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17 pages, 2401 KiB

Open AccessArticle

Ameliorating Fibrosis in Murine and Human Tissues with END55, an Endostatin-Derived Fusion Protein Made in Plants

by Logan Mlakar, Sara M. Garrett, Tomoya Watanabe, Matthew Sanderson, Tetsuya Nishimoto, Jonathan Heywood, Kristi L. Helke, Joseph M. Pilewski, Erica L. Herzog and Carol Feghali-Bostwick

Biomedicines 2022, 10(11), 2861; https://doi.org/10.3390/biomedicines10112861 - 09 Nov 2022

Cited by 2 | Viewed by 1853

Abstract

Organ fibrosis, particularly of the lungs, causes significant morbidity and mortality. Effective treatments are needed to reduce the health burden. A fragment of the carboxyl-terminal end of collagen XVIII/endostatin reduces skin and lung fibrosis. This fragment was modified to facilitate its production in [...] Read more.

Organ fibrosis, particularly of the lungs, causes significant morbidity and mortality. Effective treatments are needed to reduce the health burden. A fragment of the carboxyl-terminal end of collagen XVIII/endostatin reduces skin and lung fibrosis. This fragment was modified to facilitate its production in plants, which resulted in the recombinant fusion protein, END55. We found that expression of END55 had significant anti-fibrotic effects on the treatment and prevention of skin and lung fibrosis in a bleomycin mouse model. We validated these effects in a second mouse model of pulmonary fibrosis involving inducible, lung-targeted expression of transforming growth factor β1. END55 also exerted anti-fibrotic effects in human lung and skin tissues maintained in organ culture in which fibrosis was experimentally induced. The anti-fibrotic effect of END55 was mediated by a decrease in the expression of extracellular matrix genes and an increase in the levels of matrix-degrading enzymes. Finally, END55 reduced fibrosis in the lungs of patients with systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF) who underwent lung transplantation due to the severity of their lung disease, displaying efficacy in human tissues directly relevant to human disease. These findings demonstrate that END55 is an effective anti-fibrotic therapy in different organs. Full article

(This article belongs to the Special Issue Treatment for Pulmonary Fibrosis)

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21 pages, 7592 KiB

Open AccessArticle

Therapeutic Effects of Omentin-1 on Pulmonary Fibrosis by Attenuating Fibroblast Activation via AMP-Activated Protein Kinase Pathway

by Yan Zhou, Yunna Zhang, Haipeng Cheng, Xiaohong Li, Dandan Feng, Shaojie Yue, Jianping Xu, Hui Xie and Ziqiang Luo

Biomedicines 2022, 10(11), 2715; https://doi.org/10.3390/biomedicines10112715 - 26 Oct 2022

Cited by 2 | Viewed by 1605

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal age-related chronic lung disease, characterized by progressive scarring of the lungs by activated fibroblasts. The effect of omentin-1 against pulmonary fibrosis and fibroblast activation has not been investigated. The purpose of this experiment is to investigate [...] Read more.

Idiopathic pulmonary fibrosis (IPF) is a fatal age-related chronic lung disease, characterized by progressive scarring of the lungs by activated fibroblasts. The effect of omentin-1 against pulmonary fibrosis and fibroblast activation has not been investigated. The purpose of this experiment is to investigate the role of omentin-1 in bleomycin (BLM)-induced lung fibrosis and its mechanism. Our results showed that the loss of omentin-1 exaggerated lung fibrosis induced by BLM. On the contrary, adenoviral-overexpression of omentin-1 significantly alleviated BLM-induced lung fibrosis both in preventive and therapeutic regimens. Moreover, omentin-1 prevented fibroblast activation determined by a decreased number of S100A4⁺ (fibroblasts marker) α-SMA⁺ cells in vivo, and a decreased level of α-SMA expression both in mice primary fibroblasts and human primary fibroblasts induced by TGF-β in vitro. Furthermore, the phosphorylation of AMP-activated protein kinase (p-AMPK) was significantly lower in the fibrotic foci induced by BLM, and the adenoviral-overexpression of omentin-1 significantly increased the p-AMPK level in vivo. Importantly, Compound C, the inhibitor of AMPK, significantly attenuated the protective effect of omentin-1 on BLM-induced lung fibrosis and reversed the effect of omentin-1 on fibroblast activation by TGF-β. Omentin-1 can be a promising therapeutic agent for the prevention and treatment of lung fibrosis. Full article

(This article belongs to the Special Issue Treatment for Pulmonary Fibrosis)

