Dysregulated bidirectional epithelial-mesenchymal crosstalk:A core determinant of lung fibrosis progression

Progressive lung fibrosis is characterized by dysregulated extracellular matrix(ECM)homeostasis.Understand-ing of disease pathogenesis remains limited and has prevented the development of effective treatments.While an abnormal wound-healing response is strongly implicated in lung fibrosis initiation,factors that determine why fi-brosis progresses rather than regular tissue repair occur are not fully explained.Within human lung fibrosis,there is evidence of altered epithelial and mesenchymal populations as well as cells undergoing epithelial-mesenchymal transition(EMT),a dynamic and reversible biological process by which epithelial cells lose their cell polarity and down-regulate cadherin-mediated cell-cell adhesion to gain migratory properties.This review will focus on the role of EMT and dysregulated epithelial-mesenchymal crosstalk in progressive lung fibrosis.

Vitamin D attenuates TGF-β1-induced lung fibroblast proliferation and migration through repression of RasGRP3

Background:Transforming growth factor-β1(TGF-β1)is a pleiotropic cytokine that plays a central role in the pathogenesis of idiopathic pulmonary fibrosis(IPF).While previous studies have revealed a cross-talk between vitamin D and TGF-β1 signaling,it is still unclear how they interact with each other to regulate the progression of IPF.Methods:In this work,we searched for a novel mediator of TGF-β1 activity in lung fibroblasts and examined its regulation by vitamin D.In addition,we investigated the mechanism underlying the interaction between vitamin D and TGF-β1 signaling in lung fibroblast activation.Bioinformatic analysis was performed to identify TGF-β1 downstream target genes.Knockdown and overexpression expression experiments were conducted to determine gene function in the regulation of lung fibroblast proliferation and migration.Results:Analysis of publicly available datasets revealed that RAS guanyl releasing protein 3(RasGRP3)was upregulated in TGF-β1-treated lung fibroblasts and lung tissues from IPF patients relative to healthy controls.Our data confirmed the upregulation of RasGRP3 by TGF-β1 in human MRC5 lung fibroblasts.Overexpression of RasGRP3 enhanced MRC5 cell proliferation and migration.Knockdown of RasGRP3 blocked TGF-β1-induced MRC5 proliferation and migration.Vitamin D abolished TGF-β1-induced RasGRP3 upregulation,which was reversed by inhibition of the vitamin D receptor(VDR).Mechanistically,vitamin D promoted VDR enrichment and prevented mothers against decapentaplegic homolog(SMAD)2 and 3 occupancy at the promoter of RasGRP3.Additionally,overexpression of RasGRP3 reversed the suppressive effect of vitamin D on MRC5 cell proliferation and migration.Conclusion:In conclusion,vitamin D antagonizes TGF-β1-induced lung fibroblast activation by repressing RasGRP3 transcription.

Progress in drug delivery system for fibrosis therapy

Fibrosis is a necessary process in the progression of chronic disease to cirrhosis or even cancer,which is a serious disease threatening human health.Recent studies have shown that the early treatment of fibrosis is turning point and particularly important.Therefore,how to reverse fibrosis has become the focus and research hotspot in recent years.So far,the considerable progress has been made in the development of effective anti-fibrosis drugs and targeted drug delivery.Moreover,the existing research results will lay the foundation for more breakthrough delivery systems to achieve better anti-fibrosis effects.Herein,this review summaries anti-fibrosis delivery systems focused on three major organ fibrotic diseases such as liver,pulmonary,and renal fibrosis accompanied by the elaboration of relevant pathological mechanisms,which will provide inspiration and guidance for the design of fibrosis drugs and therapeutic systems in the future.

The relationship between platelet endothelial cell adhesion molecule-1 and paraquat-induced lung injury in rabbits

