Pharmaceutics. 2024 Oct 29;16(11):1391. doi: 10.3390/pharmaceutics16111391.

ABSTRACT

Interstitial lung diseases (ILDs) encompass a heterogeneous group of over 200 disorders that require individualized treatment. Antifibrotic agents, such as nintedanib and pirfenidone, have remarkably revolutionized the treatment landscape of patients with idiopathic pulmonary fibrosis (IPF). Moreover, the approval of nintedanib has also expanded the therapeutic options for patients with progressive pulmonary fibrosis other than IPF. However, despite recent advances, current therapeutic strategies based on antifibrotic agents and/or immunomodulation are associated with non-negligible side effects. Therefore, several studies have explored the inhalation route aiming to spread higher local concentrations while limiting systemic toxicity. In this review, we examined the currently available literature about preclinical and clinical studies testing the efficacy and safety of inhalation-based antifibrotics, immunomodulatory agents, antioxidants, mucolytics, bronchodilators, and vasodilator agents in ILDs.

PMID:39598515 | DOI:10.3390/pharmaceutics16111391

Life (Basel). 2024 Nov 19;14(11):1506. doi: 10.3390/life14111506.

ABSTRACT

BACKGROUND: The surgical treatment of concomitant lung cancer in patients with idiopathic pulmonary fibrosis is challenging due to the risk of life-threatening complications such as acute exacerbation development in the perioperative period. Few studies have investigated the role of anti-fibrotic drugs in this setting. The aim of this multicenter retrospective study was to evaluate the incidence of acute exacerbation, according to Collard, after lung resection in patients affected by concomitant idiopathic pulmonary fibrosis and lung cancer who were or were not on antifibrotic treatment. Secondary outcomes included: 30 and 90-day mortality and an estimation of overall and disease-free survival.

MATERIAL AND METHODS: The study population consisted of patients affected by idiopathic pulmonary fibrosis who received curative-intent lung surgery in three Italian academic centers between 2015 and 2022. Patients were divided into two groups based on whether they were on perioperative treatment with anti-fibrotic drugs (chronical or prophylactic use) or not. To define predictors of acute exacerbation, univariate and multivariable exact logistic regression analysis were performed. The Kaplan-Meier method with log-rank test was used to estimate survival.

RESULTS: During the study period, n = 55 patients underwent lung resection for lung cancer, including 29 patients who were treated with antifibrotic agents. Although the sample size was small and few events were studied, the incidence of acute exacerbation was significantly lower among patient on anti-fibrotic therapy (3.4% vs. 23.1%, p = 0.044); in addition, anti-fibrotic treatment was the strong factor preventing acute exacerbation at the multivariable analysis (OR 0.089, p = 0.038). Post-operative 30- and 90-day mortality rates were not significantly lower in the anti-fibrotic treatment group (0% and 0% vs. 7.7% and 11.5%, p = 0.21 and p = 0.099, respectively). Overall and disease-free survival rates were similar.

CONCLUSIONS: Considering the limitations of this retrospective study with a small sample size, anti-fibrotic perioperative treatment was associated with reduced incidence of acute exacerbation. Based on these real-world data, this pathway could be proposed as a prophylactic treatment in patients with concomitant idiopathic pulmonary fibrosis and cancer undergoing lung resection.

PMID:39598304 | DOI:10.3390/life14111506

J Clin Med. 2024 Nov 13;13(22):6823. doi: 10.3390/jcm13226823.

ABSTRACT

Objectives: Hepcidin is a biomarker produced by hepatocytes in chronic disease anemia and is known to increase during chronic inflammation. This study compares the hepcidin levels in idiopathic pulmonary fibrosis (IPF) patients and controls, evaluating its relationship with anemia and systemic inflammation in IPF patients. Methods: This study included 82 IPF patients and 31 controls. Hepcidin levels were compared between the two groups. In the IPF group, the hepcidin and anemia parameters were compared between anemic and non-anemic patients. The significance between the hepcidin and systemic inflammation parameters such as Erythrocyte Sedimentation Rate, CRP (C-reactive protein) levels, ferritin levels, and the Systemic Immune-Inflammation Index (SII) was investigated. Erythrocyte Sedimentation Rate, C-reactive protein (CRP) levels, and ferritin levels were measured using automated analyzers. Hepcidin and erythropoietin (EPO) levels were determined using ELISA kits. Results: A significant difference in hepcidin levels was found between the IPF and control groups (37.13 ± 14.92 vs. 25.77 ± 11.25, p < 0.001). No significant difference in hepcidin levels was found between anemic and non-anemic IPF patients (38.25 ± 16.2 vs. 36.7 ± 14.6, p = 0.719). No significant correlation was found between hepcidin levels and anemia parameters (serum iron, ferritin, vitamin B12, serum transferrin, transferrin saturation, total iron-binding capacity, hemoglobin, folate, and erythropoietin) in IPF patients. Despite significant differences in the systemic inflammation parameters (ferritin and CRP) between patients and controls, no significant correlation was found between their hepcidin and systemic inflammation parameters. Conclusions: Our study demonstrates that the hepcidin levels in IPF patients are elevated independently of anemia and systemic inflammation. We propose that hepcidin could be a potential biomarker to be investigated in IPF patients.

