Ther Adv Respir Dis. 2024 Jan-Dec;18:17534666241250332. doi: 10.1177/17534666241250332.

ABSTRACT

BACKGROUND: Different types of inflammatory processes and fibrosis have been implicated in the pathogenesis of interstitial lung disease (ILD), a heterogeneous, diffuse, parenchymal lung disease. Acute exacerbation (AE) of ILD is characterized by significant respiratory deterioration and is associated with high mortality rates. Several serum oncomarkers have been used to determine the prognosis of ILD; however, the prognostic value of serum oncomarker levels in patients with AE-ILD remains unclear.

OBJECTIVE: To evaluate the prognostic value of serum oncomarker levels in patients with AE-ILD and its main subtypes.

DESIGN: Retrospective study.

METHODS: The serum levels of 8 oncomarkers in 281 patients hospitalized with AE-ILD at our institution between 2017 and 2022 were retrospectively reviewed. The baseline characteristics and serum oncomarker levels were compared between the survival and non-survival groups of AE-ILD and its main subtypes. Multivariate logistic regression analysis was performed to identify independent prognosis-related markers, and the best prognostic predictor was analyzed using receiver operating characteristic curve (ROC) analysis.

RESULT: Idiopathic pulmonary fibrosis (IPF; n = 65), idiopathic nonspecific interstitial pneumonia (iNSIP; n = 26), and connective tissue disease-associated interstitial lung disease (CTD-ILD; n = 161) were the three main subtypes of ILD. The in-hospital mortality rate among patients with AE-ILD was 21%. The serum oncomarker levels of most patients with AE-ILD and its main subtypes in the non-survival group were higher than those in the survival group. Multivariate analysis revealed that ferritin and cytokeratin 19 fragments (CYFRA21-1) were independent prognostic risk factors for patients hospitalized with AE-ILD or AE-CTD-ILD. CYFRA21-1 was identified as an independent prognostic risk factor for patients hospitalized with AE-IPF or AE-iNSIP.

CONCLUSION: CYFRA21-1 may be a viable biomarker for predicting the prognosis of patients with AE-ILD, regardless of the underlying subtype of ILD. Ferritin has a prognostic value in patients with AE-ILD or AE-CTD-ILD.

PMID:38757948 | DOI:10.1177/17534666241250332

Clin Pharmacol Drug Dev. 2024 May 17. doi: 10.1002/cpdd.1417. Online ahead of print.

ABSTRACT

Dysregulated lysophosphatidic acid receptor 1 (LPAR1) signaling is implicated in fibrotic diseases, including systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF). Fipaxalparant (HZN-825) is a small molecule acting as a negative allosteric modulator of LPAR1 and is in phase 2 clinical evaluations for treating diffuse cutaneous SSc and IPF. This open-label, phase 1 study examined the pharmacokinetics (PKs), food effect, and safety of fipaxalparant in healthy volunteers. Dose proportionality was evaluated for fipaxalparant single doses of 150, 300, and 450 mg under fasted conditions. Food effect was tested with a 450-mg single dose under fasted conditions or with a high-fat meal. Multiple-dose PKs for twice-daily dosing of either 300 or 450 mg with low- or high-fat meals was also assessed. Fipaxalparant was safe and well tolerated in healthy volunteers (n = 36) under all conditions. Fipaxalparant exposure increased in a less than dose-proportional manner from 150 to 450 mg. At 450 mg, a high-fat meal increased the maximum observed concentration and area under the curve by approximately 1.9- and 2.1-fold, respectively. These results, combined with prior preclinical and phase 2a data, informed dose selection of fipaxalparant 300 mg once and twice daily with a meal for phase 2b studies.

PMID:38757472 | DOI:10.1002/cpdd.1417

Eur Respir J. 2024 May 16;63(5):2400678. doi: 10.1183/13993003.00678-2024. Print 2024 May.

