Therapeutic potential of dexamethasone Nano chitosan synthesized from chitosan as a novel treatment of pulmonary fibrosis in C57BL/6 mice

In March 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was declared a global pandemic by the World Health Organization (WHO). The clinical course of the disease is unpredictable but may lead to severe acute respiratory infection (SARI) and pneumonia leading to acute respiratory distress syndrome (ARDS). It has been shown that pulmonary fibrosis may be one of the major long-term complications of COVID-19. In animal models, the use of spironolactone was proven to be an important drug in the prevention of pulmonary fibrosis. Through its dual action as a mineralocorticoid receptor (MR) antagonist and an androgenic inhibitor, spironolactone can provide significant benefits concerning COVID-19 infection. The primary effect of spironolactone in reducing pulmonary edema may also be beneficial in COVID-19 ARDS. Spironolactone is a well-known, widely used and safe anti-hypertensive and antiandrogenic medication. It has potassium-sparing diuretic action by antagonizing mineralocorticoid receptors (MRs). Spironolactone and potassium canrenoate, exerting combined pleiotropic action, may provide a therapeutic benefit to patients with COVID-19 pneumonia through antiandrogen, MR blocking, antifibrotic and anti-hyperinflammatory action. It has been proposed that spironolactone may prevent acute lung injury in COVID-19 infection due to its pleiotropic effects with favorable renin–angiotensin–aldosterone system (RAAS) and ACE2 expression, reduction in transmembrane serine protease 2 (TMPRSS2) activity and antiandrogenic action, and therefore it may prove to act as additional protection for patients at highest risk of severe pneumonia. Future prospective clinical trials are warranted to evaluate its therapeutic potential.

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Idiopathic pulmonary fibrosis: unmasking cryptogenic environmental factors

European Respiratory Journal ◽

10.1183/13993003.01699-2018 ◽

2019 ◽

Vol 53 (2) ◽

pp. 1801699 ◽

Cited By ~ 6

Author(s):

Coralynn Sack ◽

Ganesh Raghu

Keyword(s):

Environmental Factors ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Treatment Modality ◽

Unknown Origin ◽

Clinical Implications ◽

High Morbidity ◽

Novel Treatment ◽

Progression Of Disease ◽

Fibrotic Lung Disease

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease of unknown origin that is associated with high morbidity and mortality. In this perspective, we briefly review the current understanding of the pathophysiology of IPF and the importance of environmental triggers as a precipitant of disease. We discuss occult intrinsic and extrinsic environmental factors that affect the lung microenvironment and may contribute to the development and progression of disease. The clinical implications of this framework need to be further elucidated, because prompt identification and elimination of occult exposures may represent a novel treatment modality.

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Human menstrual blood-derived stem cells mitigate bleomycin-induced pulmonary fibrosis through anti-apoptosis and anti-inflammatory effects

Stem Cell Research & Therapy ◽

10.1186/s13287-020-01926-x ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Xin Chen ◽

Yi Wu ◽

Yanling Wang ◽

Lijun Chen ◽

Wendi Zheng ◽

...

Keyword(s):

Stem Cells ◽

Pulmonary Fibrosis ◽

Therapeutic Potential ◽

Lung Fibroblasts ◽

Menstrual Blood ◽

Inflammatory Factors ◽

Mouse Lung ◽

Control Group ◽

Antibody Array

Abstract Background Idiopathic pulmonary fibrosis is a kind of diffuse interstitial lung disease, the pathogenesis of which is unclear, and there is currently a lack of good treatment to improve the survival rate. Human menstrual blood-derived mesenchymal stem cells (MenSCs) have shown great potential in regenerative medicine. This study aimed to explore the therapeutic potential of MenSCs for bleomycin-induced pulmonary fibrosis. Methods We investigated the transplantation of MenSCs in a pulmonary fibrosis mouse model induced by BLM. Mouse was divided into three groups: control group, BLM group, MenSC group. Twenty-one days after MenSC transplantation, we examined collagen content, pathological, fibrosis area in the lung tissue, and the level of inflammatory factors of serum. RNA sequence was used to examine the differential expressed gene between three groups. Transwell coculture experiments were further used to examine the function of MenSCs to MLE-12 cells and mouse lung fibroblasts (MLFs) in vitro. Results We observed that transplantation of MenSCs significantly improves pulmonary fibrosis mouse through evaluations of pathological lesions, collagen deposition, and inflammation. Transwell coculturing experiments showed that MenSCs suppress the proliferation and the differentiation of MLFs and inhibit the apoptosis of MLE-12 cells. Furthermore, antibody array results demonstrated that MenSCs inhibit the apoptosis of MLE-12 cells by suppressing the expression of inflammatory-related cytokines, including RANTES, Eotaxin, GM-CSF, MIP-1γ, MCP-5, CCL1, and GITR. Conclusions Collectively, our results suggested MenSCs have a great potential in the treatment of pulmonary fibrosis, and cytokines revealed in antibody array are expected to become the target of future therapy of MenSCs in clinical treatment of pulmonary fibrosis.