PMID:39597967 | DOI:10.3390/jcm13226823

J Clin Med. 2024 Nov 6;13(22):6657. doi: 10.3390/jcm13226657.

ABSTRACT

Interstitial lung disease (ILD) encompasses a diverse group of parenchymal lung diseases characterized by varying degrees of inflammation and/or fibrosis. Patients with ILD frequently require hospitalization, with many needing intensive care unit (ICU) admission, most often due to respiratory failure. The diagnosis and management of ILD in the ICU present unique challenges. Diagnosis primarily relies on chest CT imaging to identify fibrosis and inflammation. Acute exacerbations, whether in idiopathic pulmonary fibrosis (IPF) or non-IPF ILD, require careful evaluation of potential triggers and differential diagnoses. Bronchoalveolar lavage may provide valuable information, such as the identification of infections, but carries risks of complications. Biopsies, whether transbronchial or surgical, can also be informative but pose significant procedural risks. Corticosteroids are the cornerstone of treatment for acute exacerbations of IPF, with higher doses potentially benefiting non-IPF ILD. Additional immunosuppressive agents may be used in cases with evidence of inflammation. Oxygen supplementation, particularly with high-flow nasal cannula, is often employed to manage severe hypoxemia, while noninvasive ventilation can be useful for worsening hypoxemia and/or hypercapnia. When mechanical ventilation is used, it is recommended to target low tidal volumes to minimize lung injury; high PEEP may be less effective and even associated with increased mortality. Prone positioning can improve oxygenation in severely hypoxemic patients. In addition to ventilatory strategies, careful fluid management and addressing concomitant pulmonary hypertension are essential components of care. Extracorporeal membrane oxygenation is a high-risk intervention reserved for the most severe cases. Lung transplantation may be considered for end-stage ILD patients in the ICU, with outcomes dependent on the urgency of transplantation and the patient's overall condition. Managing ILD in the ICU requires a multidisciplinary approach, and despite recent advances, mortality remains high, emphasizing the need for continued research and individualized treatment strategies.

PMID:39597801 | DOI:10.3390/jcm13226657

Biomedicines. 2024 Nov 10;12(11):2572. doi: 10.3390/biomedicines12112572.

ABSTRACT

Patients with interstitial lung diseases (ILDs) associate a large variety of comorbidities that have a significant impact on their clinical outcomes and survival. Among these comorbidities is neurological impairment. This review highlights what is known about the cognitive function, central nervous system (CNS), depression, and anxiety in patients with specific forms of fibrosing ILDs, such as idiopathic pulmonary fibrosis, sarcoidosis, hypersensitivity pneumonitis, connective tissue diseases, etc. The most common pathogenic mechanisms for neurocognitive dysfunction as well as the screening methods and tools for their identification are also described in this review.

PMID:39595138 | DOI:10.3390/biomedicines12112572

Biomedicines. 2024 Oct 24;12(11):2439. doi: 10.3390/biomedicines12112439.