NO ABSTRACT

PMID:38754951 | DOI:10.1183/13993003.00678-2024

J Control Release. 2024 May 14:S0168-3659(24)00308-0. doi: 10.1016/j.jconrel.2024.05.024. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and life-threatening lung disease for which treatment options are limited. Glycyrrhetinic acid (GA) is a triterpenoid with multiple biological effects, such as anti-inflammatory and anti-fibrotic properties. Herein, inhalable milk-derived extracellular vesicles (mEVs) encapsulating GA (mEVs@GA) were screened and evaluated for IPF treatment. The results indicated that the loading efficiency of GA in mEVs@GA was 8.65%. Therapeutic effects of inhalable mEVs@GA were investigated in vitro and in vivo. The mEVs@GA demonstrated superior anti-inflammatory effects on LPS-stimulated MHS cells. Furthermore, repeated noninvasive inhalation delivery of mEVs@GA in bleomycin-induced IPF mice could decrease the levels of transforming growth factors β1 (TGF-β1), Smad3 and inflammatory cytokines IL-6, IL-1β and TNF-α. The mEVs@GA effectively diminished the development of fibrosis and improved pulmonary function in the IPF mice model at a quarter of the dose compared with the pirfenidone oral administration group. Additionally, compared to pirfenidone-loaded mEVs, mEVs@GA demonstrated superior efficacy at the same drug concentration in the pharmacodynamic study. Overall, inhaled mEVs@GA have the potential to serve as an effective therapeutic option in the treatment of IPF.

PMID:38754632 | DOI:10.1016/j.jconrel.2024.05.024

Lung. 2024 May 16. doi: 10.1007/s00408-024-00694-2. Online ahead of print.

ABSTRACT

INTRODUCTION: Pulmonary fibrosis is a characteristic of various interstitial lung diseases (ILDs) with differing etiologies. Clinical trials in progressive pulmonary fibrosis (PPF) enroll patients based on previously described clinical criteria for past progression, which include a clinical practice guideline for PPF classification and inclusion criteria from the INBUILD trial. In this study, we compared the ability of past FVC (forced vital capacity) progression and baseline biomarker levels to predict future progression in a cohort of patients from the PFF Patient Registry.

METHODS: Biomarkers previously associated with pathobiology and/or progression in pulmonary fibrosis were selected to reflect cellular senescence (telomere length), pulmonary epithelium (SP-D, RAGE), myeloid activation (CXCL13, YKL40, CCL18, OPN) and fibroblast activation (POSTN, COMP, PROC3).

RESULTS: PFF or INBUILD-like clinical criteria was used to separate patients into past progressor and non-past progressor groups, and neither clinical criterion appeared to enrich for patients with greater future lung function decline. All baseline biomarkers measured were differentially expressed in patient groups compared to healthy controls. Baseline levels of SP-D and POSTN showed the highest correlations with FVC slope over one year, though correlations were low.

CONCLUSIONS: Our findings provide further evidence that prior decline in lung function may not predict future disease progression for ILD patients, and elevate the need for molecular definitions of a progressive phenotype. Across ILD subtypes, certain shared pathobiologies may be present based on the molecular profile of certain biomarker groups observed. In particular, SP-D may be a common marker of pulmonary injury and future lung function decline across ILDs.

PMID:38753183 | DOI:10.1007/s00408-024-00694-2

Radiographics. 2024 Jun;44(6):e230165. doi: 10.1148/rg.230165.

ABSTRACT

With the approval of antifibrotic medications to treat patients with idiopathic pulmonary fibrosis and progressive pulmonary fibrosis, radiologists have an integral role in diagnosing these entities and guiding treatment decisions. CT features of early pulmonary fibrosis include irregular thickening of interlobular septa, pleura, and intralobular linear structures, with subsequent progression to reticular abnormality, traction bronchiectasis or bronchiolectasis, and honeycombing. CT patterns of fibrotic lung disease can often be reliably classified on the basis of the CT features and distribution of the condition. Accurate identification of usual interstitial pneumonia (UIP) or probable UIP patterns by radiologists can obviate the need for a tissue sample-based diagnosis. Other entities that can appear as a UIP pattern must be excluded in multidisciplinary discussion before a diagnosis of idiopathic pulmonary fibrosis is made. Although the imaging findings of nonspecific interstitial pneumonia and fibrotic hypersensitivity pneumonitis can overlap with those of a radiologic UIP pattern, these entities can often be distinguished by paying careful attention to the radiologic signs. Diagnostic challenges may include misdiagnosis of fibrotic lung disease due to pitfalls such as airspace enlargement with fibrosis, paraseptal emphysema, recurrent aspiration, and postinfectious fibrosis. The radiologist also plays an important role in identifying complications of pulmonary fibrosis-pulmonary hypertension, acute exacerbation, infection, and lung cancer in particular. In cases in which there is uncertainty regarding the clinical and radiologic diagnoses, surgical biopsy is recommended, and a multidisciplinary discussion among clinicians, radiologists, and pathologists can be used to address diagnosis and management strategies. This review is intended to help radiologists diagnose and manage pulmonary fibrosis more accurately, ultimately aiding in the clinical management of affected patients. ©RSNA, 2024 Supplemental material is available for this article.

