Purpose. Influenza viruses are a common cause of human respiratory infections, resulting in epidemics of high morbidity and mortality. We investigated the effect of a novel mitogen-activated protein kinase (MAPK) inhibitor in vitro and in a murine influenza model to further explore whether p38 MAPK inhibition could reduce viral replication.
Methods.In vitro, the antiviral effect of p38 MAPK inhibitor BCT194 was evaluated in differentiated human bronchial epithelial cells (HBECs); in vivo, female BALB/c mice were infected intranasally with 150 pfu of influenza H1N1 A/Puerto Rico/8/34 and treated with BCT197 (a closely related p38 MAPK inhibitor with an IC50 value of<1 µM, currently in clinical testing), dexamethasone or oseltamivir (Tamiflu) starting 24 h post infection. Body weight, bronchoalveolar lavage cells, cytokines, total protein and lactate dehydrogenase as well as serum cytokines were measured; a subset of animals was evaluated histopathologically.
Results/Key findings. p38MAP kinase inhibition with BCT194 had no impact on influenza replication in HBECs. When examining BCT197 in vivo, and comparing to vehicle-treated animals, reduced weight loss, improvement in survival and lack of impaired viral control was observed at BCT197 concentrations relevant to those being used in clinical trials of acute exacerbations of chronic obstructive pulmonary disease; at higher concentrations of BCT197 these effects were reduced.
Conclusions. Compared to vehicle treatment, BCT197 (administered at a clinically relevant concentration) improved outcomes in a mouse model of influenza. This is encouraging given that the use of innate inflammatory pathway inhibitors may raise concerns of negative effects on infection regulation.
GubarevaLV,
BesselaarTG,
DanielsRS,
FryA,
GregoryV et al. Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2015–2016. Antiviral Res2017; 146:12–20 [View Article][PubMed]
ChoiMS,
HeoJ,
YiCM,
BanJ,
LeeNJ et al. A novel p38 mitogen activated protein kinase (MAPK) specific inhibitor suppresses respiratory syncytial virus and influenza A virus replication by inhibiting virus-induced p38 MAPK activation. Biochem Biophys Res Commun2016; 477:311–316 [View Article][PubMed]
ChiarettiA,
PulitanòS,
BaroneG,
FerraraP,
RomanoV et al. IL-1β and IL-6 upregulation in children with H1N1 influenza virus infection. Mediators Inflamm2013; 2013:1–8 [View Article][PubMed]
WestraJ,
Doornbos-van der MeerB,
de BoerP,
van LeeuwenMA,
van RijswijkMH et al. Strong inhibition of TNF-α production and inhibition of IL-8 and COX-2 mRNA expression in monocyte-derived macrophages by RWJ 67657, a p38 mitogen-activated protein kinase (MAPK) inhibitor. Arthritis Res Ther2004; 6:R384–R392 [View Article][PubMed]
MarchantD,
SingheraGK,
UtokaparchS,
HackettTL,
BoydJH et al. Toll-like receptor 4-mediated activation of p38 mitogen-activated protein kinase is a determinant of respiratory virus entry and tropism. J Virol2010; 84:11359–11373 [View Article][PubMed]
NovartisAG.
5-membered heterocyle-based p38 kinase inhibitors. US 8242117 2012
de BuckS,
HueberW,
VitalitiA,
StraubeF,
EmotteC et al. Population PK-PD model for tolerance evaluation to the p38 MAP kinase inhibitor BCT197. CPT Pharmacometrics Syst Pharmacol2015; 4:691–700 [View Article][PubMed]
CBCT197A2201: an exploratory, randomized, double-blind, placebo controlled, multi-center study to assess the efficacy, safety and tolerability of a single and a repeated dose of oral BCT197 in patients with an acute COPD exacerbation. https://clinicaltrials.gov/ct2/show/NCT01332097
McCullersJA,
BartmessKC.
