Novel therapeutic roles for surfactant-inositols and -phosphatidylglycerols in a neonatal piglet ARDS model: a translational study

2018 ◽  
Vol 314 (1) ◽  
pp. L32-L53 ◽  
Author(s):  
Dietmar Spengler ◽  
Supandi Winoto-Morbach ◽  
Sarah Kupsch ◽  
Christina Vock ◽  
Katharina Blöchle ◽  
...  
Keyword(s):  
Lung Disease ◽  
Transforming Growth Factor ◽  
Alveolar Epithelial Cell ◽  
Oxygenation Index ◽  
Efficiency Index ◽  
Acid Sphingomyelinase ◽  
Lung Water ◽  
Inflammatory Lung Disease ◽  
Inflammatory Pathways ◽  
Iκb Kinase

The biological and immune-protective properties of surfactant-derived phospholipids and phospholipid subfractions in the context of neonatal inflammatory lung disease are widely unknown. Using a porcine neonatal triple-hit acute respiratory distress syndrome (ARDS) model (repeated airway lavage, overventilation, and LPS instillation into airways), we assessed whether the supplementation of surfactant (S; poractant alfa) with inositol derivatives [inositol 1,2,6-trisphosphate (IP3) or phosphatidylinositol 3,5-bisphosphate (PIP2)] or phosphatidylglycerol subfractions [16:0/18:1-palmitoyloleoyl-phosphatidylglycerol (POPG) or 18:1/18:1-dioleoyl-phosphatidylglycerol (DOPG)] would result in improved clinical parameters and sought to characterize changes in key inflammatory pathways behind these improvements. Within 72 h of mechanical ventilation, the oxygenation index (S+IP3, S+PIP2, and S+POPG), the ventilation efficiency index (S+IP3 and S+POPG), the compliance (S+IP3 and S+POPG) and resistance (S+POPG) of the respiratory system, and the extravascular lung water index (S+IP3 and S+POPG) significantly improved compared with S treatment alone. The inositol derivatives (mainly S+IP3) exerted their actions by suppressing acid sphingomyelinase activity and dependent ceramide production, linked with the suppression of the inflammasome nucleotide-binding domain, leucine-rich repeat-containing protein-3 (NLRP3)-apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)-caspase-1 complex, and the profibrotic response represented by the cytokines transforming growth factor-β1 and IFN-γ, matrix metalloproteinase (MMP)-1/8, and elastin. In addition, IκB kinase activity was significantly reduced. S+POPG and S+DOPG treatment inhibited polymorphonuclear leukocyte activity (MMP-8 and myeloperoxidase) and the production of interleukin-6, maintained alveolar-capillary barrier functions, and reduced alveolar epithelial cell apoptosis, all of which resulted in reduced pulmonary edema. S+DOPG also limited the profibrotic response. We conclude that highly concentrated inositol derivatives and phosphatidylglycerol subfractions in surfactant preparations mitigate key inflammatory pathways in inflammatory lung disease and that their clinical application may be of interest for future treatment of the acute exudative phase of neonatal ARDS.

scholarly journals OP0268 TREATMENT STATUS AFFECTS HOW PULMONARY BIOMARKERS PREDICT PROGRESSION OF SYSTEMIC SCLEROSIS-RELATED INTERSTITIAL LUNG DISEASE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 163.1-163
Author(s):  
E. Volkmann ◽  
D. Tashkin ◽  
M. Leng ◽  
N. LI ◽  
G. Kim ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Growth Factor ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Transforming Growth Factor ◽  
Selection Process ◽  
Linear Regression Models ◽  
Research Support ◽  
Gm Csf ◽  
Treatment Status

