scholarly journals Enhancing Cystic Fibrosis Immune Regulation

2021 ◽  
Vol 12 ◽  
Author(s):  
Anna M. van Heeckeren ◽  
Morgan T. Sutton ◽  
David R. Fletcher ◽  
Craig A. Hodges ◽  
Arnold I. Caplan ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Inflammatory Response ◽  
Effective Means ◽  
Treatment Regimens ◽  
Cell Based Therapy ◽  
Inflammatory Status ◽  
Clinical Consequences ◽  
Infection And Inflammation ◽  
Anti Inflammatory ◽  
Improvement In Survival

In cystic fibrosis (CF), sustained infection and exuberant inflammation results in debilitating and often fatal lung disease. Advancement in CF therapeutics has provided successful treatment regimens for a variety of clinical consequences in CF; however effective means to treat the pulmonary infection and inflammation continues to be problematic. Even with the successful development of small molecule cystic fibrosis transmembrane conductance regulator (CFTR) correctors and potentiators, there is only a modest effect on established infection and inflammation in CF patients. In the pursuit of therapeutics to treat inflammation, the conundrum to address is how to overcome the inflammatory response without jeopardizing the required immunity to manage pathogens and prevent infection. The key therapeutic would have the capacity to dull the inflammatory response, while sustaining the ability to manage infections. Advances in cell-based therapy have opened up the avenue for dynamic and versatile immune interventions that may support this requirement. Cell based therapy has the capacity to augment the patient’s own ability to manage their inflammatory status while at the same time sustaining anti-pathogen immunity. The studies highlighted in this manuscript outline the potential use of cell-based therapy for CF. The data demonstrate that 1) total bone marrow aspirates containing Cftr sufficient hematopoietic and mesenchymal stem cells (hMSCs) provide Cftr deficient mice >50% improvement in survival and improved management of infection and inflammation; 2) myeloid cells can provide sufficient Cftr to provide pre-clinical anti-inflammatory and antimicrobial benefit; 3) hMSCs provide significant improvement in survival and management of infection and inflammation in CF; 4) the combined interaction between macrophages and hMSCs can potentially enhance anti-inflammatory and antimicrobial support through manipulating PPARγ. These data support the development of optimized cell-based therapeutics to enhance CF patient’s own immune repertoire and capacity to maintain the balance between inflammation and pathogen management.

scholarly journals Anti-Inflammatory and Anti-Oxidant Effect of Dimethyl Fumarate in Cystic Fibrosis Bronchial Epithelial Cells

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2132
Author(s):  
Onofrio Laselva ◽  
Caterina Allegretta ◽  
Sante Di Gioia ◽  
Carlo Avolio ◽  
Massimo Conese
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Dimethyl Fumarate ◽  
Bronchial Epithelial Cells ◽  
Bronchial Epithelial ◽  
Inflammatory Status ◽  
Anti Oxidant ◽  
Anti Inflammatory ◽  
Oxidant Effect

Cystic Fibrosis (CF) is caused by mutations on the CF transmembrane conductance regulator (CFTR) gene and is associated with chronic infection and inflammation. Recently, it has been demonstrated that LPS-induced CFTR dysfunction in airway epithelial cells is due to an early oxidative stress. Dimethyl fumarate (DMF) is an approved anti-inflammatory and anti-oxidant drug for auto-immune and inflammatory diseases, but its role in the CF has never been investigated. In this study, we examined the effect of DMF on CF-related cytokines expression, ROS measurements and CFTR channel function. We found that DMF reduced the inflammatory response to LPS stimulation in both CF and non-CF bronchial epithelial cells, both as co-treatment and therapy, and restored LPS-mediated decrease of Trikafta™-mediated CFTR function in CF cells bearing the most common mutation, c.1521_1523delCTT (F508del). DMF also inhibited the inflammatory response induced by IL-1β/H2O2 and IL-1β/TNFα, mimicking the inflammatory status of CF patients. Finally, we also demonstrated that DMF exhibited an anti-oxidant effect on CF cells after different inflammatory stimulations. Since DMF is an approved drug, it could be further investigated as a novel anti-inflammatory molecule to ameliorate lung inflammation in CF and improve the CFTR modulators efficacy.

scholarly journals Targeted Drug Delivery Technologies Potentiate the Overall Therapeutic Efficacy of an Indole Derivative in a Mouse Cystic Fibrosis Setting