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11 pages, 284 KiB

Open AccessArticle

Positive Autoantibody Is Associated with Malignancies in Patients with Idiopathic Interstitial Pneumonias

by Takuma Koga, Masaki Okamoto, Minoru Satoh, Kiminori Fujimoto, Yoshiaki Zaizen, Tomonori Chikasue, Akiko Sumi, Shinjiro Kaieda, Norikazu Matsuo, Goushi Matama, Takashi Nouno, Masaki Tominaga, Kazuhiro Yatera, Hiroaki Ida and Tomoaki Hoshino

Biomedicines 2022, 10(10), 2469; https://doi.org/10.3390/biomedicines10102469 - 02 Oct 2022

Cited by 2 | Viewed by 1315

Abstract

Various autoantibodies are associated with clinical outcomes in patients with idiopathic interstitial pneumonias (IIPs). We retrospectively analyzed the association between autoantibodies and malignancies in IIP patients. Comprehensive analyses of autoantibodies were performed using immunoprecipitation and enzyme-linked immunosorbent assays in 193 consecutive IIP patients. [...] Read more.

Various autoantibodies are associated with clinical outcomes in patients with idiopathic interstitial pneumonias (IIPs). We retrospectively analyzed the association between autoantibodies and malignancies in IIP patients. Comprehensive analyses of autoantibodies were performed using immunoprecipitation and enzyme-linked immunosorbent assays in 193 consecutive IIP patients. Cancer-related factors were analyzed using logistic regression analysis. In total, 22 of 193 patients (11.4%) with IIP had malignant disease. In univariate analysis, positivity for any autoantibody (odds ratio (OR), 3.1; 95% confidence interval (CI), 1.2–7.7; p = 0.017) and antinuclear antibody titer ≥1:320 (OR, 3.4; CI, 1.2–9.8; p = 0.024) were significantly associated with malignancies. Positive anti-aminoacyl tRNA synthetase (ARS) (OR, 3.7; CI, 0.88–15.5; p = 0.074) and anti-Ro52 antibody (OR, 3.2; CI, 0.93–11.2; p = 0.065) tended to be associated with malignancies. In multivariate analysis, independent risk factors were male sex (OR, 3.7; CI, 1.0–13.5; p = 0.029) and positivity for any autoantibody (OR, 3.9; CI, 1.5–10.1; p = 0.004) in model 1, and male sex (OR, 3.9; CI, 1.0–15.3; p = 0.049), antinuclear antibody titer ≥1:320 (OR, 4.2; CI, 1.4–13.3; p = 0.013), and positivity for anti-ARS antibody (OR, 6.5; CI, 1.2–34.1; p = 0.026) in model 2. Positivity for any autoantibody, antinuclear and anti-ARS antibodies, and male sex were independent risk factors for malignancies in IIP patients. Testing autoantibodies in IIP patients might help the early diagnosis of malignancies. Full article

(This article belongs to the Special Issue Treatment for Pulmonary Fibrosis)

16 pages, 1406 KiB

Open AccessArticle

Safety and Effectiveness of Abatacept in a Prospective Cohort of Patients with Rheumatoid Arthritis–Associated Interstitial Lung Disease

by Natalia Mena-Vázquez, Marta Rojas-Gimenez, Clara Fuego-Varela, Aimara García-Studer, Nair Perez-Gómez, Carmen María Romero-Barco, Francisco Javier Godoy-Navarrete, Sara Manrique-Arija, Myriam Gandía-Martínez, Jerusalem Calvo-Gutiérrez, Pilar Morales-Garrido, Coral Mouriño-Rodriguez, Patricia Castro-Pérez, Isabel Añón-Oñate, Francisco Espildora, María Carmen Aguilar-Hurtado, Ana Hidalgo Conde, Rocío Arnedo Díez de los Ríos, Eva Cabrera César, Rocío Redondo-Rodriguez, María Luisa Velloso-Feijoo and Antonio Fernández-Nebro Show full author list Hide full author list

Biomedicines 2022, 10(7), 1480; https://doi.org/10.3390/biomedicines10071480 - 22 Jun 2022

Cited by 9 | Viewed by 2363

Abstract

Objective: To prospectively evaluate the safety and efficacy profile of abatacept in patients with rheumatoid arthritis–associated interstitial lung disease (RA-ILD). Methods: We performed a prospective observational multicenter study of a cohort of patients with RA-ILD treated with abatacept between 2015 and 2021. Patients [...] Read more.