ABSTRACT

Objective: Antifibrotics can improve the outcome of patients with idiopathic pulmonary fibrosis (IPF) and other fibrosing interstitial lung diseases (F-ILDs), but predictive biomarkers at diagnosis are needed to guide the use of immunomodulating and antifibrotic therapies. Methods: Flow cytometry quantification of lymphocytes and neutrophils in bronchoalveolar lavage (BAL) of 145 IPFs, 561 non-IPF-ILDs (125 F-ILDs), and 112 BAL controls were retrospectively correlated with the incidence of fibrosis and third-quartile overall survival (Q3-OS). Results: The incidence of IPF was directly proportional (9.6%, 22.2%, and 42.6%, p < 0.001) to BAL neutrophil counts (<5%, 5-15%, and >15%), but inversely proportional (34.1%, 18.6%, and 8.8%, p < 0.001) to BAL lymphocyte counts (<7%, 7-20%, and >20%). Elevated neutrophils (>5%) with low lymphocytes (<7%) were associated with an increasingly higher incidence of IPF (10.0-56.3%, p < 0.001) in patients aged 40 to 80, compared to the rest of patients (13.0-17.1%). Lymphocytes >20% compared to lymphocytes <7% strongly protected patients with neutrophils >15% (59.7% vs. 20.7%, p < 0.001) from IPF. In contrast, the incidence of F-ILD was not clearly related to BAL lymphocyte/neutrophil counts. Although, IPF and F-ILD showed a shorter Q3-OS (1.8 ± 0.3 and 4.6 ± 0.8 years; p < 0.001) than non-fibrotic-ILDs (11.1 ± 1.3 years), lymphocyte and neutrophil counts were associated with a longer and shorter Q3-OS of non-fibrotic-ILDs (p < 0.03) and F-ILDs (p < 0.04), respectively, but not with a Q3-OS of IPF patients (p < 0.708). Corticosteroids in patients with fibrosis showed a shorter Q3-OS than other immunomodulators (2.4 ± 0.3 vs. 4.0 ± 1.8 years, p = 0.011). Conclusions: Accurate counting of BAL lymphocytes and neutrophils by flow cytometry in ILD patients at diagnosis could help guide immunomodulatory and antifibrotic therapies.

PMID:39595006 | DOI:10.3390/biomedicines12112439

Respir Res. 2024 Nov 26;25(1):415. doi: 10.1186/s12931-024-03048-x.

ABSTRACT

BACKGROUND: Few data are available on acute exacerbation (AE) in patients with progressive pulmonary fibrosis (PPF) besides idiopathic pulmonary fibrosis (IPF). This study aimed to investigate the AE incidence and outcomes among patients with PPF.

METHODS: Clinical data of patients with PPF (n = 133) were retrospectively collected at a single center. PPF was defined based on the criteria used in the INBUILD trial. AE was defined as a worsening of dyspnea typically within 30 days with new bilateral lung infiltration and no evidence of cardiac failure or fluid overload.

RESULTS: Among patients with PPF, the mean age was 60.6 years old, 57.1% were females, and the most common etiology was connective tissue disease-related ILDs (63%). During the follow-up (median: 38.0 months) after PPF diagnosis, 42 patients (31.6%) experienced AE. The 1-, 3-, and 5-year AE incidences were 12.5%, 30.3%, and 38.0%, respectively. Older age, rheumatoid arthritis associated ILD, fibrotic hypersensitivity pneumonitis, and lower lung diffusing capacity for carbon monoxide were AE risk factors. Patients with AE demonstrated worse survival (median survival: 30 months vs. not reached; p < 0.001) after PPF diagnosis than those without. AE was independently associated with mortality in patients with PPF (hazard ratio [HR], 2.194; 95% confidence interval [CI], 1.285-3.747; p = 0.004) in the multivariable Cox analysis, along with older age, lower lung diffusing capacity for carbon monoxide, and the usual interstitial pneumonia-like pattern on high-resolution computed tomography.

CONCLUSIONS: Our results suggest AE is not uncommon and significantly impacts on survival in patients with PPF.

PMID:39593055 | DOI:10.1186/s12931-024-03048-x

Ann Am Thorac Soc. 2024 Nov 26. doi: 10.1513/AnnalsATS.202401-022OC. Online ahead of print.

ABSTRACT

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a complex and heterogeneous disease. Given this, we reasoned that differences in genetic profiles may be associated with unique clinical and radiologic features. Computational image analysis, sometimes referred to as radiomics, provides objective, quantitative assessments of radiologic features in subjects with pulmonary fibrosis.

OBJECTIVE: To determine if the genetic risk profile of patients with IPF identifies unique computational imaging phenotypes.

METHODS: Participants with IPF were included in this study if they had genotype data and CT scans of the chest available for computational image analysis. Extent of lung fibrosis and likelihood of a usual interstitial pneumonia (UIP) pattern were scored automatically by using two separate, previously validated deep learning techniques for CT analysis. UIP pattern was also classified visually by radiologists according to established criteria.

MEASUREMENTS AND MAIN RESULTS: Among 334 participants with IPF, MUC5B, FAM13A and ZKSCAN1 were independently associated with the deep learning-based UIP score. None of the common variants were associated with fibrosis extent by computational imaging. We did not find an association between MUC5B, FAM13A or ZKSCAN1 and visually assessed UIP pattern.