BACKGROUND:Platelet endothelial cell adhesion molecule-1(PECAM-1),also known as CD31,is mainly distributed in vascular endothelial cells.Studies have shown that PECAM-1 is a very significant indicator of angiogenesis,and has been used as an indicator for vascular endothelial cells.The present study aimed to explore the relationship between the expression of PECAM-1 and the degree of acute lung injury(ALI) and fibrosis in paraquat(PQ) induced lung injury in rabbits.METHODS:Thirty-six adult New Zealand rabbits were randomly divided into three groups(12rabbits in each group) according to PQ dosage:8 mg/kg(group A),16 mg/kg(group B),and 32 mg/kg(group C).After PQ infusion,the rabbits were monitored for 7 days and then euthanized.The lungs were removed for histological evaluation.Masson staining was used to determine the degree of lung fibrosis(LF),and semi-quantitative immune-histochemistry analysis to determine the expression of PECAM-1.Pearson's product-moment correlation analysis was performed to evaluate the relationship between the expression of PECAM-1 and the extent of lung injuries expressed by ALI score and degree of LF.RESULTS:Rabbits in the three groups showed apparent poisoning.The rabbits survived longer in group A than in groups B and C(6.47±0.99 days vs.6.09±1.04 days vs.4.77±2.04 days)(P<0.05).ALI score was lower in group A than in groups B and C(8.33±1.03 vs.9.83±1.17 vs.11.50±1.38)(P<0.05),and there was statistically significant difference between group B and group C(P=0.03).LF was slighter in group A than in groups B and C(31.09%±2.05%vs.34.37%±1.62%vs.36.54%±0.44%)(P<0.05),and there was statistically significant difference between group B and group C(P=0.026).The PEACAM-1 expression was higher in group A than in groups B and C(20.31%±0.70%vs.19.34%±0.68%vs.18.37%±0.46%)(P<0.05),and there was statistically significant difference between group B and group C(P=0.017).Pearson's correlation analysis showed that the expression of PECAM-1 was negatively correlated to both ALI score(Coe=-0.732,P=0.001)and degree of LF(Coe=-0.779,P<0.001).CONCLUSIONS:The PECAM-1 expression significantly decreases in New Zealand rabbits after PQ poisoning,and the decrease is dose-dependent.The PECAM-1 expression is negatively correlated with ALI score and LF,showing a significant role in the development of lung injuries induced by PQ.

Rat Mesenchymal Stem Cells from Adipose Tissue Reduce Bleomycin-Induced Lung Remodeling in Late Stage

Idiopathic pulmonary fibrosis (IPF) is progressive fibrosing interstitial pneumonia of unknown cause, chronic and incurable interstitial lung disease, associated with high mortality rates and unresponsive to treatments currently available. The prevalence of IPF is estimated at approximately 20/100,000 in men and 13/100,000 in women, and the mean age at the time of diagnosis is 67 years and the median survival is 2 to 5 years. Therapies available to date, proved, therefore, only palliative measures with doubtful or unsatisfactory result. Many experimental models of pulmonary fibrosis are described. Bleomycin-induced pulmonary fibrosis is a widely used experimental model to identify and validate new therapeutic targets. We have induced pulmonary fibrosis by intratracheal bleomycin and late instillation of mesenchymal stem cells (MSC) from adipose tissue as a therapeutic proposal was used. MSC have the capacity to modulate inflammatory and immune response. Furthermore, the long-term effect of MSCs could also regulate and control to collagen deposition of the myofibroblasts, a final and pivo cell of pulmonary fibrosis. MSC from adipose tissue is an effective therapy to decrease collagen synthesis and expression in late stage of bleomycin-induced pulmonary fibrosis model, which may contribute to new therapeutic targets.

肺康灵对实验性大鼠肺纤维化的作用

肺康灵可显著降低博莱霉素所致肺纤维化大鼠肺系数，明显减轻肺间质成纤维细胞增生及炎细胞浸润，显著降低纤维化大鼠肺组织羟脯氨酸含量，降低血清过氧化脂质含量及单胺氧化酶活性。

Suppression of NLRP3 inflammasome by ivermectin ameliorates bleomycin-induced pulmonary fibrosis

Ivermectin is a US Food and Drug Administration(FDA)-approved antiparasitic agent with antiviral and anti-inflammatory properties.Although recent studies reported the possible anti-inflammatory activity of ivermectin in respiratory injuries,its potential therapeutic effect on pulmonary fibrosis(PF)has not been investigated.This study aimed to explore the ability of ivermectin(0.6 mg/kg)to alleviate bleomycin-induced biochemical derangements and histological changes in an experimental PF rat model.This can provide the means to validate the clinical utility of ivermectin as a treatment option for idiopathic PF.The results showed that ivermectin mitigated the bleomycin-evoked pulmonary injury,as manifested by the reduced infiltration of inflammatory cells,as well as decreased the inflammation and fibrosis scores.Intriguingly,ivermectin decreased collagen fiber deposition and suppressed transforming growth factor-β1(TGF-β1)and fibronectin protein expression,highlighting its anti-fibrotic activity.This study revealed for the first time that ivermectin can suppress the nucleotide-binding oligomerization domain(NOD)-like receptor family pyrin domain-containing protein 3(NLRP3)inflammasome,as manifested by the reduced gene expression of NLRP3 and the apoptosis-associated speck-like protein containing a caspase recruitment domain(ASC),with a subsequent decline in the interleukin-1β(IL-1β)level.In addition,ivermectin inhibited the expression of intracellular nuclear factor-κB(NF-κB)and hypoxia‑inducible factor‑1α(HIF-1α)proteins along with lowering the oxidative stress and apoptotic markers.Altogether,this study revealed that ivermectin could ameliorate pulmonary inflammation and fibrosis induced by bleomycin.These beneficial effects were mediated,at least partly,via the downregulation of TGF-β1 and fibronectin,as well as the suppression of NLRP3 inflammasome through modulating the expression of HIF‑1αand NF-κB.