Objective: To prospectively evaluate the safety and efficacy profile of abatacept in patients with rheumatoid arthritis–associated interstitial lung disease (RA-ILD). Methods: We performed a prospective observational multicenter study of a cohort of patients with RA-ILD treated with abatacept between 2015 and 2021. Patients were evaluated using high-resolution computed tomography and pulmonary function tests at initiation, 12 months, and the end of follow-up. The effectiveness of abatacept was evaluated based on whether ILD improved, stabilized, progressed, or was fatal. We also evaluated factors such as infection, hospitalization, and inflammatory activity using the 28-joint Disease Activity Score with the erythrocyte sedimentation rate (DAS28-ESR). Cox regression analysis was performed to identify factors associated with progression of lung disease. Results: The study population comprised 57 patients with RA-ILD treated with abatacept for a median (IQR) of 27.3 (12.2–42.8) months. Lung disease had progressed before starting abatacept in 45.6% of patients. At the end of follow-up, lung disease had improved or stabilized in 41 patients (71.9%) and worsened in 13 (22.8%); 3 patients (5.3%) died. No significant decreases were observed in forced vital capacity (FVC) or in the diffusing capacity of the lung for carbon monoxide (DLCO).The factors associated with progression of RA-ILD were baseline DAS28-ESR (OR [95% CI], 2.52 [1.03–3.12]; p = 0.041), FVC (OR [95% CI], 0.82 [0.70–0.96]; p = 0.019), and DLCO (OR [95% CI], 0.83 [0.72–0.96]; p = 0.018). Only 10.5% of patients experienced severe adverse effects. Conclusion: Pulmonary function and joint inflammation stabilized in 71% of patients with RA-ILD treated with abatacept. Abatacept had a favorable safety profile. Full article

(This article belongs to the Special Issue Treatment for Pulmonary Fibrosis)

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14 pages, 6088 KiB

Open AccessArticle

Imaging Changes and Immune-Checkpoint Expression on T Cells in Bronchoalveolar Lavage Fluid from Patients with Pulmonary Sarcoidosis

by Yasuaki Kotetsu, Toyoshi Yanagihara, Kunihiro Suzuki, Hiroyuki Ando, Daisuke Eto, Kentaro Hata, Masako Arimura-Omori, Yuzo Yamamoto, Eiji Harada and Naoki Hamada

Biomedicines 2021, 9(9), 1231; https://doi.org/10.3390/biomedicines9091231 - 16 Sep 2021

Cited by 2 | Viewed by 2028

Abstract

Sarcoidosis is a systemic, granulomatous disease caused by unknown immunological abnormalities. The organs most vulnerable to sarcoidosis are the lungs. Patients often resolve spontaneously, but the lungs can also be severely affected. Although details regarding prognostic factors in sarcoidosis patients with lung involvement [...] Read more.

Sarcoidosis is a systemic, granulomatous disease caused by unknown immunological abnormalities. The organs most vulnerable to sarcoidosis are the lungs. Patients often resolve spontaneously, but the lungs can also be severely affected. Although details regarding prognostic factors in sarcoidosis patients with lung involvement remain unclear, several reports have suggested that immune checkpoint molecules are involved in the pathogenesis of sarcoidosis. In this study, we divided sarcoidosis patients into two groups based on chest computed tomography (CT) findings and compared immune checkpoint molecules expressed on T cells in bronchoalveolar lavage fluid (BALF) in the two groups, using flow cytometry. We found elevated programmed cell death 1 (PD-1) or T cell immunoglobulin- and mucin-domain-containing molecule-3 (TIM-3) expression on T cells in BALF in patients with spontaneous improvement in CT findings, compared with those in patients without improvement in CT findings. In conclusion, our study implies that PD-1 or TIM-3 expression on T cells in BALF may be a prognostic factor for pulmonary lesions in sarcoidosis. Full article

(This article belongs to the Special Issue Treatment for Pulmonary Fibrosis)

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Review

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10 pages, 279 KiB

Open AccessReview

Mesenchyme Stem Cell-Derived Conditioned Medium as a Potential Therapeutic Tool in Idiopathic Pulmonary Fibrosis

by George Kolios and Vasilis Paspaliaris

Biomedicines 2022, 10(9), 2298; https://doi.org/10.3390/biomedicines10092298 - 16 Sep 2022

Cited by 3 | Viewed by 2264

Abstract

Mesenchyme Stem Cells (MSCs) are the most used types of stem cells in regenerative medicine. Regenerative medicine is a rapidly emerging medicine section that creates new methods to regrow, restore, and replace diseased and damaged tissues, organs, and cells. Scholars have shown a [...] Read more.

