FSTL1 aggravates Cigarette smoke-induced airway inflammation and airway remodeling by regulating autophagy

Abstract Background Cigarette smoke (CS) is a major risk factor for COPD. Follistatin-like protein 1(FSTL1), a critical factor during embryogenesis particularly in respiratory lung development, is a novel mediator related to inflammation and tissue remodeling. We tried to investigate the role of FSTL1 in CS-induced autophagy dysregulaton, airway inflammation and remodeling. Methods Serum and lung specimens were obtained from COPD patients and controls. Adult female wild-type (WT) mice, FSTL1+/- mice and FSTL1flox/+ mice were exposed to room air or chronic CS. Additionally, 3-methyladenine (3-MA) ,an inhibitor of autophagy, were applied in CS exposed WT mice. The lung tissue and serum from patients and murine models were tested for FSTL1 and autophagy associated protein expression by ELISA, western blotting and immunohistochemical. Autophagosome were observed by Electron Microscope Technology(EMT). LTB4, IL-8 and TNF-α in bronchoalveolar lavage fluid of mice were examined by ELISA. Airway remodeling and lung function were also assessed. Results Both FSTL1 and autophagy biomarkers increased in COPD patients and CS exposed WT mice. Autophagy activation was upregulated in CS exposed mice accompanied by airway remodeling and airway inflammation. FSTL1+/- mice showed a lower level of CS-induced autophagy compared with control mice. FSTL1+/- mice can also resist CS-induced inflammatory response, airway remodeling and impaired lung function. CS exposed WT mice with 3-MA pretreatment have a similar manifestation with CS exposed FSTL1+/- mice. Conclusions FSTL1 promotes CS-induced COPD by modulating autophagy, therefore targeting FSTL1 and autophagy may shed light on treating cigarette smoke induced COPD.

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FSTL1 aggravates cigarette smoke-induced airway inflammation and airway remodeling by regulating autophagy

BMC Pulmonary Medicine ◽

10.1186/s12890-021-01409-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ying Liu ◽

Jiawei Xu ◽

Tian Liu ◽

Jinxiang Wu ◽

Jiping Zhao ◽

...

Keyword(s):

Lung Function ◽

Airway Inflammation ◽

Cigarette Smoke ◽

Airway Remodeling ◽

Critical Factor ◽

Lavage Fluid ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Copd Patients ◽

Impaired Lung Function

Abstract Background Cigarette smoke (CS) is a major risk factor for Chronic Obstructive Pulmonary Disease (COPD). Follistatin-like protein 1 (FSTL1), a critical factor during embryogenesis particularly in respiratory lung development, is a novel mediator related to inflammation and tissue remodeling. We tried to investigate the role of FSTL1 in CS-induced autophagy dysregulation, airway inflammation and remodeling. Methods Serum and lung specimens were obtained from COPD patients and controls. Adult female wild-type (WT) mice, FSTL1± mice and FSTL1flox/+ mice were exposed to room air or chronic CS. Additionally, 3-methyladenine (3-MA), an inhibitor of autophagy, was applied in CS-exposed WT mice. The lung tissues and serum from patients and murine models were tested for FSTL1 and autophagy-associated protein expression by ELISA, western blotting and immunohistochemical. Autophagosome were observed using electron microscope technology. LTB4, IL-8 and TNF-α in bronchoalveolar lavage fluid of mice were examined using ELISA. Airway remodeling and lung function were also assessed. Results Both FSTL1 and autophagy biomarkers increased in COPD patients and CS-exposed WT mice. Autophagy activation was upregulated in CS-exposed mice accompanied by airway remodeling and airway inflammation. FSTL1± mice showed a lower level of CS-induced autophagy compared with the control mice. FSTL1± mice can also resist CS-induced inflammatory response, airway remodeling and impaired lung function. CS-exposed WT mice with 3-MA pretreatment have a similar manifestation with CS-exposed FSTL1± mice. Conclusions FSTL1 promotes CS-induced COPD by modulating autophagy, therefore targeting FSTL1 and autophagy may shed light on treating cigarette smoke-induced COPD.

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Effect of inhaled hydrosoluble curcumin on inflammatory markers in broncho-alveolar lavage fluid of horses with LPS-induced lung neutrophilia

Multidisciplinary Respiratory Medicine ◽

10.4081/mrm.2015.290 ◽

2015 ◽

Vol 10 ◽

Cited By ~ 1

Author(s):

Charlotte Sandersen ◽

Dorothee Bienzle ◽

Simona Cerri ◽

Thierry Franck ◽

Sandrine Derochette ◽

...

