Mol Imaging Biol. 2023 Aug 23. doi: 10.1007/s11307-023-01845-2. Online ahead of print.

ABSTRACT

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a destructive lung disease with a poor prognosis, an unpredictable clinical course, and inadequate therapies. There are currently no measures of disease activity to guide clinicians making treatment decisions. The aim of this study was to develop a PET probe to identify lung fibrogenesis using a pre-clinical model of pulmonary fibrosis, with potential for translation into clinical use to predict disease progression and inform treatment decisions.

METHODS: Eight novel allysine-targeting chelators, PIF-1, PIF-2, …, PIF-8, with different aldehyde-reactive moieties were designed, synthesized, and radiolabeled with gallium-68 or copper-64. PET probe performance was assessed in C57BL/6J male mice 2 weeks after intratracheal bleomycin challenge and in naïve mice by dynamic PET/MR imaging and with biodistribution at 90 min post injection. Lung hydroxyproline and allysine were quantified ex vivo and histological staining for fibrosis and aldehyde was performed.

RESULTS: In vivo screening of probes identified 68GaPIF-3 and 68GaPIF-7 as probes with high uptake in injured lung, high uptake in injured lung versus normal lung, and high uptake in injured lung versus adjacent liver and heart tissue. A crossover, intra-animal PET/MR imaging study of 68GaPIF-3 and 68GaPIF-7 confirmed 68GaPIF-7 as the superior probe. Specificity for fibrogenesis was confirmed in a crossover, intra-animal PET/MR imaging study with 68GaPIF-7 and a non-binding control compound, 68GaPIF-Ctrl. Substituting copper-64 for gallium-68 did not affect lung uptake or specificity indicating that either isotope could be used.

CONCLUSION: A series of allysine-reactive PET probes with variations in the aldehyde-reactive moiety were evaluated in a pre-clinical model of lung fibrosis. The hydrazine-bearing probe, 68GaPIF-7, exhibited the highest uptake in fibrogenic lung, low uptake in surrounding liver or heart tissue, and low lung uptake in healthy mice and should be considered for further clinical translation.

PMID:37610609 | DOI:10.1007/s11307-023-01845-2

Front Pharmacol. 2023 Aug 7;14:1205948. doi: 10.3389/fphar.2023.1205948. eCollection 2023.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a long-lasting, continuously advancing, and irrevocable interstitial lung disorder with an obscure origin and inadequately comprehended pathological mechanisms. Despite the intricate and uncharted causes and pathways of IPF, the scholarly consensus upholds that the transformation of fibroblasts into myofibroblasts-instigated by injury to the alveolar epithelial cells-and the disproportionate accumulation of extracellular matrix (ECM) components, such as collagen, are integral to IPF's progression. The introduction of two novel anti-fibrotic medications, pirfenidone and nintedanib, have exhibited efficacy in decelerating the ongoing degradation of lung function, lessening hospitalization risk, and postponing exacerbations among IPF patients. Nonetheless, these pharmacological interventions do not present a definitive solution to IPF, positioning lung transplantation as the solitary potential curative measure in contemporary medical practice. A host of innovative therapeutic strategies are presently under rigorous scrutiny. This comprehensive review encapsulates the recent advancements in IPF research, spanning from diagnosis and etiology to pathological mechanisms, and introduces a discussion on nascent therapeutic methodologies currently in the pipeline.

PMID:37608885 | PMC:PMC10440605 | DOI:10.3389/fphar.2023.1205948

Sci Rep. 2023 Aug 22;13(1):13664. doi: 10.1038/s41598-023-40508-8.

