study used bioinformation technologies, including network pharmacology, molecular docking, and molecular dynamic simulation, with a substantial amount of data based on realistic constituents.

METHODS: Using network pharmacology, we loaded 118 realistic compounds into the SwissTargetPrediction and SwissADME databases and screened the active compounds and target proteins. IPF-related targets were collected from the OMIM, DisGeNET, and GeneCards databases, and the network of IPF-active constituents was built with Cytoscape 3.10.1. The GO and KEGG pathway enrichment analyses were carried out using Metascape, and the protein-protein interaction (PPI) network was constructed to screen the key targets with the STRING database. Finally, the reciprocal affinity between the active molecules and the crucial targets was assessed through the use of molecular docking and molecular dynamics simulation.

RESULTS: A total of 122 targets and 34 tested active compounds were summarized in this investigation. Among these, kaempferol, apigenin, baicalein were present in high degree. PPI networks topological analysis identified eight key target proteins. AGE-RAGE, EGFR, and PI3K-Akt signaling pathways were found to be regulated during the phases of cell senescence, inflammatory response, autophagy, and immunological response in anti-IPF of JBOL. It was verified by molecular docking and molecular dynamics simulation that the combining way and binding energy between active ingredients and selected targets.

CONCLUSIONS: This work forecasts the prospective core ingredients, targets, and signal pathways of JBOL in anti-IPF, which has confirmed the multiple targets and pathways of JBOL in anti-IPF and provided the first comprehensive assessment with bioinformatic approaches. With empirical backing and an innovative approach to the molecular mechanism, JBOL is being considered as a potential new medication.

PMID:39364246 | PMC:PMC11447332 | DOI:10.1016/j.heliyon.2024.e38173

Front Med (Lausanne). 2024 Sep 19;11:1393778. doi: 10.3389/fmed.2024.1393778. eCollection 2024.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a rare, chronic, and progressive interstitial lung disease with an average survival of approximately 3 years. The evolution of IPF is unpredictable, with some patients presenting a relatively stable condition with limited progression over time, whereas others deteriorate rapidly. In addition to IPF, other interstitial lung diseases can lead to pulmonary fibrosis, and up to a third have a progressive phenotype with the same prognosis as IPF. Clinical, biological, and radiological risk factors of progression were identified, but no specific biomarkers of fibrogenesis are currently available. A recent interest in the fibroblast activation protein alpha (FAPα) has emerged. FAPα is a transmembrane serine protease with extracellular activity. It can also be found in a soluble form, also named anti-plasmin cleaving enzyme (APCE). FAPα is specifically expressed by activated fibroblasts, and quinoline-based specific inhibitors (FAPI) were developed, allowing us to visualize its distribution in vivo by imaging techniques. In this review, we discuss the use of FAPα as a useful biomarker for the progression of lung fibrosis, by both its assessment in human fluids and/or its detection by imaging techniques and immunohistochemistry.

PMID:39364020 | PMC:PMC11446883 | DOI:10.3389/fmed.2024.1393778