CONCLUSIONS: Select genetic variants are associated with computer-based classification of UIP on CT among patients with IPF. Analysis of radiologic features using deep learning may enhance our ability to identify important genotype-phenotype associations in fibrotic lung diseases.

PMID:39591102 | DOI:10.1513/AnnalsATS.202401-022OC

Respirol Case Rep. 2024 Nov 25;12(11):e01413. doi: 10.1002/rcr2.1413. eCollection 2024 Nov.

ABSTRACT

This study examines the radiological and clinical evolution of a case involving mixed idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis, utilizing conventional CT imaging and artificial intelligence tool. Through a series of exams and clinical assessments, the patient was followed for over 3 years, highlighting the challenge in differentiating these interstitial pathologies and the importance of a multidisciplinary approach. The radiological progression towards pulmonary fibrosis was correlated with clinical symptoms, emphasizing the significance of early diagnosis and regular follow-up. The combined use of advanced technologies offers a more comprehensive framework in managing complex lung diseases, enhancing the quality of care and understanding of interstitial pathologies.

PMID:39588330 | PMC:PMC11588411 | DOI:10.1002/rcr2.1413

ERJ Open Res. 2024 Nov 25;10(6):00550-2024. doi: 10.1183/23120541.00550-2024. eCollection 2024 Nov.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrosing and progressive interstitial lung disease of unknown aetiology with a pathogenesis still partly unknown. Several microvascular and macrovascular abnormalities have been demonstrated in the pathogenesis of IPF and related pulmonary hypertension (PH), a complication of the disease.

METHODS: We carried out a non-systematic, narrative literature review aimed at describing the role of the vasculature in the natural history of IPF.

RESULTS: The main molecular pathogenetic mechanisms involving vasculature (i.e. endothelial-to-mesenchymal transition, vascular remodelling, endothelial permeability, occult alveolar haemorrhage, vasoconstriction and hypoxia) and the genetic basis of vascular remodelling are described. The prevalence and clinical relevance of associated PH are highlighted with focus on the vasculature as a prognostic marker. The vascular effects of current antifibrotic therapies, the role of pulmonary vasodilators in the treatment of disease, and new pharmacological options with vascular-targeted activity are described.

CONCLUSIONS: The vasculature plays a key role in the natural history of IPF from the early phases of disease until development of PH in a subgroup of patients, a complication related to a worse prognosis. Pulmonary vascular volume has emerged as a novel computed tomography finding and a predictor of mortality, independent of PH. New pharmacological options with concomitant vascular-directed activity might be promising in the treatment of IPF.

PMID:39588083 | PMC:PMC11587140 | DOI:10.1183/23120541.00550-2024

Food Funct. 2024 Nov 26. doi: 10.1039/d4fo01474j. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic age-related lung disease with a high mortality rate. Kaempferol (KMP), an active ingredient in common plants and foods with anti-inflammatory, antioxidant and immunomodulatory properties, has been shown to be effective against fibrotic diseases. However, the molecular mechanisms underlying the treatment of IPF with KMP remain unclear. Therefore, IPF mice were established by intratracheal instillation of bleomycin (BLM) to explore the efficacy and underlying mechanism of KMP in the treatment of IPF. We found that KMP improved the body weight changes of BLM-induced IPF mice, alleviated inflammatory infiltration and collagen deposition, and decreased the expression levels of hydroxyproline, α-SMA, Col3a1, Mmp2, Timp1, Vim, Fn, TNF-α, TGF-β1, IL-6 and IL-8, while up-regulating the expression E-cadherin in lung tissues. The transcriptomic results showed that KMP may exert therapeutic effects against IPF by regulating the PPARG/TNC signaling pathway to reduce extracellular matrix (ECM) deposition. Interestingly, ROC curve analysis suggested that TNC and PPARG had good diagnostic performance for IPF, and TF prediction revealed that PPARG is an important upstream gene regulating TNC, and the IF experiment confirmed the co-localization of TNC and PPARG. Molecular docking showed that KMP bound well to PPARG and TNC, and IF results revealed that KMP significantly reduced the interaction between PPARG and TNC. Furthermore, RT-PCR, WB, IHC and IF experiments confirmed that KMP elevated the expression of PPARG and inhibited the expression of TNC, thus inhibiting the ECM-receptor interaction pathway and ultimately serving as a therapeutic treatment for IPF mice. These findings revealed that KMP reduced inflammatory infiltration and collagen deposition in the lungs of IPF mice and that the PPARG/TNC signaling pathway may be an important mechanism for the treatment of IPF with KMP, which provides a new perspective for the development of therapeutic approaches for IPF.