ABSTRACT

While high-level evidence is lacking, numerous retrospective studies have depicted the value of supplemental oxygen in idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases, and its use should be encouraged where necessary. The clinical course and survival of patients with IPF who have been introduced to oxygen therapy is still not fully understood. The objective of this study was to clarify overall survival, factors associated with prognosis, and causes of death in IPF patients after the start of oxygen therapy. This is a prospective cohort multicenter study, enrolling patients with IPF who started oxygen therapy at 19 hospitals with expertise in interstitial lung disease. Baseline clinical data at the start of oxygen therapy and 3-year follow-up data including death and cause of death were assessed. Factors associated with prognosis were analyzed using univariable and multivariable analyses. One hundred forty-seven eligible patients, of whom 86 (59%) were prescribed ambulatory oxygen therapy and 61 (41%) were prescribed long-term oxygen therapy, were recruited. Of them, 111 died (76%) during a median follow-up of 479 days. The median survival from the start of oxygen therapy was 537 ± 74 days. In the univariable analysis, low body mass index (BMI), low forced vital capacity (FVC), low diffusion capacity (DLCO), resting hypoxemia, short 6 min-walk distance, and high COPD assessment test (CAT) score were significantly associated with poor prognosis. Multivariable analysis revealed low BMI, low FVC, low DLCO, low minimum SpO2 on 6MWT, and high CAT score were independent factors for poor prognosis. The overall survival of IPF patients after starting oxygen therapy is about 1.5 years. In addition to pulmonary function tests, 6MWT and patient reported outcomes can be used to predict prognosis more accurately.Clinical Trial Registration: UMIN000009322.

PMID:37608014 | DOI:10.1038/s41598-023-40508-8

Rheumatology (Oxford). 2023 Aug 22:kead409. doi: 10.1093/rheumatology/kead409. Online ahead of print.

ABSTRACT

OBJECTIVE: To explore whether cytokines could be potential biomarkers to predict the occurrence of progressive fibrosis (PF) phenotype among interstitial pneumonia with autoimmune features (IPAF) patients.

METHODS: This study prospectively collected 51 IPAF and 15 Idiopathic Pulmonary Fibrosis (IPF) patients who were diagnosed at First Affiliated Hospital of Guangzhou Medical University from July 2020 to June 2021. All IPAF patients were followed up for one year to assess the development of PF phenotype. Paired Broncho Alveolar Lavage Fluid (BALF) and serum samples were collected at enrolment and analyzed for differences in 39 cytokines expression. Principal component analysis (PCA) and cluster analysis were conducted to identify a high-risk subgroup of IPAF patients for developing the PF phenotype. Finally, cytokine differences were compared between subgroups to identify potential biomarkers for PF-IPAF occurrence.

RESULTS: According to the PCA analysis, 81.25% of PF-IPAF patients share overlapped BALF cytokine profiles with IPF. Cluster analysis indicated IPAF patients in subtype 2 had a higher risk to develop PF phenotype within one year (P = 0.048), characterized by higher levels of CCL2, CXCL12 and lower lymphocyte proportion (LYM%) in BALF. Elevated levels of BALF CCL2 (>299.16 pg./ml) or CXCL12 (>600.115 pg./ml) were associated with a significantly higher risk of developing PF phenotype within one year follow-up period (P = 0.009, 0.001).

CONCLUSION: PF-IPAF phenotype exhibits similar inflammatory cytokine profiles to IPF. Cytokine CCL2, CXCL12, and LYM% in BALF serving as potential biomarkers for predicting the PF phenotype in IPAF patients.

CLINICAL TRIAL REGISTRATION: Register: Qian Han, Website: http://www.chictr.org.cn/showproj.aspx?proj=61619, Registration number: ChiCTR2000040998.

PMID:37606981 | DOI:10.1093/rheumatology/kead409

Pathol Int. 2023 Aug 22. doi: 10.1111/pin.13368. Online ahead of print.

ABSTRACT

We present a case of lung carcinoma with a unique biphasic feature. The patient was a 67-year-old male smoker with idiopathic pulmonary fibrosis (IPF). A subpleural tumor in the left lower lobe, embedded in fibrotic tissue, was resected. Histologically, the tumor consisted of major and minor components of mucoepidermoid carcinoma (MEC) and surrounding conventional lepidic adenocarcinoma, respectively. Both components had the same TP53 somatic mutation (p.V157F) but not Mastermind-like 2 (MAML2) gene rearrangement. The two components may have developed from an identical origin. The tumor could be trans-differentiating from lepidic adenocarcinoma to MEC, possibly promoted by IPF-induced tissue damage. The final diagnosis was "adenosquamous carcinoma with mucoepidermoid-like features (that may originate from lepidic adenocarcinoma)." This case has implications for the potential histogenesis of peripheral lung MEC. Over time, the MEC would expand and outgrow the lepidic adenocarcinoma, making it impossible to distinguish between fake and true MEC. The present case suggests that peripheral MEC could differ from proximal MEC in its histogenesis and molecular genetics. Thus, careful examination is necessary to diagnose peripheral lung MEC, particularly in patients with interstitial lung diseases.