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1601
Author(s):  
Matteo Puccetti ◽  
Marilena Pariano ◽  
Giorgia Renga ◽  
Ilaria Santarelli ◽  
Fiorella D’Onofrio ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Targeted Drug Delivery ◽  
Fungal Infections ◽  
Murine Models ◽  
Multisystem Disease ◽  
Aryl Hydrocarbon ◽  
Target Organs ◽  
Infection And Inflammation ◽  
Anti Inflammatory ◽  
Inflammatory Toxicity

Inflammation plays a major role in the pathophysiology of cystic fibrosis (CF), a multisystem disease. Anti-inflammatory therapies are, therefore, of interest in CF, provided that the inhibition of inflammation does not compromise the ability to fight pathogens. Here, we assess whether indole-3-aldehyde (3-IAld), a ligand of the aryl hydrocarbon receptor (AhR), may encompass such an activity. We resorted to biopharmaceutical technologies in order to deliver 3-IAld directly into the lung, via dry powder inhalation, or into the gut, via enteric microparticles, in murine models of CF infection and inflammation. We found the site-specific delivery of 3-IAld to be an efficient strategy to restore immune and microbial homeostasis in CF organs, and mitigate lung and gut inflammatory pathology in response to fungal infections, in the relative absence of local and systemic inflammatory toxicity. Thus, enhanced delivery to target organs of AhR agonists, such as 3-IAld, may pave the way for the development of safe and effective anti-inflammatory agents in CF.

scholarly journals Interleukin-17 Pathophysiology and Therapeutic Intervention in Cystic Fibrosis Lung Infection and Inflammation

2016 ◽  
Vol 84 (9) ◽  
pp. 2410-2421 ◽  
Author(s):  
Daniel Hsu ◽  
Patricia Taylor ◽  
Dave Fletcher ◽  
Rolf van Heeckeren ◽  
Jean Eastman ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Inflammatory Response ◽  
Therapeutic Intervention ◽  
Lung Infection ◽  
Cystic Fibrosis Lung ◽  
Interleukin 17 ◽  
Intratracheal Administration ◽  
Content Type ◽  
Mucin Production ◽  
Infection And Inflammation

Cystic fibrosis (CF) is characterized by an excessive neutrophilic inflammatory response within the airway as a result of defective cystic fibrosis transmembrane receptor (CFTR) expression and function. Interleukin-17A induces airway neutrophilia and mucin production associated withPseudomonas aeruginosacolonization, which is associated with the pathophysiology of cystic fibrosis. The objectives of this study were to use the preclinical murine model of cystic fibrosis lung infection and inflammation to investigate the role of IL-17 in CF lung pathophysiology and explore therapeutic intervention with a focus on IL-17.Cftr-deficient mice (CF mice) and wild-type mice (WT mice) infected withP. aeruginosahad robust IL-17 production early in the infection associated with a persistent elevated inflammatory response. Intratracheal administration of IL-17 provoked a neutrophilic response in the airways of WT and CF animals which was similar to that observed withP. aeruginosainfection. The neutralization of IL-17 prior to infection significantly improved the outcomes in the CF mice, suggesting that IL-17 may be a therapeutic target. We demonstrate in this report that the pathophysiological contribution of IL-17 may be due to the induction of chemokines from the epithelium which is augmented by a deficiency ofCftrand ongoing inflammation. These studies demonstrate thein vivocontribution of IL-17 in cystic fibrosis lung disease and the therapeutic validity of attenuating IL-17 activity in cystic fibrosis.

scholarly journals Hyperbilirubinemia in Gunn Rats Is Associated with Decreased Inflammatory Response in LPS-Mediated Systemic Inflammation

2019 ◽  
Vol 20 (9) ◽  
pp. 2306 ◽  
Author(s):  
Petra Valaskova ◽  
Ales Dvorak ◽  
Martin Lenicek ◽  
Katerina Zizalova ◽  
Nikolina Kutinova-Canova ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Systemic Inflammation ◽  
Primary Hepatocytes ◽  
Inflammatory Status ◽  
Gunn Rats ◽  
Tnf Α ◽  
Before And After ◽  
Anti Inflammatory ◽  
Inflammatory Profile