PMID:38752767 | DOI:10.1148/rg.230165

Clin Lab. 2024 May 1;70(5). doi: 10.7754/Clin.Lab.2023.231216.

ABSTRACT

BACKGROUND: Organizing pneumonia (OP) is a pathologic diagnosis with clinical and imaging manifestations that often resemble other diseases, such as infections and cancers, which can lead to delays in diagnosis and inappropriate management of the underlying disease. In this article, we present a case of organized pneumonia that resembles lung cancer.

METHODS: We report a case of initial suspicion of pulmonary malignancy, treated with anti-inflammatory medication and then reviewed with CT suggesting no improvement, and finally confirmed to be OP by pathological biopsy taken via transbronchoscopy. A joint literature analysis was performed to raise clinicians' awareness of the diagnosis and treatment of OP.

RESULTS: Initially, because of the atypical auxiliary findings, we thought that the disease turned out to be a lung tumor, which was eventually confirmed as OP by pathological diagnosis.

CONCLUSIONS: The diagnosis and treatment of OP requires a combination of clinical information and radiological expertise, as well as biopsy to obtain histopathological evidence. That is, clinical-imaging-pathological tripartite cooperation and comprehensive analysis.

PMID:38747927 | DOI:10.7754/Clin.Lab.2023.231216

Acta Radiol. 2024 May 15:2841851241246881. doi: 10.1177/02841851241246881. Online ahead of print.

ABSTRACT

BACKGROUND: The results of a quantitative analysis of computed tomography (CT) of interstitial lung disease (ILD) using a computer-aided detection (CAD) technique were correlated with the results of pulmonary function tests.

PURPOSE: To evaluate the correlation between a quantitative analysis of CT of progressive fibrosing interstitial lung disease (PF-ILD) including idiopathic pulmonary fibrosis (IPF) and non-IPF, which can manifest progressive pulmonary fibrosis and the vital capacity (VC), and to identify indicators for the assessment of a decreased VC.

MATERIAL AND METHODS: A total of 73 patients (46 patients with IPF and 27 patients with non-IPF) were included in this study. Associations between the quantitative analysis of CT and the %VC using a CAD software program were investigated using Spearman's rank correlation and a logistic regression analysis. The appropriate cutoff vale for predicting a decreased VC was determined (%VC <80) and the area under the curve (AUC) was calculated.

RESULTS: A multiple logistic regression analysis showed that the total extent of interstitial pneumonia on CT was a significant indicator of a decreased VC (P = 0.0001; odds ratio [OR]=1.15; 95% confidence interval [CI]=1.06-1.27 in IPF and P = 0.0025; OR=1.16; 95% CI=1.03-1.30 in non-IPF). The cutoff values of the total extent of interstitial pneumonia in IPF and non-IPF for predicting a decreased VC were determined to be 23.3% and 21.5%, and the AUCs were 0.83 and 0.91, respectively.

CONCLUSION: A quantitative analysis of CT of PF-ILD using a CAD software program could be useful for predicting a decreased VC.

PMID:38747886 | DOI:10.1177/02841851241246881

Am J Respir Crit Care Med. 2024 May 15. doi: 10.1164/rccm.202401-0249OC. Online ahead of print.

ABSTRACT

RATIONALE: Idiopathic pulmonary fibrosis (IPF) affects subpleural lung, but is considered to spare small airways. Micro-CT studies demonstrated small airway reduction in end-stage IPF explanted lungs, raising questions about small airway involvement in early-stage disease. Endobronchial optical coherence tomography (EB-OCT) is a volumetric imaging modality that detects microscopic features from subpleural to proximal airways. We use EB-OCT to evaluate small airways in early IPF and control subjects in vivo.

METHODS: EB-OCT was performed in 12 IPF and 5 control subjects (matched by age, sex, smoking-history, height, BMI). IPF subjects had early disease with mild restriction (FVC: 83.5% predicted), diagnosed per current guidelines and confirmed by surgical biopsy. EB-OCT volumetric imaging was acquired bronchoscopically in multiple, distinct, bilateral lung locations (total: 97 sites). IPF imaging sites were classified by severity into affected (all criteria for UIP present) and less affected (some but not all criteria for UIP present) sites. Bronchiole count and small airway stereology metrics were measured for each EB-OCT imaging site.