PMID:37606200 | DOI:10.1111/pin.13368

Iran J Basic Med Sci. 2023;26(9):1001-1015. doi: 10.22038/IJBMS.2023.69023.15049.

ABSTRACT

Pulmonary fibrosis (PF) is the end stage of severe lung diseases, in which the lung parenchyma is replaced by fibrous scar tissue. The result is a remarkable reduction in pulmonary compliance, which may lead to respiratory failure and even death. Idiopathic pulmonary fibrosis (IPF) is the most prevalent form of PF, with no reasonable etiology. However, some factors are believed to be behind the etiology of PF, including prolonged administration of several medications (e.g., bleomycin and amiodarone), environmental contaminant exposure (e.g., gases, asbestos, and silica), and certain systemic diseases (e.g., systemic lupus erythematosus). Despite significant developments in the diagnostic approach to PF in the last few years, efforts to find more effective treatments remain challenging. With their immunomodulatory, anti-inflammatory, and anti-fibrotic properties, stem cells may provide a promising approach for treating a broad spectrum of fibrotic conditions. However, they may lose their biological functions after long-term in vitro culture or exposure to harsh in vivo situations. To overcome these limitations, numerous modification techniques, such as genetic modification, preconditioning, and optimization of cultivation methods for stem cell therapy, have been adopted. Herein, we summarize the previous investigations that have been designed to assess the effects of stem cell preconditioning or genetic modification on the regenerative capacity of stem cells in PF.

PMID:37605719 | PMC:PMC10440137 | DOI:10.22038/IJBMS.2023.69023.15049

EPMA J. 2023 Jul 31;14(3):417-442. doi: 10.1007/s13167-023-00334-4. eCollection 2023 Sep.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a rare interstitial lung disease with a poor prognosis that currently lacks effective treatment methods. Preventing the acute exacerbation of IPF, identifying the molecular subtypes of patients, providing personalized treatment, and developing individualized drugs are guidelines for predictive, preventive, and personalized medicine (PPPM / 3PM) to promote the development of IPF. Oxidative stress (OS) is an important pathological process of IPF. However, the relationship between the expression levels of oxidative stress-related genes (OSRGs) and clinical indices in patients with IPF is unclear; therefore, it is still a challenge to identify potential beneficiaries of antioxidant therapy. Because PPPM aims to recognize and manage diseases by integrating multiple methods, patient stratification and analysis based on OSRGs and identifying biomarkers can help achieve the above goals.

METHODS: Transcriptome data from 250 IPF patients were divided into training and validation sets. Core OSRGs were identified in the training set and subsequently clustered to identify oxidative stress-related subtypes. The oxidative stress scores, clinical characteristics, and expression levels of senescence-associated secretory phenotypes (SASPs) of different subtypes were compared to identify patients who were sensitive to antioxidant therapy to conduct differential gene functional enrichment analysis and predict potential therapeutic drugs. Diagnostic markers between subtypes were obtained by integrating multiple machine learning methods, their expression levels were tested in rat models with different degrees of pulmonary fibrosis and validation sets, and nomogram models were constructed. CIBERSORT, single-cell RNA sequencing, and immunofluorescence staining were used to explore the effects of OSRGs on the immune microenvironment.

RESULTS: Core OSRGs classified IPF into two subtypes. Patients classified into subtypes with low oxidative stress levels had better clinical scores, less severe fibrosis, and lower expression of SASP-related molecules. A reliable nomogram model based on five diagnostic markers was constructed, and these markers' expression stability was verified in animal experiments. The number of neutrophils in the immune microenvironment was significantly different between the two subtypes and was closely related to the degree of fibrosis.

CONCLUSION: Within the framework of PPPM, this work comprehensively explored the role of OSRGs and their mediated cellular senescence and immune processes in the progress of IPF and assessed their capabilities aspredictors of high oxidative stress and disease progression,targets of the vicious loop between regulated pulmonary fibrosis and OS for targeted secondary and tertiary prevention, andreferences for personalized antioxidant and antifibrotic therapies.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-023-00334-4.