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HDAC8 inhibition ameliorates pulmonary fibrosis

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00551.2017 ◽

2019 ◽

Vol 316 (1) ◽

pp. L175-L186 ◽

Cited By ~ 9

Author(s):

Shigeki Saito ◽

Yan Zhuang ◽

Takayoshi Suzuki ◽

Yosuke Ota ◽

Marjorie E. Bateman ◽

...

Keyword(s):

Smooth Muscle ◽

Pulmonary Fibrosis ◽

Transforming Growth Factor ◽

Therapeutic Potential ◽

Smooth Muscle Actin ◽

Lung Fibroblasts ◽

Peroxisome Proliferator ◽

Collagen Gels ◽

Cell Contractility

Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative lung disease, and fibroblast-myofibroblast differentiation (FMD) is thought to be a key event in the pathogenesis of IPF. Histone deacetylase-8 (HDAC8) has been shown to associate with α-smooth muscle actin (α-SMA; a marker of FMD) and regulates cell contractility in vascular smooth muscle cells. However, the role of HDAC8 in FMD or pulmonary fibrosis has never been reported. This study investigated the role of HDAC8 in pulmonary fibrosis with a focus on FMD. We observed that HDAC8 expression was increased in IPF lung tissue as well as transforming growth factor (TGF)β1-treated normal human lung fibroblasts (NHLFs). Immunoprecipitation experiments revealed that HDAC8 was associated with α-SMA in TGFβ1-treated NHLFs. HDAC8 inhibition with NCC170 (HDAC8-selective inhibitor) repressed TGFβ1-induced fibroblast contraction and α-SMA protein expression in NHLFs cultured in collagen gels. HDAC8 inhibition with HDAC8 siRNA also repressed TGFβ1-induced expression of profibrotic molecules such as fibronectin and increased expression of antifibrotic molecules such as peroxisome proliferator-activated receptor-γ (PPARγ). Chromatin immunoprecipitation quantitative PCR using an antibody against H3K27ac (histone H3 acetylated at lysine 27; a known HDAC8 substrate and a marker for active enhancers) suggested that HDAC8 inhibition with NCC170 ameliorated TGFβ1-induced loss of H3K27ac at the PPARγ gene enhancer. Furthermore, NCC170 treatment significantly decreased fibrosis measured by Ashcroft score as well as expression of type 1 collagen and fibronectin in bleomycin-treated mouse lungs. These data suggest that HDAC8 contributes to pulmonary fibrosis and that there is a therapeutic potential for HDAC8 inhibitors to treat IPF as well as other fibrotic lung diseases.

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Potential of imatinib mesylate as a novel treatment for pulmonary fibrosis

Expert Review of Respiratory Medicine ◽

10.1586/17476348.2.4.419 ◽

2008 ◽

Vol 2 (4) ◽

pp. 419-431

Author(s):

Mantej Chhina ◽

Oksana A Shlobin ◽

Geraldine Grant ◽

Steven D Nathan

Keyword(s):

Pulmonary Fibrosis ◽

Imatinib Mesylate ◽

Novel Treatment

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Hydrogen Peroxide Preconditioning Promotes Protective Effects of Umbilical Cord Vein Mesenchymal Stem Cells in Experimental Pulmonary Fibrosis

Advanced Pharmaceutical Bulletin ◽

10.15171/apb.2020.009 ◽

2019 ◽

Vol 10 (1) ◽

pp. 72-80 ◽

Cited By ~ 1

Author(s):