PMID:39587935 | DOI:10.1039/d4fo01474j

J Transl Med. 2024 Nov 25;22(1):1058. doi: 10.1186/s12967-024-05895-0.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) stands as a significant contributor to global mortality rates. Presently, there exists a dearth of effective anti-fibrotic treatments for this condition. While itraconazole (ITR) has exhibited potential in mitigating pulmonary fibrosis, its oral administration is hampered by unfavorable pharmacokinetics, which elevate the risk of adverse reactions, thus limiting its clinical utility.

METHODS: An inhalable formulation of ITR were engineered which aimed at enhancing its pulmonary dispersion. First, pharmacokinetics were conducted to investigate the blood concentration and tissue residue of ITR after inhalation administration. In addition, bleomycin induced mouse pulmonary fibrosis model was used to compare the therapeutic effects of ITR administered by inhalation and intragastric administration. Finally, single-cell RNA sequencing (scRNAseq) was used to explore the mechanism of ITR inhalation administration.

RESULTS: We found that a large amount of drugs accumulated in the lung tissue for a long time after inhalation administration, thus maximizing the therapeutic effect of drugs. Inhalation of ITR daily at for 21 days significantly attenuated bleomycin-induced lung fibrosis and inflammation in murine models. Additionally, our findings revealed that ITR inhalation diminished the proportion of diseased fibroblasts while promoting reparative fibroblast populations in the murine model. Furthermore, it effectively reversed the proportion of activated phagocytic macrophages. Mechanistically, ITR inhalation exerted its effects by regulating SPP1 and C3 signaling pathway pivotal in the interaction between phagocytic macrophages and diseased fibroblasts.

CONCLUSIONS: These insights into the molecular mechanisms underlying ITR's therapeutic effects on IPF underscore the favorable pharmacokinetic profile conferred by inhalation, thus presenting a promising formulation poised for clinical translation.

PMID:39587675 | DOI:10.1186/s12967-024-05895-0

Pharmacol Ther. 2024 Nov 23:108757. doi: 10.1016/j.pharmthera.2024.108757. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) remains a challenging disease with no drugs available to change the trajectory. It is a condition associated with excessive and highly progressive scarring of the lungs with remodelling and extracellular matrix deposition. It is a highly "destructive" disease of the lungs. The diagnosis of IPF is challenging due to continuous evolution of the disease, which also makes early interventions very difficult. The role of vascular endothelial cells has not been explored in IPF in great detail. We do not know much about their contribution to arterial or vascular remodelling, extracellular matrix changes and contribution to pulmonary hypertension and lung fibrosis in general. Endothelial to mesenchymal transition appears to be central to such changes in IPF. Similarly, for epithelial changes, the process of epithelial to mesenchymal transition seem to be the key both for airway epithelial cells and type-2 pneumocytes. We focus here on endothelial and epithelial cell changes and its contributions to IPF. In this review we revisit the pathology of IPF, mechanistic signalling pathways, clinical definition, update on diagnosis and new advances made in treatment of this disease. We discuss ongoing clinical trials with mode of action. A multidisciplinary collaborative approach is needed to understand this treacherous disease for new therapeutic targets.

PMID:39586361 | DOI:10.1016/j.pharmthera.2024.108757

Adv Respir Med. 2024 Nov 6;92(6):466-471. doi: 10.3390/arm92060042.

ABSTRACT

Background: Depression and anxiety represent significant comorbidities in idiopathic pulmonary fibrosis (IPF) patients, affecting their quality of life. The COVID-19 pandemic has had an uneven impact on global mental health. The Hospital Anxiety and Depression Scale (HADS) constitutes a validated tool to identify anxiety disorders and depression. The aim of this multicentre study was to evaluate the effect of COVID-19 vaccination on depression and anxiety in IPF patients. Methods: Consecutive IPF patients (median 73.5 years) who are regularly followed-up with were included in the study. Demographics, functional, and clinical were recorded. The HADS score was calculated before and one month after vaccination against COVID-19 in all participants. A Wilcoxon signed ranks test was conducted. Results: A total of 180 IPF patients (median 73.5 years) were included in the study. Among them, 145 patients (81%) received antifibrotic treatment. A significant reduction in HADS, both in anxiety and depression scales, was observed one month after vaccination against SARS-COV-2), independent of age, smoking, lung function impairment, and prior history of depression (p < 0.01). Conclusions: A higher Hospital Anxiety and Depression Scale score was detected before vaccination against COVID-19. It seems that vaccination also offered a beneficial effect on depression and anxiety in IPF patients, independent of age, smoking, lung function impairment, and prior history of depression.