Keyword(s):

Airway Inflammation ◽

Airway Remodeling ◽

Lavage Fluid ◽

Chronic Respiratory Disease ◽

Secretory Protein ◽

Large Animal ◽

Beneficial Effects ◽

Club Cell ◽

Large Animal Models ◽

Tnf Α

Background: Horses commonly suffer from chronic respiratory disease and are also used in large animal models of spontaneous or induced airway inflammation. The anti-inflammatory properties of curcumin are largely described but its low bioavailability precludes its clinical use. NDS27, a lysin salt of curcumin incorporated in beta-cyclodextrine, has high bioavailability and can be administered by inhalation. The aim of this study was to investigate the effects of inhaled NDS27 on inflammatory cytokines and proteins in the broncho-alveolar lavage fluid using a model of neutrophilic airway inflammation. Methods: Airway neutrophilia was induced in eight horses by inhalation of lipopolysaccharides (LPS). Horses were treated with either inhalation of NDS27 or with placebo in a randomized cross-over design. Broncho-alveolar lavages were performed 6 hours after stimulation with LPS. Percentage of neutrophils, concentrations of IL-1β, TNF-α, IL-6, Club cell secretory protein, myeloperoxidase (MPO) and elastase (ELT) concentrations were determined. Results: LPS stimulation induced significant increases in neutrophil counts and concentrations of IL-6 (70.2 ± 66.0 pg/ml), TNF-α (43.9 ± 31.2 pg/ml), MPO (580.9 ± 327.0 ng/ml) and ELT (27.6 ± 16.7 ng/ml). Treatment with NDS27 significantly prevented the increase in active and total MPO (216.4 ± 118.1 ng/ml) and ELT (5.9 ± 3.2 ng/ml) while there was a trend towards reduced IL-6 concentration. Conclusions: Results show that, although not reducing neutrophil recruitment, NDS27 largely abolishes LPS-induced neutrophil degranulation. Reduced levels of ELT and MPO, as well as reduced MPO activity may have beneficial effects via a reduced production of reactive oxygen species implicated in chronic inflammation and airway remodeling.

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Blockade of the NLRP3/Caspase-1 Axis Ameliorates Airway Neutrophilic Inflammation in a Toluene Diisocyanate-Induced Murine Asthma Model

Toxicological Sciences ◽

10.1093/toxsci/kfz099 ◽

2019 ◽

Vol 170 (2) ◽

pp. 462-475 ◽

Cited By ~ 5

Author(s):

Shuyu Chen ◽

Lihong Yao ◽

Peikai Huang ◽

Qiaoling He ◽

Hongbing Guan ◽

...

Keyword(s):

Airway Inflammation ◽

Airway Remodeling ◽

Lavage Fluid ◽

Vital Role ◽

Toluene Diisocyanate ◽

Receptor Protein ◽

Th2 Response ◽

Caspase 1 ◽

Asthma Model

Abstract Multiple studies have addressed the vital role of Nod-like receptor protein 3(NLRP3)/caspase-1/IL-1β signaling in asthma. Yet, the role of NLRP3/caspase-1 in toluene diisocyanate (TDI)-induced asthma is still obscure. The aim of this study is to investigate the role of the NLRP3/caspase-1 axis in TDI-induced asthma. Using an established murine model of TDI-induced asthma as described previously, we gave the asthmatic mice a highly selective NLRP3 inhibitor, MCC950, as well as the specific caspase-1 inhibitors VX-765 and Ac-YVAD-CHO for therapeutic purposes. Airway resistance was measured and bronchoalveolar lavage fluid was analyzed. Lungs were examined by histology, immunohistochemistry, Western blotting, and flow cytometry. TDI exposure elevated the expression of NLRP3 and caspase-1 that was coupled with increased airway hyperresponsiveness (AHR), neutrophil-dominated cell infiltration, pronounced goblet cell metaplasia, extensive collagen deposition, and increased TH2/TH17 responses. Both VX-765 and Ac-YVAD-CHO effectively inhibited the activation of caspase-1 in TDI-asthmatic mice that was accompanied by dramatic attenuation of AHR, airway inflammation, and airway remodeling, in addition to a decreased TH2 response and lower levels of IL-18 and IL-1β. MCC950 blocked the activation of NLRP3 and downregulated protein expression of caspase-1, IL-1β, and IL-18 in TDI-exposed mice. Furthermore, MCC950 remarkably alleviated AHR, airway inflammation, airway remodeling, and significantly suppressed TH2/TH17 responses. These findings suggested that blockade of the NLRP3/caspase-1 axis effectively prevents the progression of TDI-induced asthma and could be used as therapeutic targets for asthmatics.