Decreased inflammatory status has been reported in subjects with mild unconjugated hyperbilirubinemia. However, mechanisms of the anti-inflammatory actions of bilirubin (BR) are not fully understood. The aim of this study is to assess the role of BR in systemic inflammation using hyperbilirubinemic Gunn rats as well as their normobilirubinemic littermates and further in primary hepatocytes. The rats were treated with lipopolysaccharide (LPS, 6 mg/kg intraperitoneally) for 12 h, their blood and liver were collected for analyses of inflammatory and hepatic injury markers. Primary hepatocytes were treated with BR and TNF-α. LPS-treated Gunn rats had a significantly decreased inflammatory response, as evidenced by the anti-inflammatory profile of white blood cell subsets, and lower hepatic and systemic expressions of IL-6, TNF-α, IL-1β, and IL-10. Hepatic mRNA expression of LPS-binding protein was upregulated in Gunn rats before and after LPS treatment. In addition, liver injury markers were lower in Gunn rats as compared to in LPS-treated controls. The exposure of primary hepatocytes to TNF-α with BR led to a milder decrease in phosphorylation of the NF-κB p65 subunit compared to in cells without BR. In conclusion, hyperbilirubinemia in Gunn rats is associated with an attenuated systemic inflammatory response and decreased liver damage upon exposure to LPS.

scholarly journals Role of Excessive Inflammatory Response to Stenotrophomonas maltophilia Lung Infection in DBA/2 Mice and Implications for Cystic Fibrosis

2010 ◽  
Vol 78 (6) ◽  
pp. 2466-2476 ◽  
Author(s):  
Giovanni Di Bonaventura ◽  
Arianna Pompilio ◽  
Roberta Zappacosta ◽  
Francesca Petrucci ◽  
Ersilia Fiscarelli ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Inflammatory Response ◽  
Stenotrophomonas Maltophilia ◽  
Bacterial Load ◽  
Lung Pathology ◽  
Necrosis Factor Alpha ◽  
Inflammatory Protein ◽  
Infection And Inflammation ◽  
Factor Alpha

ABSTRACT Stenotrophomonas maltophilia is a pathogen that causes infections mainly in immunocompromised patients. Despite increased S. maltophilia isolation from respiratory specimens of patients with cystic fibrosis (CF), the real contribution of the microorganism to CF pathogenesis still needs to be clarified. The aim of the present study was to evaluate the pathogenic role of S. maltophilia in CF patients by using a model of acute respiratory infection in DBA/2 mice following a single exposure to aerosolized bacteria. The pulmonary bacterial load was stable until day 3 and then decreased significantly from day 3 through day 14, when the bacterial load became undetectable in all infected mice. Infection disseminated in most mice, although at a very low level. Severe effects (swollen lungs, large atelectasis, pleural adhesion, and hemorrhages) of lung pathology were observed on days 3, 7, and 14. The clearance of S. maltophilia observed in DBA/2 mouse lungs was clearly associated with an early and intense bronchial and alveolar inflammatory response, which is mediated primarily by neutrophils. Significantly higher levels of interleukin-1β (IL-1β), IL-6, IL-12, gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), GROα/KC, MCP-1/JE, MCP-5, macrophage inflammatory protein 1α (MIP-1α), MIP-2, and TARC were observed in infected mice on day 1 with respect to controls. Excessive pulmonary infection and inflammation caused systemic effects, manifested by weight loss, and finally caused a high mortality rate. Taken together, our results show that S. maltophilia is not just a bystander in CF patients but has the potential to contribute to the inflammatory process that compromises respiratory function.

scholarly journals The Involvement of Glycosaminoglycans in Airway Disease Associated with Cystic Fibrosis

2011 ◽  
Vol 11 ◽  
pp. 959-971 ◽  
Author(s):  
Emer P. Reeves ◽  
David A. Bergin ◽  
Michelle A. Murray ◽  
Noel G. McElvaney
Keyword(s):  
Cystic Fibrosis ◽  
Inflammatory Response ◽  
Respiratory Disease ◽  
Heparan Sulphate ◽  
Airway Disease ◽  
Parallel Process ◽  
Neutrophil Recruitment ◽  
Present Review ◽  
Infection And Inflammation