PMID:39584853 | DOI:10.3390/arm92060042

Immun Inflamm Dis. 2024 Nov;12(11):e70042. doi: 10.1002/iid3.70042.

ABSTRACT

RATIONALE: Elevated levels of CD11c+ myeloid cells are observed in various pulmonary disorders, including Idiopathic Pulmonary Fibrosis (IPF). Dendritic cells (DCs) and macrophages (MΦ) are critical antigen-presenting cells (APCs) that direct adaptive immunity. However, the role of CD11c+ myeloid cells in lung extracellular matrix (ECM) accumulation and pulmonary fibrosis is poorly understood.

OBJECTIVE: We aimed to investigate the impact of depleting CD11c+ myeloid cells, including DCs and macrophages, during bleomycin-induced pulmonary fibrosis in mice.

METHODS: We used a diphtheria toxin (DTx) receptor (DTR) transgenic mouse model (CD11c-DTR-Tg) to deplete CD11c+ myeloid cells through two methods: Systemic Depletion (SD) via intraperitoneal injection (i.p.) and local depletion (LD) via intranasal instillation (i.n.). We then assessed the effects of CD11c+ cell depletion during bleomycin-induced lung inflammation and fibrosis.

RESULTS: Fourteen days after bleomycin instillation, there was a progressive accumulation of myeloid cells, specifically F4/80-MHCII+CD11c+ DCs and F4/80 + MHCII+CD11c+ MΦ, preceding mortality and pulmonary fibrosis. Systemic depletion of CD11c+ DCs and MΦ via i.p. DTx administration in CD11c-DTR-Tg mice protected against bleomycin-induced mortality and pulmonary fibrosis compared to wild-type (WT) mice. Systemic depletion reduced myeloid cells, airway inflammation (total leukocytes, neutrophils, and CD4+ lymphocytes in bronchoalveolar lavage (BAL), inflammatory and fibrogenic mediators, and fibrosis-related mRNAs (Collagen-1α1 and α-SMA). Increased anti-inflammatory cytokine IL-10 and CXCL9 levels were observed, resulting in lower lung hydroxyproline content and Ashcroft fibrosis score. Conversely, local depletion of CD11c+ cells increased mortality by acute leukocyte influx (predominantly neutrophils, DCs, and MΦ in BAL) correlated to IL-1β, with lung hyper-inflammation and early fibrosis development.

CONCLUSION: Systemic depletion of CD11c+ cells confers protection against inflammation and fibrosis induced by Bleomycin, underscoring the significance of myeloid cells expressing F4/80-MHCII+CD11c+ DCs and F4/80 + MHCII+CD11c+ MΦ orchestrating the inflammatory milieu within the lungs, potentially as a source of cytokines sustaining pulmonary chronic inflammation leading to progressive fibrosis and mortality.

PMID:39582275 | DOI:10.1002/iid3.70042

Cancer Radiother. 2024 Nov 23:S1278-3218(24)00155-0. doi: 10.1016/j.canrad.2024.05.004. Online ahead of print.

ABSTRACT

PURPOSE: Bronchiolitis obliterans with pneumonic organization, or organizing pneumonia (OP), is an inflammatory disorder of the lungs, which can be triggered following pulmonary attacks of infectious or non-infectious origin. The non-infectious origins of OP include various entities including connective tissue diseases, exposure to toxic substances, medications, autoimmune diseases, and thoracic radiotherapy. The objective of this article is to summarize the literature on post-radiotherapy organized pneumonia, its etiologies, its clinical and radiological characteristics, as well as its treatment.

MATERIALS AND METHODS: A systematic review was performed in Medline database using the search engine PubMed. Keywords for the search included cryptogenic organizing pneumonia, bronchiolitis obliterans organizing pneumonia (BOOP), idiopathic organizing pneumonia and radiation, radiotherapy, breast cancer. The selected articles had to study the link between bronchiolitis obliterans with pneumonic organization and radiotherapy.

RESULTS: A total of 96 articles were identified. Of these 96 articles, 49 fulfilled the defined selection criteria. Fourteen epidemiological studies were found in the literature. These epidemiological studies have published incidences of post-radiotherapy organizing pneumonia of less than 2.9% for patients treated for breast cancer. The predictive risk factors for bronchiolitis obliterans with pneumonic organization syndrome were age, smoking and the volume of irradiated lung. In a post-radiation context, bronchiolitis obliterans with pneumonic organization could be diagnosed several months, or even up to a year, after the end of irradiation. Treatment was based on the prescription of long-term corticosteroid therapy. Bronchiolitis obliterans with pneumonic organization should not be confused with post-radiation pulmonary fibrosis, which is inflammatory, dose-dependent, non-immunological, and localized in the irradiation area.