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Role of Neuro‐immune Interactions in a Cigarette Smoke‐induced Chronic Airway Inflammation Mouse Model

The FASEB Journal ◽

10.1096/fasebj.2019.33.1_supplement.lb69 ◽

2019 ◽

Vol 33 (S1) ◽

Author(s):

Kata Csekő ◽

István Szitter ◽

Zsófia Hajna ◽

Krisztián Elekes ◽

Ágnes Kemény ◽

...

Keyword(s):

Mouse Model ◽

Airway Inflammation ◽

Cigarette Smoke ◽

Chronic Airway

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Grain dust-induced lung inflammation is reduced byRhodobacter sphaeroidesdiphosphoryl lipid A

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1998.274.1.l26 ◽

1998 ◽

Vol 274 (1) ◽

pp. L26-L31 ◽

Cited By ~ 10

Author(s):

Paul J. Jagielo ◽

Timothy J. Quinn ◽

Nilofer Qureshi ◽

David A. Schwartz

Keyword(s):

Inflammatory Response ◽

Airway Inflammation ◽

Lipid A ◽

Partial Agonist ◽

Inhibitory Effect ◽

Sterile Saline ◽

Endotoxin Activity ◽

Tnf Α ◽

Grain Dust

To further determine the importance of endotoxin in grain dust-induced inflammation of the lower respiratory tract, we evaluated the efficacy of pentaacylated diphosphoryl lipid A derived from the lipopolysaccharide of Rhodobacter sphaeroides (RsDPLA) as a partial agonist of grain dust-induced airway inflammation. RsDPLA is a relatively inactive compound compared with lipid A derived from Escherichia coli (LPS) and has been demonstrated to act as a partial agonist of LPS-induced inflammation. To assess the potential stimulatory effect of RsDPLA in relation to LPS, we incubated THP-1 cells with RsDPLA (0.001–100 μg/ml), LPS (0.02 μg endotoxin activity/ml), or corn dust extract (CDE; 0.02 μg endotoxin activity/ml). Incubation with RsDPLA revealed a tumor necrosis factor (TNF)-α stimulatory effect at 100 μg/ml. In contrast, incubation with LPS or CDE resulted in TNF-α release at 0.02 μg/ml. Pretreatment of THP-1 cells with varying concentrations of RsDPLA before incubation with LPS or CDE (0.02 μg endotoxin activity/ml) resulted in a dose-dependent reduction in the LPS- or CDE-induced release of TNF-α with concentrations of RsDPLA of up to 10 μg/ml but not at 100 μg/ml. To further understand the role of endotoxin in grain dust-induced airway inflammation, we utilized the unique LPS inhibitory property of RsDPLA to determine the inflammatory response to inhaled CDE in mice in the presence of RsDPLA. Ten micrograms of RsDPLA intratracheally did not cause a significant inflammatory response compared with intratracheal saline. However, pretreatment of mice with 10 μg of RsDPLA intratracheally before exposure to CDE (5.4 and 0.2 μg/m3) or LPS (7.2 and 0.28 μg/m3) resulted in significant reductions in the lung lavage concentrations of total cells, neutrophils, and specific proinflammatory cytokines compared with mice pretreated with sterile saline. These results confirm the LPS-inhibitory effect of RsDPLA and support the role of endotoxin as the principal agent in grain dust causing airway inflammation.

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Co-exposure to lipopolysaccharide and desert dust causes exacerbation of ovalbumin-induced allergic lung inflammation in mice via TLR4/MyD88-dependent and -independent pathways

Allergy Asthma & Clinical Immunology ◽

10.1186/s13223-019-0396-4 ◽

2019 ◽

Vol 15 (1) ◽

Author(s):

Yahao Ren ◽

Takamichi Ichinose ◽

Miao He ◽

Seiichi Youshida ◽

Masataka Nishikawa ◽

...

Keyword(s):