Pulmonary fibrosis:A short-or long-term sequelae of severe COVID-19?

The pandemic of coronavirus disease 2019(COVID-19),caused by a novel severe acute respiratory syndrome(SARS)coronavirus 2(SARS-CoV-2),has caused an enormous impact on the global healthcare.SARS-CoV-2 infec-tion primarily targets the respiratory system.Although most individuals testing positive for SARS-CoV-2 present mild or no upper respiratory tract symptoms,patients with severe COVID-19 can rapidly progress to acute respira-tory distress syndrome(ARDS).ARDS-related pulmonary fibrosis is a recognized sequelae of COVID-19.Whether post-COVID-19 lung fibrosis is resolvable,persistent,or even becomes progressive as seen in human idiopathic pulmonary fibrosis(IPF)is currently not known and remains a matter of debate.With the emergence of effective vaccines and treatments against COVID-19,it is now important to build our understanding of the long-term se-quela of SARS-CoV-2 infection,to identify COVID-19 survivors who are at risk of developing chronic pulmonary fibrosis,and to develop effective anti-fibrotic therapies.The current review aims to summarize the pathogenesis of COVID-19 in the respiratory system and highlights ARDS-related lung fibrosis in severe COVID-19 and the potential mechanisms.It envisions the long-term fibrotic lung complication in COVID-19 survivors,in particular in the aged population.The early identification of patients at risk of developing chronic lung fibrosis and the development of anti-fibrotic therapies are discussed.

NLRP3 inflammasome activation determines the fibrogenic potential of PM_(2.5) air pollution particles in the lung

Airborne fine particulate matter(PM_(2.5))is known to cause respiratory inflammation such as chronic obstructive pulmonary disease and lung fibrosis.NLRP3 inflammasome activation has been implicated in these diseases;however,due to the complexity in PM_(2.5)compositions,it is difficult to differentiate the roles of the components in triggering this pathway.We collected eight real-life PM_(2.5)samples for a comparative analysis of their effects on NLRP3 inflammasome activation and lung fibrosis.In vitro assays showed that although the PM_(2.5)particles did not induce significant cytotoxicity at the dose range of 12.5to 100μg/m L,they induced potent TNF-αand IL-1βproduction in PMA differentiated THP-1 human macrophages and TGF-β1 production in BEAS-2B human bronchial epithelial cells.At the dose of 100μg/m L,PM_(2.5)induced NLRP3 inflammasome activation by inducing lysosomal damage and cathepsin B release,leading to IL-1βproduction.This was confirmed by using NLRP3-and ASC-deficient cells as well as a cathepsin B inhibitor,ca-074 ME.Administration of PM_(2.5)via oropharyngeal aspiration at 2 mg/kg induced significant TGF-β1 production in the bronchoalveolar lavage fluid and collagen deposition in the lung at 21days post-exposure,suggesting PM_(2.5)has the potential to induce pulmonary fibrosis.The ranking of in vitro IL-1βproduction correlates well with the in vivo total cell count,TGF-β1 production,and collagen deposition.In summary,we demonstrate that the PM_(2.5)is capable of inducing NLRP3 inflammasome activation,which triggers a series of cellular responses in the lung to induce fibrosis.

Ion therapy of pulmonary fibrosis by inhalation of ionic solution derived from silicate bioceramics

Pulmonary fibrosis(PF)is a chronic and progressively fatal disease,but clinically available therapeutic drugs are limited due to efficacy and side effects.The possible mechanism of pulmonary fibrosis includes the damage of alveolar epithelial cells II(AEC2),and activation of immune cells such as macrophages.The ions released from bioceramics have shown the activity in stimulating soft tissue derived cells such as fibroblasts,endothelia cells and epithelia cells,and regulating macrophage polarization.Therefore,this study proposes an“ion therapy”approach based on the active ions of bioceramic materials,and investigates the therapeutic effect of bioactive ions derived from calcium silicate(CS)bioceramics on mouse models of pulmonary fibrosis.We demonstrate that silicate ions significantly reduce pulmonary fibrosis by simultaneously regulating the functions of AEC2 and macrophages.This result suggests potential clinical applications of ion therapy for lung fibrosis.