CONCLUSION: Organized pneumonia secondary to radiotherapy is a syndrome affecting approximately 1.4 to 3% of patients treated with radiotherapy for breast cancer. The main risk factors found are age, smoking and the volume of lung irradiated. Post-radiotherapy organized pneumonia needs to be known to all radiotherapists to improve patient care.

PMID:39581827 | DOI:10.1016/j.canrad.2024.05.004

Tissue Cell. 2024 Nov 19;91:102624. doi: 10.1016/j.tice.2024.102624. Online ahead of print.

ABSTRACT

Cancer-associated fibroblasts (CAFs) are a heterogeneous cell population within the tumor that have recently come into the spotlight. By extracellular matrix (ECM) remodeling and robust cross-talk with cancer cells via different secretions such as cytokines, chemokines, and growth factors, CAFs contribute to cancer progression and poorer prognoses in patients. Novel candidates have been developed to inhibit CAFs; however, due to safety and efficacy issues, none have successfully passed clinical trials. Despite these shortcomings, one concept embraced by many researchers is to repurpose non-oncology drugs with potential anti-cancer properties for cancer treatment. One such example is pirfenidone (PFD), an oral anti-fibrotic medication, primarily administered for idiopathic pulmonary fibrosis. Emerging evidence suggests that PFD has promising anti-cancer effects, mainly manifesting through targeting CAFs. With inhibitory effects on CAFs, PFD restricts cancer proliferation, metastasis, immunosuppression, drug resistance, and tumor stiffness. To improve efficacy and minimize adverse effects, several innovative approaches have been proposed for targeting CAFs via PFD. Interestingly, combination therapy comprising PFD and chemotherapeutics e.g. doxorubicin has shown synergistic anti-cancer effects while protecting normal tissue. Furthermore, novel drug delivery systems, e.g. biomimetic liposomes and multilayer core-shell nanoparticles, have enhanced the pharmacokinetic properties of PFD and further increased its intratumoral delivery. Single-cell RNA sequencing (scRNA-seq) has also been suggested to characterize different subpopulations of CAFs and design precise PFD-based therapeutic strategies. Herein, we discuss the promising anti-cancer effects of PFD via inhibition of CAFs. We then provide findings on novel PFD-based approaches to target CAFs using combination therapy, nanocarrier-based drug delivery, and scRNA-seq.

PMID:39581071 | DOI:10.1016/j.tice.2024.102624

Phytomedicine. 2024 Nov 17;136:156266. doi: 10.1016/j.phymed.2024.156266. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options. Our previous research has shown that the Jinshui Huanxian formula (JHF) is effective in treating IPF. However, the biomechanical mechanisms of its refined components, known as the effective-component compatibility of JHF II (ECC-JHF II), are not well understood.

PURPOSE: This study aims to explore how bioactive components from traditional Chinese medicine (TCM) impact the biomechanical progression of pulmonary fibrosis.

STUDY DESIGN AND METHODS: A mouse model of pulmonary fibrosis was established by a single intratracheal instillation of bleomycin (Bleomycin). Pulmonary function, pathological changes, collagen deposition, lung tissue stiffness, and EMT markers were evaluated at the end of the study. Polyethylene glycol hydrogels with adjustable stiffness were used to mimic both normal and pathological lung conditions. The effects of ECC-JHF II on matrix stiffness-mediated EMT were assessed by quantitative real-time PCR, western blot, and immunofluorescence. The biomechanical mechanisms underlying ECC-JHF II on EMT and pulmonary fibrosis were verified both in vivo and in vitro.

RESULTS: ECC-JHF II significantly improved bleomycin (Bleomycin)-induced pulmonary fibrosis in mice, manifested as increased tidal volume and 50 % tidal volume expiratory flow, reduced lung tissue stiffness, and decreased EMT markers. Histopathological analysis showed reduced inflammation, alveolar damage, and collagen deposition. In vitro, ECC-JHF II reversed the EMT phenotypic transition induced by substrate stiffness, demonstrated by the upregulation of E-cadherin, occludin, and zonula occluden-1, and the downregulation of N-cadherin, vimentin, caldesmon 1 and tropomyosin 1. Moreover, ECC-JHF II could inhibit integrin/ROCK/MRTF signaling in vitro and in vivo. Silencing integrin β1 or activating it with pyrintegrin further confirmed the role of integrin β1 in the mechanotransduction pathway and the efficacy of ECC-JHF II.