RESULTS: Compared to control subjects (mean: 11.2 bronchioles/cm3; SD: 6.2), there was significant bronchiole reduction in IPF subjects (42% loss; mean: 6.5/cm3; SD: 3.4; p=0.0039), including in IPF affected (48% loss; mean: 5.8/cm3; SD: 2.8; p<0.00001) and IPF less affected (33% loss; mean: 7.5/cm3; SD: 4.1; p=0.024) sites. Stereology metrics showed IPF affected small airways were significantly larger and more distorted/irregular than in IPF less affected sites and control subjects. IPF less affected and control airways were statistically indistinguishable for all stereology parameters (p=0.36-1.0).

CONCLUSION: EB-OCT demonstrated marked bronchiolar loss in early IPF (between 30 and 50%), even in areas minimally affected by disease, compared to matched controls. These findings support small airway disease as a feature of early IPF, providing novel insight into pathogenesis and potential therapeutic targets.

PMID:38747674 | DOI:10.1164/rccm.202401-0249OC

J Clin Invest. 2024 Mar 26;134(10):e159884. doi: 10.1172/JCI159884.

ABSTRACT

Transforming growth factor β (TGF-β) signaling is a core pathway of fibrosis, but the molecular regulation of the activation of latent TGF-β remains incompletely understood. Here, we demonstrate a crucial role of WNT5A/JNK/ROCK signaling that rapidly coordinates the activation of latent TGF-β in fibrotic diseases. WNT5A was identified as a predominant noncanonical WNT ligand in fibrotic diseases such as systemic sclerosis, sclerodermatous chronic graft-versus-host disease, and idiopathic pulmonary fibrosis, stimulating fibroblast-to-myofibroblast transition and tissue fibrosis by activation of latent TGF-β. The activation of latent TGF-β requires rapid JNK- and ROCK-dependent cytoskeletal rearrangements and integrin αV (ITGAV). Conditional ablation of WNT5A or its downstream targets prevented activation of latent TGF-β, rebalanced TGF-β signaling, and ameliorated experimental fibrosis. We thus uncovered what we believe to be a novel mechanism for the aberrant activation of latent TGF-β in fibrotic diseases and provided evidence for targeting WNT5A/JNK/ROCK signaling in fibrotic diseases as a new therapeutic approach.

PMID:38747285 | DOI:10.1172/JCI159884

Breathe (Sheff). 2024 Mar;20(1):240006. doi: 10.1183/20734735.0006-2024. Epub 2024 May 14.

ABSTRACT

High-resolution computed tomography (HRCT) plays a pivotal role in the diagnosis and management of interstitial lung diseases (ILDs), particularly given the approval of antifibrotic agents for conditions like idiopathic pulmonary fibrosis and progressive pulmonary fibrosis. Diagnosing fibrotic pulmonary disorders through HRCT involves a detailed and methodical examination. The identification of specific lung tissue changes, including ground-glass opacities and reticulation, along with signs of fibrosis like honeycombing, traction bronchiectasis and lung volume loss, establishes clear HRCT patterns indicative of various ILDs. The reliability of these patterns in predicting pathological conditions depends largely on the clinical context. For instance, when a usual interstitial pneumonia pattern is present, the predictive value of this diagnosis is so high that a lung biopsy is considered to be redundant. This review intends to delineate the HRCT signs of fibrosis, elucidate the specific radiological patterns of fibrotic lung diseases, and identify the clinical circumstances under which these patterns emerge. Additionally, we introduce and discuss novel imaging techniques that hold promise for the diagnosis, screening and early detection of ILDs.

PMID:38746908 | PMC:PMC11091715 | DOI:10.1183/20734735.0006-2024

Res Sq [Preprint]. 2024 Apr 22:rs.3.rs-4177351. doi: 10.21203/rs.3.rs-4177351/v1.

ABSTRACT

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

PMID:38746309 | PMC:PMC11092845 | DOI:10.21203/rs.3.rs-4177351/v1

Front Immunol. 2024 Apr 30;15:1404828. doi: 10.3389/fimmu.2024.1404828. eCollection 2024.