PMID:37605652 | PMC:PMC10439879 | DOI:10.1007/s13167-023-00334-4

J Gastroenterol Hepatol. 2023 Aug 22. doi: 10.1111/jgh.16325. Online ahead of print.

ABSTRACT

BACKGROUND AND AIM: Gastroesophageal reflux has been associated with idiopathic pulmonary fibrosis (IPF), although the directionality of the relationship has been debated. Data on the value of objective reflux measures in predicting IPF disease progression and mortality remain limited. We aimed to evaluate the association between multichannel intraluminal impedance and pH testing (MII-pH) and 3-year pulmonary outcomes in IPF patients.

METHODS: This was a retrospective cohort study of adults with IPF who underwent pre-lung transplant MII-pH off acid suppression at a tertiary center. Patients were followed for 3 years after MII-pH for poor pulmonary outcomes (hospitalization for respiratory exacerbation or death). A secondary analysis was performed using mortality as outcome of interest. Time-to-event analyses using Kaplan-Meier and Cox regression were performed to evaluate associations between MII-pH and poor outcomes.

RESULTS: One hundred twenty-four subjects (mean age = 61.7 ± 8 years, 62% male) were included. Increased bolus exposure time (BET) on MII-pH was associated with decreased time to poor pulmonary outcomes and death (log-ranked P-value = 0.017 and 0.031, respectively). On multivariable Cox regression analyses controlling for potential confounders including age, sex, smoking history, body mass index, proton pump inhibitor use, baseline pulmonary function, and anti-fibrotic therapy, increased BET was an independent predictor for poor pulmonary outcomes [hazard ratio 3.18 (95% confidence interval: 1.25-8.09), P = 0.015] and mortality [hazard ratio 11.3 (95% confidence interval: 1.37-63.9), P = 0.025] over 3 years.

CONCLUSIONS: Increased BET on MII-pH is an independent predictor of poor pulmonary outcomes and mortality over 3 years in IPF patients. These findings also support a role for gastroesophageal reflux in IPF disease progression and the potential impact of routine reflux testing and treatment.

PMID:37605548 | DOI:10.1111/jgh.16325

Geriatr Gerontol Int. 2023 Aug 21. doi: 10.1111/ggi.14653. Online ahead of print.

ABSTRACT

Cellular senescence serves as a significant tumor suppression mechanism in mammals. Cellular senescence is induced in response to various stressors and acts as a safeguard against the uncontrolled proliferation of damaged cells that could lead to malignant transformation. Senescent cells also exhibit a distinctive feature known as the senescence-associated secretory phenotype (SASP), wherein they secrete a range of bioactive molecules, including pro-inflammatory cytokines, growth factors, and proteases. These SASP components have both local and systemic effects, influencing the surrounding microenvironment and distant tissues, and have been implicated in the processes of tissue aging and the development of chronic diseases. Recent studies utilizing senolysis models have shed light on the potential therapeutic implications of targeting senescent cells. The targeting of senescent cell may alleviate the detrimental effects associated with cellular senescence and its SASP components. Senolytics have shown promise in preclinical studies for treating age-related pathologies and chronic diseases, including cancer, cardiovascular disorders, and neurodegenerative conditions. Respiratory diseases have emerged as a significant global health concern, responsible for a considerable number of deaths worldwide. Extensive research conducted in both human subjects and animal models has demonstrated the involvement of cellular senescence in the pathogenesis of respiratory diseases. Chronic pulmonary conditions such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis have been linked to the accumulation of senescent cells. This review aims to present the findings from research on respiratory diseases that have utilized systems targeting senescent cells and to identify potential therapeutic strategies for the clinical management of these conditions. Geriatr Gerontol Int ••; ••: ••-•• Geriatr Gerontol Int 2023; ••: ••-••.

PMID:37604771 | DOI:10.1111/ggi.14653

Heliyon. 2023 Aug 5;9(8):e18618. doi: 10.1016/j.heliyon.2023.e18618. eCollection 2023 Aug.