Airway Inflammation ◽

Immune Cell ◽

Adaptor Protein ◽

Lavage Fluid ◽

Specific Ige ◽

Pathological Changes ◽

Th2 Response ◽

Lung Eosinophilia ◽

High Concentrations

Abstract Background Lipopolysaccharide (LPS) often presents in high concentrations in particulate matter (PM), few studies have reported the enhancing effects of both LPS and PM on airway inflammation in mice and the role of toll-like receptors (TLRs) in this process. Asian sand dust (ASD) is observed most frequently during the spring. This study aimed to clarify the role of TLRs in murine lung eosinophilia exacerbated by ASD and LPS. Methods The effects of LPS and ASD co-treatment on ovalbumin (OVA)-induced lung eosinophilia were investigated using wild-type (WT), TLR2−/−, TLR4−/−, and adaptor protein myeloid differentiation factor 88 (MyD88)−/− BALB/c mice. ASD was heated (H-ASD) to remove the toxic organic substances. WT, TLR2−/−, TLR4−/− and MyD88−/− BALB/c mice were intratracheally instilled with four different combinations of LPS, H-ASD and OVA treatment. Subsequently, the pathological changes in lungs, immune cell profiles in bronchoalveolar lavage fluid (BALF), inflammatory cytokines/chemokines levels in BALF and OVA-specific immunoglobulin (Ig) in serum were analyzed. Results In WT mice, H-ASD + LPS exacerbated OVA-induced lung eosinophilia. This combination of treatments increased the proportion of eosinophils and the levels of IL-5, IL-13, eotaxin in BALF, as well as the production of OVA-specific IgE and IgG1 in serum compared to OVA treatment alone. Although these effects were stronger in TLR2−/− mice than in TLR4−/− mice, the expression levels of IL-5, IL-13, eotaxin were somewhat increased in TLR4−/− mice treated with OVA + H-ASD + LPS. In MyD88−/− mice, this pro-inflammatory mediator-induced airway inflammation was considerably weak and the pathological changes in lungs were negligible. Conclusions These results suggest that LPS and H-ASD activate OVA-induced Th2 response in mice, and exacerbate lung eosinophilia via TLR4/MyD88, TLR4/TRIF and other TLR4-independent pathways.

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Tsc2 disruption in mesenchymal progenitors results in tumors with vascular anomalies overexpressing Lgals3

eLife ◽

10.7554/elife.23202 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 6

Author(s):

Peter J Klover ◽

Rajesh L Thangapazham ◽

Jiro Kato ◽

Ji-an Wang ◽

Stasia A Anderson ◽

...

Keyword(s):

Lung Function ◽

Tuberous Sclerosis Complex ◽

Serum Levels ◽

Limb Bud ◽

Mesenchymal Progenitors ◽

Expression Signature ◽

Mtorc1 Signaling ◽

Impaired Lung Function ◽

Galectin 3

Increased mTORC1 signaling from TSC1/TSC2 inactivation is found in cancer and causes tuberous sclerosis complex (TSC). The role of mesenchymal-derived cells in TSC tumorigenesis was investigated through disruption of Tsc2 in craniofacial and limb bud mesenchymal progenitors. Tsc2cKOPrrx1-cre mice had shortened lifespans and extensive hamartomas containing abnormal tortuous, dilated vessels prominent in the forelimbs. Abnormalities were blocked by the mTORC1 inhibitor sirolimus. A Tsc2/mTORC1 expression signature identified in Tsc2-deficient fibroblasts was also increased in bladder cancers with TSC1/TSC2 mutations in the TCGA database. Signature component Lgals3 encoding galectin-3 was increased in Tsc2-deficient cells and serum of Tsc2cKOPrrx1-cre mice. Galectin-3 was increased in TSC-related skin tumors, angiomyolipomas, and lymphangioleiomyomatosis with serum levels in patients with lymphangioleiomyomatosis correlating with impaired lung function and angiomyolipoma presence. Our results demonstrate Tsc2-deficient mesenchymal progenitors cause aberrant morphogenic signals, and identify an expression signature including Lgals3 relevant for human disease of TSC1/TSC2 inactivation and mTORC1 hyperactivity.

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Mibefradil and Flunarizine, Two T-Type Calcium Channel Inhibitors, Protect Mice against Lipopolysaccharide-Induced Acute Lung Injury

Mediators of Inflammation ◽

10.1155/2020/3691701 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Limei Wan ◽

Weibin Wu ◽

Shunjun Jiang ◽

Shanhe Wan ◽

Dongmei Meng ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Calcium Channel ◽

Lavage Fluid ◽

Cell Number ◽

Effector Cells ◽

Potent Inhibition ◽

Tnf Α ◽

Calcium Channel Inhibitors

Recent studies have illuminated that blocking Ca2+ influx into effector cells is an attractive therapeutic strategy for lung injury. We hypothesize that T-type calcium channel may be a potential therapeutic target for acute lung injury (ALI). In this study, the pharmacological activity of mibefradil (a classical T-type calcium channel inhibitor) was assessed in a mouse model of lipopolysaccharide- (LPS-) induced ALI. In LPS challenged mice, mibefradil (20 and 40 mg/kg) dramatically decreased the total cell number, as well as the productions of TNF-α and IL-6 in bronchoalveolar lavage fluid (BALF). Mibefradil also suppressed total protein concentration in BALF, attenuated Evans blue extravasation, MPO activity, and NF-κB activation in lung tissue. Furthermore, flunarizine, a widely prescripted antimigraine agent with potent inhibition on T-type channel, was also found to protect mice against lung injury. These data demonstrated that T-type calcium channel inhibitors may be beneficial for treating acute lung injury. The important role of T-type calcium channel in the acute lung injury is encouraged to be further investigated.

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