Tayebeh Mahmoudi ◽

Kamal Abdolmohammadi ◽

Hamed Bashiri ◽

Mehdi Mohammadi ◽

Mohammad Jafar Rezaie ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Umbilical Cord ◽

Lung Tissue ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Therapeutic Potential ◽

Human Umbilical Cord ◽

Therapeutic Effects ◽

Umbilical Cord Vein ◽

Tgf Β1

Purpose: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disorder with few available treatments. Mesenchymal stem cell therapy (MSCT), an innovative approach, has high therapeutic potential when used to treat IPF. According to recent data, preconditioning of MSCs can improve their therapeutic effects. Our research focuses on investigating the anti-inflammatory and antifibrotic effects of H2 O2 -preconditioned MSCs (p-MSCs) on mice with bleomycin-induced pulmonary fibrosis (PF). Methods: Eight-week-old male C57BL/6 mice were induced with PF by intratracheal (IT) instillation of bleomycin (4 U/kg). Human umbilical cord vein-derived MSCs (hUCV-MSCs) were isolated and exposed to a sub-lethal concentration (15 μM for 24 h) of H2 O2 in vitro. One week following the injection of bleomycin, 2×105 MSCs or p-MSCs were injected (IT) into the experimental PF. The survival rate and weight of mice were recorded, and 14 days after MSCs injection, all mice were sacrificed. Lung tissue was removed from these mice to examine the myeloperoxidase (MPO) activity, histopathological changes (hematoxylin-eosin and Masson’s trichrome) and expression of transforming growth factor beta 1 (TGF-β1) and alpha-smooth muscle actin (α-SMA) through immunohistochemistry (IHC) staining. Results: Compared to the PF+MSC group, p-MSCs transplantation results in significantly decreased connective tissue (P<0.05) and collagen deposition. Additionally, it is determined that lung tissue in the PF+pMSC group has increased alveolar space (P<0.05) and diminished expression of TGF-β1 and α-SMA. Conclusion: The results demonstrate that MSCT using p-MSCs decreases inflammatory and fibrotic factors in bleomycin-induced PF, while also able to increase the therapeutic potency of MSCT in IPF

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PTX3 Regulation of Inflammation, Hemostatic Response, Tissue Repair, and Resolution of Fibrosis Favors a Role in Limiting Idiopathic Pulmonary Fibrosis

Frontiers in Immunology ◽

10.3389/fimmu.2021.676702 ◽

2021 ◽

Vol 12 ◽

Author(s):

Andrea Doni ◽

Alberto Mantovani ◽

Barbara Bottazzi ◽

Remo Castro Russo

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Lung Fibrosis ◽

Tissue Repair ◽

Therapeutic Potential ◽

Tissue Injury ◽

Life Quality ◽

Unknown Origin ◽

Protective Role

PTX3 is a soluble pattern recognition molecule (PRM) belonging to the humoral innate immune system, rapidly produced at inflammatory sites by phagocytes and stromal cells in response to infection or tissue injury. PTX3 interacts with microbial moieties and selected pathogens, with molecules of the complement and hemostatic systems, and with extracellular matrix (ECM) components. In wound sites, PTX3 interacts with fibrin and plasminogen and favors a timely removal of fibrin-rich ECM for an efficient tissue repair. Idiopathic Pulmonary Fibrosis (IPF) is a chronic and progressive interstitial lung disease of unknown origin, associated with excessive ECM deposition affecting tissue architecture, with irreversible loss of lung function and impact on the patient’s life quality. Maccarinelli et al. recently demonstrated a protective role of PTX3 using the bleomycin (BLM)-induced experimental model of lung fibrosis, in line with the reported role of PTX3 in tissue repair. However, the mechanisms and therapeutic potential of PTX3 in IPF remained to be investigated. Herein, we provide new insights on the possible role of PTX3 in the development of IPF and BLM-induced lung fibrosis. In mice, PTX3-deficiency was associated with worsening of the disease and with impaired fibrin removal and subsequently increased collagen deposition. In IPF patients, microarray data indicated a down-regulation of PTX3 expression, thus suggesting a potential rational underlying the development of disease. Therefore, we provide new insights for considering PTX3 as a possible target molecule underlying therapeutic intervention in IPF.

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