ABSTRACT

RATIONALE AND OBJECTIVES: Lung transplantation is a potentially life-saving treatment option for patients with idiopathic pulmonary fibrosis (IPF); however, not all eligible candidates get referred and listed for transplantation. Amongst IPF patients within the Pulmonary Fibrosis Foundation Patient Registry (PFF-R), we sought to determine the proportion of patients who undergo lung transplant listing and the characteristics associated with transplant listing.

METHODS: An analysis of IPF patients with at least six months of follow-up data was performed. Patients with well-established contraindications to lung transplantation were excluded. Two complementary analyses were performed. The "prevalent" population included all patients with IPF at time of enrollment into the registry. The "incident severe" population included all patients with IPF who progressed to GAP Stage 3.

RESULTS: Of the 2003 patients in the PFF-R, 475 patients were included in the "prevalent" population. Of this group, only 42 (8.8%) were either listed for or underwent lung transplant. Univariable analysis of the "prevalent" population found age (per 10 year increase, OR 0.531, p = 0.0025), percent predicted FVC (OR 0.572, p=<0.0001), percent predicted DLCO (OR 0.606, p < 0.0001), 6-min walk distance (per 50 m, OR 0.831, p = 0.019), and oxygen use at rest (OR 5.157, p < 0.0001) were predictive of listing. On multivariable analysis, age (per 10 year increase, OR 0.558, p = 0.0088), percent predicted FVC (OR 0.728, p = 0.0161), and oxygen use at rest (OR 3.264, p = 0.0029) remained significant predictors for lung transplant listing. The "incident severe" group consisted of 176 patients (8.8%). 24 patients (13.6%) from this cohort were either listed for or received a transplant. Only age (per 10 year increase, OR 0.0286, p = 0.0465) was associated with transplant listing on univariable analysis in the Incident severe population.

CONCLUSION: Only a small proportion of potentially eligible patients with IPF are listed for lung transplantation, even when seen at pulmonary fibrosis centers of excellence. Advanced age appears to be the primary factor associated with failure to be listed. Further refinement of future registry data is required to more clearly delineate exact reasons for low rates of listing.

PMID:37600402 | PMC:PMC10432603 | DOI:10.1016/j.heliyon.2023.e18618

Health Sci Rep. 2023 Aug 16;6(8):e1449. doi: 10.1002/hsr2.1449. eCollection 2023 Aug.

ABSTRACT

BACKGROUND AND AIMS: Antifibrotic therapies reduce lung function decline in patients with idiopathic pulmonary fibrosis (IPF). This single-arm, open-label, nonrandomized study aimed to determine the influence of antifibrotic treatment on patients' reported symptoms and expectations of the therapy.

METHODS: Fifty-two patients with confirmed IPF at a mean age of 65 ± 8.63 years (73% male) completed the following surveys at baseline and after 12 months of Pirfenidone treatment: Short Form Healthy Survey (SF-36), St. George's Respiratory Questionnaire (SGRQ), Baseline Dyspnea Index (BDI), Fatigue Assessment Scale (FAS), Leicester Cough Questionnaire (LCQ), and Patient's Needs and Expectations Authors' Survey.

RESULTS: The most important patients' needs were access to novel therapy, fast and easy access to health centers specializing in IPF treatment, and the improvement of the general condition or the maintenance of its level. These needs did not change with time, except for the significantly more important right of deciding on disease management after 12 months of treatment (p = 0.014). The quality of life per SF-36, after 1 year of Pirfenidone treatment, significantly improved in the physical cumulative score (p = 0.004) and mental cumulative score (p = 0.003). Significant deteriorations were observed in bodily pain and vitality. For the remaining questionnaires (SGRQ, BDI, FAS, and LCQ), no significant changes in the course of the study were noticed. Around one in 10 patients subjected to Pirfenidone therapy had achieved general symptom improvement in all areas; that is, quality of life improvement as well as cough and dyspnea reduction.

CONCLUSIONS: One year of antifibrotic treatment resulted in a general improvement in the quality of life per the SF-36 questionnaire. Patients' expectations of disease management did not change; also, access to novel therapies and easy access to health centers specializing in IPF management remained their top needs.

PMID:37599655 | PMC:PMC10432581 | DOI:10.1002/hsr2.1449

BMJ Open Respir Res. 2023 Aug;10(1):e001563. doi: 10.1136/bmjresp-2022-001563.