Role of neuraminidase in lethal synergism between influenza virus and Streptococcus pneumoniae
. J Infect Dis2003; 187:1000–1009 [View Article][PubMed]
KaoRY,
YangD,
LauLS,
TsuiWH,
HuL et al. Identification of influenza A nucleoprotein as an antiviral target. Nat Biotechnol2010; 28:600–605 [View Article][PubMed]
ParkinJM,
HardakerEL.
Effects of Acumapimod (BCT197), an oral p38 inhibitor, on tobacco smoke and lipopolysaccharide-induced lung inflammation in a corticosteroid-resistant rat model. Am J Respir Crit Care Med2017; 195:A6305
WeiD,
HuangZH,
ZhangRH,
WangCL,
XuMJ et al. Roles of p38 MAPK in the regulation of the inflammatory response to swine influenza virus-induced acute lung injury in mice. Acta Virol2014; 58:374–379 [View Article][PubMed]
MacNeeW,
AllanRJ,
JonesI,
de SalvoMC,
TanLF.
Efficacy and safety of the oral p38 inhibitor PH-797804 in chronic obstructive pulmonary disease: a randomised clinical trial. Thorax2013; 68:738–745 [View Article][PubMed]
WalshKB,
TeijaroJR,
WilkerPR,
JatzekA,
FremgenDM et al. Suppression of cytokine storm with a sphingosine analog provides protection against pathogenic influenza virus. Proc Natl Acad Sci USA2011; 108:12018–12023 [View Article][PubMed]
BarlowPG,
SvobodaP,
MacKellarA,
NashAA,
YorkIA et al. Antiviral activity and increased host defense against influenza infection elicited by the human cathelicidin LL-37. PLoS One2011; 6:e25333 [View Article][PubMed]
TeijaroJR,
WalshKB,
CahalanS,
FremgenDM,
RobertsE et al. Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection. Cell2011; 146:980–991 [View Article][PubMed]
XuT,
QiaoJ,
ZhaoL,
HeG,
LiK et al. Effect of dexamethasone on acute respiratory distress syndrome induced by the H5N1 virus in mice. Eur Respir J2009; 33:852–860 [View Article][PubMed]
BauerCM,
ZavitzCC,
BotelhoFM,
LambertKN,
BrownEG et al. Treating viral exacerbations of chronic obstructive pulmonary disease: insights from a mouse model of cigarette smoke and H1N1 influenza infection. PLoS One2010; 5:e13251 [View Article][PubMed]
GrowcottEJ,
CoulthardA,
AmisonR,
HardakerEL,
GrevotA et al. The effect of budesonide in a refined rat model of respiratory infection with Pseudomonas aeruginosa. Proceedings of the British Pharmacological Society at http://pA2online.org/abstracts/Vol7Issue4abst142P.pdf
Quispe-LaimeAM,
BraccoJD,
BarberioPA,
CampagneCG,
RolfoVE et al. H1N1 influenza A virus-associated acute lung injury: response to combination oseltamivir and prolonged corticosteroid treatment. Intensive Care Med2010; 36:33–41 [View Article][PubMed]
Brun-BuissonC,
RichardJC,
MercatA,
ThiébautAC,
BrochardL.
Early corticosteroids in severe influenza A/H1N1 pneumonia and acute respiratory distress syndrome. Am J Respir Crit Care Med2011; 183:1200–1206 [View Article][PubMed]
Martin-LoechesI,
LisboaT,
RhodesA,
MorenoRP,
SilvaE et al. Use of early corticosteroid therapy on ICU admission in patients affected by severe pandemic (H1N1)v influenza A infection. Intensive Care Med2011; 37:272–283 [View Article][PubMed]
FritzRS,
HaydenFG,
CalfeeDP,
CassLM,
PengAW et al. Nasal cytokine and chemokine responses in experimental influenza A virus infection: results of a placebo-controlled trial of intravenous zanamivir treatment. J Infect Dis1999; 180:586–593 [View Article][PubMed]