ABSTRACT

OBJECTIVES: Interstitial lung disease (ILD) is one of the common extramuscular involvement in idiopathic inflammatory myopathies (IIMs) (1). Several patients develop a progressive fibrosing ILD (PF-ILD) despite conventional treatment, resulting in a progressive deterioration in their quality of life (2). Here, we investigated the clinical and immune characteristics of IIM-ILD and risk factors for PF-ILD in IIM, mainly in anti-melanoma differentiation-associated protein 5 (anti-MDA5+) dermatomyositis (DM) and anti-synthetase syndrome (ASS).

METHODS: Here, a prospective cohort of 156 patients with IIM-ILD were included in the longitudinal analysis and divided into the PF-ILD (n=65) and non-PF-ILD (n=91) groups, and their baseline clinical characteristics were compared. Univariate and multivariate Cox analyses were performed to identify the variables significantly associated with pulmonary fibrosis progression in the total cohort, then anti-MDA5+ DM and ASS groups separately.

RESULTS: Peripheral blood lymphocyte counts, including T, B, and NK cell counts, were significantly lower in the PF-ILD group than in the non-PF-ILD group. This characteristic is also present in the comparison between patients with anti-MDA5+ DM and ASS. The multivariate Cox regression analysis revealed that age > 43.5 years [HR: 7.653 (95% CI: 2.005-29.204), p = 0.003], absolute NK cell count < 148 cells/μL [HR: 6.277 (95% CI: 1.572-25.067), p = 0.009] and absolute Th cell count < 533.2 cells/μL [HR: 4.703 (95% CI: 1.014-21.821), p = 0.048] were independent predictors of progressive fibrosing during 1-year follow-up for patients with anti-MDA5+ DM, while absolute count of NK cells < 303.3 cells/µL [HR: 19.962 (95% CI: 3.108-128.223), p = 0.002], absolute count of lymphocytes < 1.545×109/L [HR: 9.684 (95% CI: 1.063-88.186), p = 0.044], and ferritin > 259.45 ng/mL [HR: 6 (95% CI: 1.116-32.256), p = 0.037] were independent predictors of PF-ILD for patients with ASS.

CONCLUSIONS: Patients with anti-MDA5+ DM and ASS have independent risk factors for PF-ILD. Lymphocyte depletion (particularly NK cells) was significantly associated with PF-ILD within 1-year of follow-up for IIM-ILD.

PMID:38745647 | PMC:PMC11091831 | DOI:10.3389/fimmu.2024.1404828

J Am Coll Radiol. 2024 May 11:S1546-1440(24)00435-6. doi: 10.1016/j.jacr.2024.04.022. Online ahead of print.

NO ABSTRACT

PMID:38740119 | DOI:10.1016/j.jacr.2024.04.022

Jpn J Radiol. 2024 May 14. doi: 10.1007/s11604-024-01590-8. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Idiopathic dendriform pulmonary ossification (DPO) is mostly asymptomatic, and detected incidentally in lung CT. There have been no reports on the precise CT-pathologic correlation and the prevalence of idiopathic DPO. This study aimed to clarify the histological background and prevalence of idiopathic DPO.

MATERIALS AND METHODS: Sixteen patients with histologically confirmed idiopathic DPO (12 men and 4 women; mean age, 38.8 years; range 22-56 years) were identified in a nationwide epidemiological survey. Local HRCT findings of pre-biopsy examinations, such as branching, round, linear structures with or without high attenuation were compared side by side with histological findings. The attenuation of branching, round, and linear structures was classified into three-point levels on bone window images (width, 2500 HU; level, 500 HU). Furthermore, we collected continuous pulmonary CT images of 8111 cases for checking up metastasis from extrathoracic malignancy at a single institution, and evaluated the prevalence of interstitial lung abnormalities (ILAs) and DPO.

RESULTS: In all 16 cases, branching (n = 15, 93%), round (n = 5, 31%), or linear (n = 5, 31%) structures were identified, histologically corresponding to dendriform ossification and cicatricial organizing pneumonia (OP)/fibrosis. Histologically, ossification was confirmed in all the 16 patients. However, in two cases, a highly attenuated structure could not be detected on the pre-biopsy CT of the same area. Regarding the prevalence of idiopathic DPO, 283 (3.5%) of 8111 patients had ILAs, of which a total of 26 (0.3% of all cases, 9.2% of ILAs cases) had DPO.

CONCLUSION: Idiopathic DPO showed linear or branching structures with or without high attenuation on CT, corresponded to ossification, cicatricial OP/fibrosis. DPO was seen in 9.2% of ILAs cases. Idiopathic DPO is one of pathologic phenotypes of ILAs.