ABSTRACT

IntroductionThere is an unmet need for new treatments for idiopathic pulmonary fibrosis (IPF). The oral preferential phosphodiesterase 4B inhibitor, BI 1015550, prevented a decline in forced vital capacity (FVC) in a phase II study in patients with IPF. This study design describes the subsequent pivotal phase III study of BI 1015550 in patients with IPF (FIBRONEER-IPF).

METHODS AND ANALYSIS: In this placebo-controlled, double-blind, phase III trial, patients are being randomised in a 1:1:1 ratio to receive 9 mg or 18 mg of BI 1015550 or placebo two times per day over at least 52 weeks, stratified by use of background antifibrotics (nintedanib/pirfenidone vs neither). The primary endpoint is the absolute change in FVC at week 52. The key secondary endpoint is a composite of time to first acute IPF exacerbation, hospitalisation due to respiratory cause or death over the duration of the trial.

ETHICS AND DISSEMINATION: The trial is being carried out in compliance with the ethical principles of the Declaration of Helsinki, in accordance with the International Council on Harmonisation Guideline for Good Clinical Practice and other local ethics committees. The results of the study will be disseminated at scientific congresses and in peer-reviewed publications.

TRIAL REGISTRATION NUMBER: NCT05321069.

PMID:37597969 | DOI:10.1136/bmjresp-2022-001563

J Pharmacol Exp Ther. 2023 Sep;386(3):274-276. doi: 10.1124/jpet.123.001661.

NO ABSTRACT

PMID:37591657 | DOI:10.1124/jpet.123.001661

Eur Respir J. 2023 Aug 17;62(2):2301076. doi: 10.1183/13993003.01076-2023. Print 2023 Aug.

NO ABSTRACT

PMID:37591552 | DOI:10.1183/13993003.01076-2023

Eur Respir J. 2023 Aug 17:2300441. doi: 10.1183/13993003.00441-2023. Online ahead of print.

ABSTRACT

Studies suggest a harmful pharmacogenomic interaction exists between short leukocyte telomere length (LTL) and immunosuppressants in idiopathic pulmonary fibrosis (IPF). It remains unknown if a similar interaction exists in non-IPF interstitial lung disease (ILD).A retrospective, multi-centre cohort analysis was performed in fibrotic hypersensitivity pneumonitis, unclassifiable ILD, and connective tissue disease ILD patients from five centres. LTL was measured by qPCR for discovery and replication cohorts and expressed as age-adjusted percentiles of normal. Inverse probability of treatment weights based on propensity scores were used to assess the association between mycophenolate or azathioprine exposure and age-adjusted LTL on two-year transplant-free survival using weighted Cox proportional hazards regression incorporating time-dependent immunosuppressant exposure.The discovery and replication cohorts included 613 and 325 patients, respectively. In total, 40% of patients were exposed to immunosuppression and 22% had LTL <10th percentile of normal. Fibrotic hypersensitivity pneumonitis and unclassifiable ILD patients with LTL <10th percentile experienced reduced survival when exposed to either mycophenolate or azathioprine in the discovery cohort (mortality HR 4.97, 95% CI 2.26-10.92, p<0.001) and replication cohort (mortality HR 4.90, 95% CI 1.74-13.77, p=0.003). Immunosuppressant exposure was not associated with differential survival in patients with LTL ≥10th percentile. There was a significant interaction between LTL <10th percentile and immunosuppressant exposure (Discovery p-interaction=0.013; Replication p-interaction=0.011). Low event rate and prevalence of LTL <10th percentile precluded subgroup analyses for connective tissue disease ILD.Similar to IPF, fibrotic hypersensitivity pneumonitis and unclassifiable ILD patients with age-adjusted LTL <10th percentile may experience reduced survival when exposed to immunosuppression.

PMID:37591536 | DOI:10.1183/13993003.00441-2023

Int J Pharm. 2023 Aug 15:123322. doi: 10.1016/j.ijpharm.2023.123322. Online ahead of print.