Background:The course of interstitial lung disease (ILD) varies considerably in patients with systemic sclerosis (SSc), and no biomarkers have been found to consistently predict ILD progression in this population. Treatment may affect how a candidate biomarker correlates with improvement/worsening of SSc-ILD. We hypothesized that specific proteins recovered from bronchoalveolar lavage (BAL) would differentially predict progression of SSc-ILD based on whether a patient was receiving ILD therapy.Objectives:(1) To assess the relationship between 68 unique BAL proteins measured in participants of Scleroderma Lung Study (SLS) I1 and changes in radiographic extent of SSc-ILD; (2) To determine if treatment affects whether a specific protein predicts improvement or worsening of SSc-ILD.Methods:Bronchoscopy was performed on 144 of the 158 participants in SLS I (Cyclophosphamide [CYC] vs. placebo) with 103 BAL samples available for analysis. BAL was lyophilized, concentrated 10X and used in a multiplex protein analysis of 68 distinct cytokines, chemokines and growth factors. Quantitative imaging analysis (QIA) was used to calculate the extent of radiographic fibrosis (QLF) in the whole lung using HRCT of the chest at baseline and 12 months. Multivariable linear regression models were created to determine the key BAL proteins associated with change in QLF scores using a backward selection process adjusting for treatment arm and ILD severity. The bootstrap procedure was employed for internal validation.Results:A number of BAL proteins were significantly associated with change in QLF scores at 12 months; however, the directionality of these associations was often based on the presence/absence of treatment. For example, increased levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1, monocyte chemoattractant protein (MCP)-3, chemokine ligand (CCL)-5, transforming growth factor (TGF)-β, hepatocyte growth factor (HGF), stem cell factor (SCF), IL-4, TGF-α, were associated with worse QLF scores in patients who received placebo; whereas, increased levels of these same proteins were associated with improved QLF scores in patients who received CYC (Figure). Increased levels of Fractalkine were associated with worse in QLF scores, and increased levels of IL-7 were associated with improved QLF scores, regardless of treatment arm. In the multivariable model adjusting for treatment arm and baseline severity of ILD, IL-1, MCP-3, surfactant protein C, IL-7, and CCL-5 were independently associated with change in QLF scores.Figure 1.Example of a specific BAL protein (GM-CSF) that predicts worse QLF scores in patients receiving placebo (Group B, Red dotted line) and improved QLF scores in patients receiving CYC (Group A, Blue solid line). Shaded areas represent 95% confidence intervals.Conclusion:Proteins that mediate both inflammation and fibrosis differentially affected progression of SSc-ILD based on treatment status. Higher levels of certain proteins predicted worsening of ILD in patients receiving placebo, but improvement in patients receiving CYC. Measuring these proteins could help to identify patients who: (1) are at risk for ILD progression, and (2) may preferentially benefit from treatment with immunosuppression.References:[1]Tashkin DP, et al. NEJM 2006.Disclosure of Interests:Elizabeth Volkmann Consultant of: Boehringer Ingelheim, Grant/research support from: Corbus, Forbius, Donald Tashkin: None declared, Mei Leng: None declared, Ning Li: None declared, Grace Kim: None declared, Jonathan Goldin: None declared, Airi Harui: None declared, Michael Roth Grant/research support from: Genentech/Roche

Transforming growth factor-alpha enhances alveolar epithelial cell repair in a new in vitro model

1994 ◽  
Vol 267 (6) ◽  
pp. L728-L738 ◽  
Author(s):  
F. Kheradmand ◽  
H. G. Folkesson ◽  
L. Shum ◽  
R. Derynk ◽  
R. Pytela ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cell ◽  
Wound Repair ◽  
Wound Closure ◽  
Transforming Growth Factor ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial ◽  
Factor Alpha ◽  
Vitro Model

Alveolar epithelial type II cells are essential for regenerating an intact alveolar barrier after destruction of type I cells in vivo. The first objective of these experimental studies was to develop an in vitro model to quantify alveolar epithelial cell wound repair. The second objective was to investigate mechanisms of alveolar epithelial cell wound healing by studying the effects of serum and transforming growth factor-alpha (TGF-alpha) on wound closure. Primary cultures of rat alveolar type II cells were prepared by standard methods and grown to form confluent monolayers in 48 h. Then a wound was made by denuding an area (mean initial area of 2.1 +/- 0.6 mm2) of the monolayer. Re-epithelialization of the denuded area over time in the presence or absence of serum was measured using quantitative measurements from time-lapse video microscopy. The half time of wound healing was significantly enhanced in the presence of serum compared with serum-free conditions (2.4 +/- 0.2 vs. 17.4 +/- 0.8 h, P < 0.001). We then tested the hypothesis that TGF-alpha is an important growth factor for stimulating wound repair of alveolar epithelial cells. Exogenous addition of TGF-alpha in serum-free medium resulted in a significantly more rapid wound closure, and, furthermore, the addition of a monoclonal antibody to TGF-alpha in the presence of serum significantly decreased fourfold the rate of wound closure. Measurement of internuclear cell distance confirmed that both cell motility and cell spreading were responsible for closure of the wound. These data demonstrate that 1) the mechanisms of alveolar cell repair can be studied in vitro and that 2) TGF-alpha is a potent growth factor that enhances in vitro alveolar epithelial cell wound closure.