PMID:38740642 | DOI:10.1007/s11604-024-01590-8

High Blood Press Cardiovasc Prev. 2024 May 13. doi: 10.1007/s40292-024-00638-0. Online ahead of print.

ABSTRACT

INTRODUCTION: Prevalence of cardiac and vascular fibrosis in patients with Idiopathic Pulmonary Fibrosis (IPF) has not been extensively evaluated.

AIM: In this study, we aimed to evaluate the heart and vessels functional and structural properties in patients with IPF compared to healthy controls. An exploratory analysis regarding disease severity in IPF patients has been done.

METHODS: We enrolled 50 patients with IPF (at disease diagnosis before antifibrotic therapy initiation) and 50 controls matched for age and gender. Heart was evaluated through echocardiography and plasmatic NT-pro-brain natriuretic peptide that, together with patients' symptoms, allow to define the presence of Heart Failure (HF) and diastolic dysfunction. Vessels were evaluated through Flow Mediated Dilation (FMD - endothelial function) and Pulse Wave Velocity (PWV-arterial stiffness) RESULTS: Patients with IPF had a prevalence of diastolic disfunction of 83.8%, HF of 37.8% and vascular fibrosis of 76.6%. No statistically significant difference was observed in comparison to the control group who showed prevalence of diastolic disfunction, HF and vascular fibrosis of 67.3%, 24.5% and 84.8%, respectively. Disease severity seems not to affect PWV, FMD, diastolic dysfunction and HF.

CONCLUSIONS: Patients with IPF early in the disease course do not present a significant CV fibrotic involvement when compared with age- and sex-matched controls. Bigger and adequately powered studies are needed to confirm our preliminary data and longitudinal studies are required in order to understand the time of appearance and progression rate of heart and vascular involvement in IPF subjects.

PMID:38739257 | DOI:10.1007/s40292-024-00638-0

J Thorac Dis. 2024 Apr 30;16(4):2244-2258. doi: 10.21037/jtd-23-1349. Epub 2024 Apr 16.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease with a high mortality rate and limited treatment efficacy. Nintedanib, a tyrosine kinase inhibitor, is clinically used to treat pulmonary fibrosis. At present, only nintedanib is on the market for the treatment of pulmonary fibrosis. Pazopanib is a drug for the treatment of renal cell carcinoma and advanced soft tissue sarcoma.

METHODS: In this study, we explored whether pazopanib can attenuate bleomycin (BLM)-induced pulmonary fibrosis and explored its antifibrotic mechanism. In vivo and in vitro investigations were carried out to investigate the efficacy and mechanism of action of pazopanib in pulmonary fibrosis.

RESULTS: In vivo experiments showed that pazopanib can alleviate pulmonary fibrosis caused by BLM, reduce the degree of collagen deposition and improve lung function. In vitro experiments showed that pazopanib suppressed transforming growth factor-β1 (TGF-β1)-induced myofibroblast activation and promoted apoptosis and autophagy in myofibroblasts. Further mechanistic studies demonstrated that pazopanib inhibited the TGF-β1/Smad and non-Smad signaling pathways during fibroblast activation.

CONCLUSIONS: In conclusion, pazopanib attenuated BLM-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway. Pazopanib inhibits myofibroblast activation, migration, autophagy, apoptosis, and extracellular matrix (ECM) buildup by downregulating the TGF-β1/Smad signal route and the TGF-β1/non-Smad signal pathway. It has the same target as nintedanib and is a tyrosine kinase inhibitor.

PMID:38738240 | PMC:PMC11087596 | DOI:10.21037/jtd-23-1349

J Med Life. 2024 Jan;17(1):35-40. doi: 10.25122/jml-2023-0324.