ABSTRACT

Nintedanib (NIN) is one of the FDA-approved tyrosine kinase inhibitor drugs used to treat idiopathic pulmonary fibrosis (IPF). This study aimed to formulate a long-circulating injection of Nintedanib to treat bedridden patients with IPF. Nintedanib was incorporated into chitosan nanoparticles (NIN-NP) via the ionic gelation method, and N-acetyl cysteine (NAC), a known antioxidant and mucolytic agent, was added to the NIN-NP (NAC-NIN-NP). The lyophilized formulation had a particle size of 174nm, a polydispersity index of 0.511, and a zeta potential of 18.6 mV. The spherical nanoparticles were observed in transmission electron microscopy, whereas field emission scanning electron microscopy showed irregular clusters of NP. The thiolation of the chitosan in NAC-NIN-NP was confirmed by ATR-FTIR and NMR, which improved drug release profiles showing >90 % drug release that was 2.42-folds greater than NIN-NP lasting for five days. The DPPH assay showed that adding NAC increased the % inhibition of oxidation in blank-NP (from 54.59% to 87.17%) and NIN-NP (58.65% to 89.19%). The MTT assay on A549 cells showed 67.57% cell viability by NAC-NIN-NP with an IC50 value of 28 μg/mL. The NAC formulation reduced hydroxyproline content (56.77 μg/mL) compared to NIN-NP (69.48μg/mL) in WI-38 cell lines. Meanwhile, the healthy cells count with NAC-NIN-NP was higher (5.104x103) than with NIN-NP (4.878x103). In Hoechst staining, no significant damage to DNA was observed by the drug or formulation. Therefore, NAC-NIN-NP could be a promising treatment option for IPF patients and can be studied further clinically.

PMID:37591474 | DOI:10.1016/j.ijpharm.2023.123322

Ther Deliv. 2023 Aug 16. doi: 10.4155/tde-2023-0045. Online ahead of print.

ABSTRACT

Aim: Idiopathic pulmonary fibrosis is a rare disease with few efficient drugs in the market. The consequences of this disease are mainly respiratory failure and pulmonary hypertension. Materials & methods: In our experiment we used the drugs pirfenidone, nintetanib and macitentan. We performed nebulization experiments with three jet nebulizers and three ultrasound nebulizers with different combinations of residual cup designs, and residual cup loadings in order to identify which combination produces droplets of less than 5 μm in mass median aerodynamic diameter. Results: Pirfenidone versus nintetanib had smaller droplet size formation at both inhaled technologies (1.37 < 2.23 and 1.92 < 3.11, jet and ultrasound respectively). Discussion: Pirfenidone and nintetanib can be administered as aerosol in any type of nebulization system.

PMID:37584210 | DOI:10.4155/tde-2023-0045

World J Clin Cases. 2023 Jul 16;11(20):4932-4936. doi: 10.12998/wjcc.v11.i20.4932.

ABSTRACT

BACKGROUND: Pulmonary alveolar proteinosis (PAP) often presents nonspecifically and can be easily confused with: (1) Idiopathic interstitial lung fibrosis; (2) alveolar carcinoma; (3) pulmonary tuberculosis; and (4) other lung diseases such as viral pneumonia, mycoplasma pneumonia, and chlamydial pneumonia.

CASE SUMMARY: Diagnosis: In this case, a patient was diagnosed with PAP through transbronchial cryobiopsy (TBCB) and quantitative metagenomic next-generation sequencing, which confirmed the impairment of surfactant turnover as the underlying cause of PAP. Interventions: High-volume total lung lavage was performed for this patient. Outcomes: The patient's clinical condition had improved significantly by the 6-month follow-up, with a 92% finger oxygen saturation. A repeat chest computed tomography scan revealed scattered patchy ground-glass shadows in both lungs, which was consistent with alveolar protein deposition but with a lower density than in the radiograph from October 23, 2022.

CONCLUSION: TBCB has unique advantages in diagnosing atypical alveolar protein deposition, particularly for enabling the early detection of PAP. This information can help patients take preventive measures to prevent or halt PAP development by avoiding dusty environments and seeking treatment with total lung lavage and inhaled granulocyte macrophage colony-stimulating factor.