Metabolic profiling of asthma in mice and the interventional effects of SPA using liquid chromatography and Q-TOF mass spectrometry

2017 ◽  
Vol 13 (6) ◽  
pp. 1172-1181 ◽  
Author(s):  
Li Su ◽  
Lei Shi ◽  
Jian Liu ◽  
Lifei Huang ◽  
Yi Huang ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Lung Disease ◽  
Metabolic Profiling ◽  
Inflammatory Lung Disease

Asthma is a chronic inflammatory lung disease that leads to 250 000 deaths annually.

scholarly journals GED-0507 attenuates lung fibrosis by counteracting myofibroblast transdifferentiation in vivo and in vitro

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257281
Author(s):  
Silvia Speca ◽  
Caroline Dubuquoy ◽  
Christel Rousseaux ◽  
Philippe Chavatte ◽  
Pierre Desreumaux ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Alveolar Epithelial Cell ◽  
Lung Fibroblasts ◽  
Epithelial Cell Line ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Ppar Γ

The development of more effective, better tolerated drug treatments for progressive pulmonary fibrosis (of which idiopathic pulmonary fibrosis is the most common and severe form) is a research priority. The peroxisome proliferator-activated receptor gamma (PPAR-γ) is a key regulator of inflammation and fibrosis and therefore represents a potential therapeutic target. However, the use of synthetic PPAR-γ agonists may be limited by their potentially severe adverse effects. In a mouse model of bleomycin (BLM)-induced pulmonary fibrosis, we have demonstrated that the non-racemic selective PPAR-γ modulator GED-0507 is able to reduce body weight loss, ameliorate clinical and histological features of pulmonary fibrosis, and increase survival rate without any safety concerns. Here, we focused on the biomolecular effects of GED-0507 on various inflammatory/fibrotic pathways. We demonstrated that preventive and therapeutic administration of GED-0507 reduced the BLM-induced mRNA expression of several markers of fibrosis, including transforming growth factor (TGF)-β, alpha-smooth muscle actin, collagen and fibronectin as well as epithelial-to-mesenchymal transition (EMT) and expression of mucin 5B. The beneficial effect of GED-0507 on pulmonary fibrosis was confirmed in vitro by its ability to control TGFβ-induced myofibroblast activation in the A549 human alveolar epithelial cell line, the MRC-5 lung fibroblast line, and primary human lung fibroblasts. Compared with the US Food and Drug Administration-approved antifibrotic drugs pirfenidone and nintedanib, GED-0507 displayed greater antifibrotic activity by controlling alveolar epithelial cell dysfunction, EMT, and extracellular matrix remodeling. In conclusion, GED-0507 demonstrated potent antifibrotic properties and might be a promising drug candidate for the treatment of pulmonary fibrosis.

scholarly journals High levels of circulating osteopontin in inflammatory lung disease regardless of Sars‐CoV‐2 infection

2021 ◽  
Author(s):  
Giuseppe Cappellano ◽  
Hugo Abreu ◽  
Davide Raineri ◽  
Lorenza Scotti ◽  
Luigi Castello ◽  
...  
Keyword(s):  
Lung Disease ◽  
Inflammatory Lung Disease

scholarly journals Key profibrotic and pro-inflammatory pathways in the pathogenesis of diabetic kidney disease

2021 ◽  
Vol 1 (1) ◽  
pp. 15-26
Author(s):  
Devang M. Patel ◽  
Yuxin Yang ◽  
Kexin Shi ◽  
Tieqiao Wu ◽  
Mark E. Cooper ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Renal Fibrosis ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Large Body ◽  
Noncommunicable Disease ◽  
Sirtuin 1 ◽  
Type I ◽  
Diabetic Kidney ◽  
Inflammatory Pathways

Abstract Diabetes is a noncommunicable disease and arguably represents the greatest pandemic in human history. Diabetic kidney disease (DKD) is seen in both type 1 and type 2 diabetes and can be detected in up to 30–50% of diabetic subjects. DKD is a progressive chronic kidney disease (CKD) and is a leading cause of mortality and morbidity in patients with diabetes. Renal fibrosis and inflammation are the major pathological features of DKD. There are a large number of independent and overlapping profibrotic and pro-inflammatory pathways involved in the pathogenesis and progression of DKD. Among these pathways, the transforming growth factor-β (TGF-β) pathway plays a key pathological role by promoting fibrosis. Sirtuin-1 (SIRT1) is a protein deacetylase that has been shown to be renoprotective with an anti-inflammatory effect. It is postulated that a reduction in renal SIRT1 levels could play a key role in the pathogenesis of DKD and that restoration of SIRT1 will attenuate DKD. Cell division autoantigen 1 (CDA1) synergistically enhances the profibrotic effect of TGF-β in DKD by regulating the expression of the TGF-β type I receptor (TβRI). CDA1 has also been found to be an inhibitor of SIRT1 in the DNA damage response. Indeed, targeting CDA1 in experimental DKD not only attenuates diabetes-associated renal fibrosis but also attenuates the expression of key pro-inflammatory genes such as tumor necrosis factor-α (TNF-α) and Monocyte Che moattractant Protein-1 (MCP-1). In conclusion, there is a large body of experimental data to support the view that targeting CDA1 is a superior approach to directly targeting TGF-β in DKD since it is not only safe but also efficacious in retarding both fibrosis and inflammation.

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