CONCLUSION: Taken together, the findings of this study indicate that ECC-JHF II exerts a therapeutic effect on pulmonary fibrosis through the attenuation of lung tissue stiffness and inhibition of EMT, potentially via the integrin/ROCK/MRTF signaling pathway.

PMID:39580995 | DOI:10.1016/j.phymed.2024.156266

J Pharm Pharmacol. 2024 Nov 23:rgae143. doi: 10.1093/jpp/rgae143. Online ahead of print.

ABSTRACT

OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fibrotic interstitial lung disease. The two drugs indicated for IPF have limited efficacy and there is an urgent need to develop new drugs. Thymosin β4 (Tβ4) is a natural endogenous repair factor whose antifibrotic effects have been reported. This study aimed to evaluate the effect of exogenous recombinant human thymosin beta 4 (rhTβ4) on pulmonary fibrosis.

METHODS: Pulmonary fibrosis was induced in mice with bleomycin, and rhTβ4 was administrated by nebulization following three strategies: early dosing, mid-term dosing, and late dosing. The rhTβ4 efficacy was assessed by hydroxyproline, lung function, and lung histopathology. In vitro, the effects of rhTβ4 on fibroblast and lung epithelial cell phenotypes, as well as the TGF-β1 pathway, were evaluated.

KEY FINDINGS: Aerosol administration of rhTβ4 could alleviate bleomycin-induced pulmonary fibrosis in mice at different stages of fibrosis. Studies conducted in vitro suggested that rhTβ4 could suppress lung fibroblasts from proliferating, migrating, and activation via regulating the TGF-β1 signalling pathway. In vitro, rhTβ4 also inhibited the epithelial-mesenchymal transition-like process of pulmonary epithelial cells.

CONCLUSIONS: This study suggests that nebulized rhTβ4 is a potential treatment for IPF.

PMID:39579076 | DOI:10.1093/jpp/rgae143

Orphanet J Rare Dis. 2024 Nov 22;19(1):432. doi: 10.1186/s13023-024-03410-8.

ABSTRACT

BACKGROUND: Genetic polymorphisms in Toll-interacting protein (TOLLIP) have been documented in relation to clinical manifestations of interstitial lung disease (ILD). Nevertheless, the findings across studies present inconsistencies. The present meta-analysis endeavors to elucidate the nexus between genetic variations in TOLLIP and the onset and prognosis of interstitial lung disease (ILD), with the overarching aim of providing insight into the pathophysiological underpinnings of ILD.

METHOD: This systematic review was registered in PROSPERO. The OVID MEDLINE, OVID EMBASE, and Web of Science electronic databases were searched.

RESULTS: Fourteen studies with a total of 4821 cases and 9765 controls were examined. The final TOLLIP variants to be included in this meta-analysis were rs5743890, rs111521887, and rs3750920. There were significantly fewer TOLLIP rs5743890 minor allele C carriers among individuals with interstitial lung disease (ILD) than among those without this condition (11.42% vs. 18.92%). Conversely, patients with ILD exhibited higher frequencies of rs111521887 minor allele G carriers (28.92% vs. 22.44%) and rs3750920 minor allele T carriers (40.06% vs. 34.00%). A potential association between rs5743890_C and a reduced incidence of ILD was plausible (p = 0.04, OR = 0.72, 95% CI = 0.53-0.99). Furthermore, a stratified analysis revealed that rs5743890_C was significantly associated with a decreased risk of IPF (p = 0.004, OR = 0.62, 95% CI = 0.44-0.86). There was a significant correlation between susceptibility to ILD and rs111521887 G (p < 0.00001, OR = 1.48, 95% CI = 1.33-1.65) and rs3750920 T (p < 0.00001, OR = 1.34, 95% CI = 1.26-1.44). The survival of IPF patients was correlated with the TOLLIP rs5743890 SNP, and patients with the rs5743890_C genotype had worse survival (p = 0.02, HR = 1.59, 95% CI = 1.07-2.36).

CONCLUSION: This study showed that rs5743890_C was associated with a lower incidence of ILD and a worse survival rate in patients with IPF. Rs111521887_G and rs3750920_T were found to be associated with an elevated risk of ILD incidence, while no significant association was observed with ILD prognosis. Furthermore, studies are warranted to validate our results and assess the effects of TOLLIP genetic variants on ILD.

PMID:39578840 | DOI:10.1186/s13023-024-03410-8