Mesenchyme Stem Cells (MSCs) are the most used types of stem cells in regenerative medicine. Regenerative medicine is a rapidly emerging medicine section that creates new methods to regrow, restore, and replace diseased and damaged tissues, organs, and cells. Scholars have shown a positive correlation between MSCs-based therapies and successful treatment of diseases like cardiac ischemia, cartilage problems, bone diseases, diabetes, and even neurological disorders. Although MSCs have several varying features that make them unique, their immuno-regulatory effects in tissue repair emerge from their secretion of paracrine growth factors, exosomes, and cytokines. These cells secrete a secretome, which has regenerative and reparative properties that lead to injury amelioration, immune modulation, or fibrosis reduction. Recent studies have shown that the administration MCSs derived conditioned medium (MSCs-CM) in acute doses in humans is safe and well-tolerated. Studies from animal models and human clinical trials have also shown that they are efficacious tools in regenerative medicine. In this review, we will explore the therapeutic potential of MSCs-CM in pulmonary fibrosis, with further insight into the treatment of Idiopathic Pulmonary Fibrosis (IPF). Full article

(This article belongs to the Special Issue Treatment for Pulmonary Fibrosis)

12 pages, 2039 KiB

Open AccessReview

Insights into Potential Pathogenesis and Treatment Options for Immune-Checkpoint Inhibitor-Related Pneumonitis

by Hiroyuki Ando, Kunihiro Suzuki and Toyoshi Yanagihara

Biomedicines 2021, 9(10), 1484; https://doi.org/10.3390/biomedicines9101484 - 16 Oct 2021

Cited by 11 | Viewed by 3355

Abstract

Immune-checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death-1 (PD-1), and programmed cell death-1-ligand 1 (PD-L1) have become new treatment options for various malignancies. ICIs bind to immune-checkpoint inhibitory receptors or to the foregoing ligands and block inhibitory signals to [...] Read more.

Immune-checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death-1 (PD-1), and programmed cell death-1-ligand 1 (PD-L1) have become new treatment options for various malignancies. ICIs bind to immune-checkpoint inhibitory receptors or to the foregoing ligands and block inhibitory signals to release the brakes on the immune system, thereby enhancing immune anti-tumor responses. On the other hand, unlike conventional chemotherapies, ICIs can cause specific side effects, called immune-related adverse events (irAEs). These toxicities may affect various organs, including the lungs. ICI-related pneumonitis (ICI-pneumonitis) is not the most frequent adverse event, but it is serious and can be fatal. In this review, we summarize recent findings regarding ICI-pneumonitis, with a focus on potential pathogenesis and treatment. Full article

(This article belongs to the Special Issue Treatment for Pulmonary Fibrosis)

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11 pages, 282 KiB

Open AccessReview

Progressive Fibrosing Interstitial Lung Diseases: A Current Perspective

by Carlo Albera, Giulia Verri, Federico Sciarrone, Elena Sitia, Mauro Mangiapia and Paolo Solidoro

Biomedicines 2021, 9(9), 1237; https://doi.org/10.3390/biomedicines9091237 - 16 Sep 2021

Cited by 11 | Viewed by 3461

Abstract

Interstitial lung diseases (ILDs) are a large and diverse group of rare and chronic respiratory disorders, with idiopathic pulmonary fibrosis (IPF) being the most common and best-studied member. Increasing interest in fibrosis as a therapeutic target and the appreciation that fibrotic mechanisms may [...] Read more.

Interstitial lung diseases (ILDs) are a large and diverse group of rare and chronic respiratory disorders, with idiopathic pulmonary fibrosis (IPF) being the most common and best-studied member. Increasing interest in fibrosis as a therapeutic target and the appreciation that fibrotic mechanisms may be a treatable target of IPF prompted the development and subsequent approval of the antifibrotics, pirfenidone and nintedanib. The management of ILDs has changed considerably following an understanding that IPF and some ILDs share similar disease behavior of progressive fibrosis, termed “progressive fibrosing phenotype”. Indeed, antifibrotic treatment has shown to be beneficial in ILDs characterized by the progressive fibrosing phenotype. This narrative review summarizes current knowledge in the field of progressive fibrosing ILDs. Here, we discuss the clinical characteristics and pathogenesis of lung fibrosis and highlight relevant literature concerning the mechanisms underlying progressive fibrosing ILDs. We also summarize current diagnostic approaches and the available treatments of progressive fibrosing ILDs and address the optimization of treating progressive fibrosing ILDs with antifibrotics in clinical practice. Full article

(This article belongs to the Special Issue Treatment for Pulmonary Fibrosis)

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