PMID:37583994 | PMC:PMC10424030 | DOI:10.12998/wjcc.v11.i20.4932

Sci Rep. 2023 Aug 14;13(1):13183. doi: 10.1038/s41598-023-40531-9.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive respiratory disease. Arguably, the complex interplay between immune cell subsets, coupled with an incomplete understanding of disease pathophysiology, has hindered the development of successful therapies. Despite efforts to understand its pathophysiology and develop effective treatments, IPF remains a fatal disease, necessitating the exploration of new treatment options. Mesenchymal stromal/stem cell (MSC) therapy has shown promise in experimental models of IPF, but further investigation is needed to understand its therapeutic effect. This study aimed to assess the therapeutic effect of adipose-derived mesenchymal stem cells in a bleomycin-induced pulmonary fibrosis model. First, MSC cells were obtained from mice and characterized using flow cytometry and cell differentiation culture methods. Then adult C57BL/6 mice were exposed to endotracheal instillation of bleomycin and concurrently treated with MSCs for reversal models on day 14. Experimental groups were evaluated on days 14, 21, or 28. Additionally, lung fibroblasts challenged with TGF-β1 were treated with MSCs supernatant or MSCs to explore the mechanisms underlying of pulmonary fibrosis reversal. Mesenchymal stem cells were successfully isolated from mouse adipose tissue and characterized based on their differentiation ability and cell phenotype. The presence of MSCs or their supernatant stimulated the proliferation and migration of lung fibrotic cells. MSCs supernatant reduced lung collagen deposition, improved the Ashcroft score and reduced the gene and protein expression of lung fibrosis-related substances. Bleomycin-challenged mice exhibited severe septal thickening and prominent fibrosis, which was effectively reversed by MSCs treatment. MSC supernatant could suppress the TGF-β1/Smad signaling pathway and supernatant promotes fibroblast autophagy. In summary, this study demonstrates that MSCs supernatant treatment is as effective as MSCs in revert the core features of bleomycin-induced pulmonary fibrosis. The current study has demonstrated that MSCs supernatant alleviates the BLM-induced pulmonary fibrosis in vivo. In vitro experiments further reveal that MSC supernatant could suppress the TGF-β1/Smad signaling pathway to inhibit the TGF-β1-induced fibroblast activation, and promotes fibroblast autophagy by Regulating p62 expression. These findings contribute to the growing body of evidence supporting the therapeutic application of MSCs in cell therapy medicine for IPF.

PMID:37580529 | DOI:10.1038/s41598-023-40531-9

Eur J Pharmacol. 2023 Aug 12:175981. doi: 10.1016/j.ejphar.2023.175981. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease characterized by myofibroblast proliferation and extracellular matrix deposition that has a high mortality rate and limited therapeutic options. Flavokawain A(FKA) is the major component of chalcone in kava extract. FKA has been reported to inhibit TGF-β1-induced cardiomyocyte fibrosis by suppressing ROS production in A7r5 cells, but the role and mechanism of FKA in pulmonary fibrosis are unknown. In this study, we evaluated the effect of FKA on pulmonary fibrosis using an animal model of bleomycin-induced pulmonary fibrosis and showed that FKA alleviated the development of pulmonary fibrosis in a dose-dependent manner and improved lung function as well as collagen deposition and extracellular matrix accumulation in mice. In vitro studies showed that FKA inhibited myofibroblast activation and lung fibrosis progression by inhibiting TGF-β1/Smad signaling in a dose-dependent manner. In addition, we identified CXCL12 as a potential target of FKA through target prediction. Molecular docking, CETSA(cellular thermal displacement assay) and silver staining assays further demonstrated that FKA could interact with CXCL12 and that FKA could inhibit CXCL12 dimerization in vitro. Further analysis revealed that FKA could inhibit fibroblast activation and reduce extracellular matrix (ECM) production and collagen deposition by blocking CXCL12/CXCR4 signaling, and knocking down CXCR4 expression could weaken the inhibitory effect of FKA on CXCL12/CXCR4 signal transduction. In conclusion, our study showed that FKA inhibited CXCL12/CXCR4 signaling by inhibiting CXCL12 dimerization, blocked the CXCL12/CXCR4 signaling pathway and inhibited the TGF-β1-mediated signaling pathway to ameliorate pulmonary fibrosis, and FKA is a promising therapeutic agent for pulmonary fibrosis.

PMID:37579968 | DOI:10.1016/j.ejphar.2023.175981