ABSTRACT

Pulmonary hypertension (PH) often complicates idiopathic pulmonary fibrosis (IPF), a progressive parenchymal lung disease. We investigated predictors of PH in IPF hospitalizations in the United States. We identified IPF hospital- izations with or without PH using the National Inpatient Sample (2018) and relevant ICD-10-CM codes. We com- pared demographics, comorbidities, PH prevalence, and its multivariable predictors adjusted for confounders among patients with IPF. In 2018, 30,335 patients from 30,259,863 hospitalizations had IPF, of which 8,075 (26.6%) had PH. Black (41%), Hispanic (21.3%), and female (28.7%) patients had higher rates of PH compared to white patients (25%). The IPF-PH cohort was hospitalized more often in urban teaching (77.7% vs. 72.2%), Midwest, and West hospitals vs. non-PH cohort. Comorbidities including congestive heart failure (2.08 [1.81-2.39]), valvular disease (2.12 [1.74-2.58]), rheumatoid arthritis/collagen vascular disease (1.32 [1.08-1.61]) predicted higher odds of PH. The PH-IPF cohort was less often routinely discharged (35.4%) and more likely to be transferred to intermediate care facilities (22.6%) and home health care (27.1%) (P < 0.001). The PH-IPF group had higher rates of all-cause mortality (12.3% vs. 9.4%), cardiogenic shock (2.4% vs. 1%), dysrhythmia (37.6% vs. 29%), and cardiac arrest (2.7% vs. 1.5%) vs. non-PH cohort (all P < 0.001). Patients with PH-IPF also had longer hospital stays (9 vs. 8) and a higher median cost ($23,054 vs. $19,627, P < 0.001). Nearly 25% of IPF hospitalizations with PH were linked to higher mortality, extended stays, and costs, emphasizing the need to integrate demographic and comorbidity predictors into risk stratification for improved outcomes in patients with IPF-PH.

PMID:38737661 | PMC:PMC11080510 | DOI:10.25122/jml-2023-0324

J Respir Biol Transl Med. 2024 Jun;1(2):10006. doi: 10.35534/jrbtm.2024.10006. Epub 2024 Apr 30.

ABSTRACT

The molecular mechanisms that regulate progressive pulmonary fibrosis remain poorly understood. Type 2 alveolar epithelial cells (AEC2s) function as adult stem cells in the lung. We previously showed that there is a loss of AEC2s and a failure of AEC2 renewal in the lungs of idiopathic pulmonary fibrosis (IPF) patients. We also reported that beta-arrestins are the key regulators of fibroblast invasion, and beta-arrestin 1 and 2 deficient mice exhibit decreased mortality, decreased matrix deposition, and increased lung function in bleomycin-induced lung fibrosis. However, the role of beta-arrestins in AEC2 regeneration is unclear. In this study, we investigated the role and mechanism of Arrestin beta 1 (ARRB1) in AEC2 renewal and in lung fibrosis. We used conventional deletion as well as cell type-specific deletion of ARRB1 in mice and found that Arrb1 deficiency in fibroblasts protects mice from lung fibrosis, and the knockout mice exhibit enhanced AEC2 regeneration in vivo, suggesting a role of fibroblast-derived ARRB1 in AEC2 renewal. We further found that Arrb1-deficient fibroblasts promotes AEC2 renewal in 3D organoid assays. Mechanistically, we found that CCL7 is among the top downregulated cytokines in Arrb1 deficient fibroblasts and CCL7 inhibits AEC2 regeneration in 3D organoid experiments. Therefore, fibroblast ARRB1 mediates AEC2 renewal, possibly by releasing chemokine CCL7, leading to fibrosis in the lung.

PMID:38736470 | PMC:PMC11087074 | DOI:10.35534/jrbtm.2024.10006

J Med Invest. 2024;71(1.2):9-22. doi: 10.2152/jmi.71.9.

ABSTRACT

Patients with interstitial lung disease (ILD), especially those with idiopathic pulmonary fibrosis, are at increased risk of developing lung cancer (LC). Pharmacotherapy for advanced LC has dramatically progressed in recent years;however, management of LC with pre-existing ILD (LC-ILD) is challenging due to serious concerns about the risk of acute exacerbation of ILD (AE-ILD). As patients with LC-ILD have been excluded from most prospective clinical trials of advanced LC, optimal pharmacotherapy remains to be elucidated. Although the antitumor activity of first-line platinum-based cytotoxic chemotherapy appears to be similar in advanced LC patients with or without ILD, its impact on the survival of patients with LC-ILD is limited. Immune checkpoint inhibitors may hold promise for long-term survival, but many challenges remain, including safety and appropriate patient selection. Further understanding the predictive factors for AE-ILD after receiving pharmacotherapy in LC-ILD may lead to appropriate patient selection and lower treatment risk. The aim of this review was to summarize the current evidence related to pharmacotherapy for advanced LC-ILD and discuss emerging areas of research. J. Med. Invest. 71 : 9-22, February, 2024.

PMID:38735730 | DOI:10.2152/jmi.71.9