Individuals with cystic fibrosis (CF) present with severe airway destruction and extensive bronchiectasis. It has been assumed that these structural airway changes have occurred secondary to infection and inflammation, but recent studies suggest that glycosaminoglycan (GAG) remodelling may be an important independent parallel process. Evidence is accumulating that not only the concentration, but also sulphation of GAGs is markedly increased in CF bronchial cells and tissues. Increased expression of GAGs and, in particular, heparan sulphate, has been linked to a sustained inflammatory response and neutrophil recruitment to the CF airways. This present review discusses the biological role of GAGs in the lung, as well as their involvement in CF respiratory disease, and their potential as therapeutic targets.

scholarly journals Cell based therapy aides in infection and inflammation resolution in the murine model of cystic fibrosis lung disease

2013 ◽  
Vol 03 (02) ◽  
pp. 139-153 ◽  
Author(s):  
Tracey L. Bonfield ◽  
Donald Lennon ◽  
Santosh K. Ghosh ◽  
Amy M. DiMarino ◽  
Aaron Weinberg ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Murine Model ◽  
Cystic Fibrosis Lung ◽  
Cell Based Therapy ◽  
Cystic Fibrosis Lung Disease ◽  
Infection And Inflammation ◽  
Inflammation Resolution

scholarly journals Complex Probiotics Supplementation Improves Overtraining-Induced Muscle Inflammatory Response and Antioxidant Status Via LPS-TLR4/NF-κb Signalling Pathway in Rats

2021 ◽  
Author(s):  
Yali Xia ◽  
Jing Shao ◽  
Hui Wang ◽  
Qiushi Tan ◽  
Qi Han ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Protein Expression ◽  
Caspase 3 ◽  
Well Being ◽  
Mucosal Barrier ◽  
Caspase 9 ◽  
Excessive Exercise ◽  
Inflammatory Status ◽  
Anti Inflammatory ◽  
Exercise Induced

Abstract Background: Prolonged endurance and intensive exercise has shown detrimental effects on muscle health as well as causes intestinal dysbiosis. Probiotics are known as live microorganisms effective in improving gut microbiota and immunity to warrant health and well-being, which exert global and local biological functions on gut and muscle comprising of anti-oxidative stress, anti-inflammatory and anti-apoptosis, etc,. This research was conducted to investigate whether complex probiotics supplementation could alleviate excessive exercise-induced muscle damage and underlying signaling mechanism in rats.Methods: Thirty-two male SD rats were randomly allocated to four groups: control (SC), exercise (EC), probiotics (SP) and exercise with probiotics (EP) (n = 8 each). In the overtraining model, rats were arranged to an incremental load training on the treadmill 6 days/week for 8 weeks and gavaged with complex-probiotic-preparation (4 × 109 CFU/g) containing maltodextrin or maltodextrin only once a day. Serum and soleus were collected at the end of experiment. Serum creatine kinase (CK) and lactate dehydrogenase (LDH) activities, the levels of lipopolysaccharide (LPS), interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), and muscle total antioxidant capacity (T-AOC), glutathione peroxidase (GPx), catalase (CAT) in soleus were measured. Furthermore, soleus protein expression of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), p-p65/p65, Bax, Bcl-2, caspase-9 and caspase-3 were determined by western blotting assay. Results: The findings indicated that excessive exercise induced a significant increased CK and LDH activities, LPS levels, relative protein expression of TLR4, MyD88, p-p65/p65, inflammatory cytokines and lipid peroxidation (p < 0.05). Simultaneously, the antioxidant elements including T-AOC, GPx, CAT were markedly decreased in the muscle of EC group (p < 0.05). In addition, up-regulated the protein expression of Bax/Bcl-2, cleaved caspase-9/procaspase-9 and cleaved caspase-3/procaspase-3 in muscle (p < 0.05). Administration of complex probiotics attenuated overtraining-induced inflammatory response, oxidative injury and TLR4/nuclear factor-kappa B (NF-kB) signaling factors expression as a result of reversing the most of above altered biochemical parameters (p < 0.05), and there was only tendency downregulation in the expression of apoptosis-regulated proteins (p > 0.05). Conclusions: Administration of complex probiotics could improve capability of the anti-oxidant, anti-inflammatory status induced by excessive exercise in rat skeletal muscle possibly via protecting the gut mucosal barrier, inhibiting the outflow of endotoxin, attenuating the action of TLR4-mediated NF-kB pathway.

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