Targeting PI3K{delta} attenuates influenza virus-induced inflammation in a murine model of asthma exacerbation

We report here the pharmacological characterization of the tool compound CHD39359, a PI3K selective inhibitor, and, in particular, its activity in a murine model of asthma exacerbation induced by IAV. CHD39359 inhibited PI3K enzyme and Akt phosphorylation in THP-1 monocytes with nanomolar potency (IC50=0.79nM and IC50=0.50nM, respectively) and showed>500-fold selectivity against PI3K, PI3Kβ and PI3Kα. CHD39359 inhibited mouse neutrophil chemotaxis with IC50=0.32nM and reduced oxidative burst with IC50=4.2nM in neutrophils obtained from COPD patients. In a corticosteroid-insensitive model of exacerbation induced by intranasal challenge with influenza virus (H3N2) in mice immunized and challenged with house dust mite (HDM), CHD39359 (0.1mg/kg) or budesonide (0.1mg/kg) as single agents did not counteract H3N2-elicited neutrophils increase in BAL. However, CHD39359 alone at 1mg/kg significantly reduced the neutrophils influx in BAL. When the two inactive doses of both compounds (0.1mg/kg) were combined together, a significant reduction in neutrophil recruitment was observed, showing a synergistic anti-inflammatory effect. Thus, PI3K seems involved in the inflammatory response following IAV infection in the lung and targeting this isoform with selective inhibitors in combination with ICS might provide a useful strategy to treat exacerbations in severe asthma.
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Airway Cell Biology and Immunopathology Source Type: research

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Authors: Hallmann-Szelińska E, Łuniewska K, Szymański K, Kowalczyk D, Sałamatin R, Masny A, Brydak LB Abstract The World Health Organization estimates that influenza virus infects 3-5 million people worldwide every year, of whom 290,000 to 650,000 die. In the 2016/2017 epidemic season in Poland, the incidence of influenza was 1,692 per 100,000 population. The influenza A virus, subtype A/H3N2/, was the predominant one in that season. However, in the most recent 2017/2018 epidemic season, the incidence exceeded 1,782 per 100,000 already by August of 2018. In this season, influenza B virus predominated, while the...
Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research
Publication date: Available online 14 December 2019Source: Biochimica et Biophysica Acta (BBA) - BiomembranesAuthor(s): Athina Konstantinidi, Maria Chountoulesi, Nikolaos Naziris, Barbara Sartori, Heinz Amenitsch, Gregor Mali, Tomaž Čendak, Maria Plakantonaki, Iro Triantafyllakou, Theodore Tselios, Costas Demetzos, David D. Busath, Thomas Mavromoustakos, Antonios KolocourisAbstractWe have investigated the perturbation of influenza A M2TM in DMPC bilayers. We have shown that (a) DSC and SAXS detect changes in membrane organization caused by small changes (micromolar) in M2TM or aminoadamantane concentration and aminoadama...
Source: Biochimica et Biophysica Acta (BBA) Biomembranes - Category: Biochemistry Source Type: research
Abstract The human para influenza virus (HPIV) type 3 is an imperative respiratory virus which cause upper and lower respiratory infections. The receptor involved in the viral infection is haem agglutinin neuraminidase. It is of interest to study the interaction of haem agglutinin neuraminidase with zanamavir (4-GU-DANA), a known antiviral drug. We used the PDB structures with PDB IDs 1V2I, 1V3B, 1V3D and 1V3E for studying the interactions with zanamavir. The binding features of zanamavir with 1V2I (1.41kcal/mol) and 1V3E (11.81kcal/mol) having optimal interactions is reported for further consideration. PMID: 31831955 [PubMed]
Source: Bioinformation - Category: Bioinformatics Authors: Tags: Bioinformation Source Type: research
ConclusionThis may be achieved through adoption of stringent air pollution regulations and sustainable city planning. Increase in urban green infrastructures and improving road transportation will reduce PM2.5 levels in urban environment, thereby safeguarding human health from air pollution and improving citizens’ well-being.
Source: Clinical Epidemiology and Global Health - Category: Epidemiology Source Type: research
Publication date: Available online 13 December 2019Source: The Egyptian RheumatologistAuthor(s): Maryam Ahmed Abdulrahman, Samah A. Elbakry, Nagham Safwat Samy, Rehab M. Abdelrahman, Nermeen SamyAbstractBackgroundFemale patients with rheumatoid arthritis (RA) can have successful pregnancies. However, those who experience a higher disease activity during pregnancy and require continued treatment have a potential risk of maternal and neonatal complications.Aim of the workTo assess pregnancy outcome (adverse maternal and neonatal outcomes) in an Egyptian cohort of female RA patients.Patients and methodsThiscross-sectional stu...
Source: The Egyptian Rheumatologist - Category: Rheumatology Source Type: research
Journal of Aerosol Medicine and Pulmonary Drug Delivery, Ahead of Print.
Source: Journal of Aerosol Medicine and Pulmonary Drug Delivery - Category: Respiratory Medicine Authors: Source Type: research
Conclusions: In this cohort of elderly patients, those with cardiac failure and COPD or asthma were more prone to being submitted to NIV or IMV. RSV infection was associated with higher mortality independently of significant co-morbidities.
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Respiratory infections Source Type: research
We report here the effect of CHF6297, a potent and selective inhaled p38MAPK inhibitor, in three murine models of steroid-resistant lung inflammation. In mice exposed to tobacco smoke (TS), CHF6297, administered intranasally (i.n.) b.i.d. for 4 days at 0.03 or 0.3mg/kg, dose-dependently inhibited the corticosteroid-resistant TS-induced neutrophil influx in bronchoalveolar lavage (BAL) reaching a % of inhibition of 29.7±15.3 (n.s.) and 62±8.4 (p
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Airway Pharmacology and Treatment Source Type: research
Steroids are a mainstay of treatment for chronic respiratory diseases, such as asthma and COPD. Intriguingly, data emerging from the 2009 flu pandemic suggests that corticosteroid may have explained the association of asthma with less severe outcomes in patients hospitalised with influenza1. Since macrophages are a major target of influenza infection, the aim of the present study was to analyse the effect of corticosteroids on macrophage infection by influenza.Human monocyte-derived macrophages (MDM) were exposed to H3N2 X31 influenza virus or UV-irradiated virus (UVX31) for 24 h in the presence or absence of 10–7 M ...
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: 10.1 Respiratory Infections Source Type: research
Conclusion: Our data suggest that carbocisteine might protect against FluA replication in vivo.
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: 5.1 Airway Pharmacology and Treatment Source Type: research
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