Role of p38 Mitogen-Activated Protein Kinase in Asthma and COPD: Pathogenic Aspects and Potential Targeted Therapies

References

• PapiA, BrightlingC, PedersenSE, ReddelHK. Asthma. Lancet. 2018;391(10122):783–800. doi:10.1016/S0140-6736(17)33311-129273246
   PubMed Web of Science ®Google Scholar
• KhalafK, PaolettiG, PuggioniF, et al. Asthma from immune pathogenesis to precision medicine. Semin Immunol. 2019;46:101294. doi:10.1016/j.smim.2019.10129431387788
   PubMed Web of Science ®Google Scholar
• AgustiA, HoggJC. Update on the pathogenesis of chronic obstructive pulmonary disease. N Engl J Med. 2019;381:1248–1256. doi:10.1056/NEJMra190047531553836
   PubMed Web of Science ®Google Scholar
• BarnesPJ. Inflammatory mechanisms in COPD. J Allergy Clin Immunol. 2016;138:16–27. doi:10.1016/j.jaci.2016.05.01127373322
   PubMed Web of Science ®Google Scholar
• LambrechtBN, HammadH, FahyJV. The cytokines of asthma. Immunity. 2019;50:975–991.30995510
   PubMed Web of Science ®Google Scholar
• BarnesPJ. Inflammatory endotypes in COPD. Allergy. 2019;74:1249–1256. doi:10.1111/all.1376030834543
   PubMed Web of Science ®Google Scholar
• PelaiaC, VatrellaA, CrimiC, GallelliL, TerraccianoR, PelaiaG. Clinical relevance of understanding mitogen-activated protein kinases involved in asthma. Expert Rev Respir Med. 2020;14(5):501–510. doi:10.1080/17476348.2020.173536532098546
   PubMed Web of Science ®Google Scholar
• PelaiaC, VatrellaA, SciacquaA, TerraccianoR, PelaiaG. Role of p38-mitogen-activated protein kinase in COPD: pathological implications and therapeutic perspectives. Expert Rev Respir Med. 2020;14:485–491. doi:10.1080/17476348.2020.173282132077346
   PubMed Web of Science ®Google Scholar
• BarnesPJ. Kinases as novel therapeutic targets in asthma and chronic obstructive pulmonary disease. Pharmacol Rev. 2016;68:788–815. doi:10.1124/pr.116.01251827363440
   PubMed Web of Science ®Google Scholar
• HanJ, WuJ, SilkeJ. An overview of mammalian p38 mitogen-activated protein kinases, central regulators of cell stress and receptor signaling. F100Res. 2020;9:653.
   Google Scholar
• KhorasasanizadehM, EskianM, GelfandEW, RezaeiN. Mitogen-activated protein kinases as therapeutic targets for asthma. Pharmacol Ther. 2017;174:112–126. doi:10.1016/j.pharmthera.2017.02.02428223227
   PubMed Web of Science ®Google Scholar
• O’NeilJD, AmmitAJ, ClarkAR. MAPK p38 regulates inflammatory gene expression via tristetraprolin: doing good by stealth. Int J Biochem Cell Biol. 2018;94:6–9. doi:10.1016/j.biocel.2017.11.00329128684
   PubMed Web of Science ®Google Scholar
• MoosaviSM, PrabhalaP, AmmitAJ. Role and regulation of MKP-1 in airway inflammation. Respir Res. 2017;18(1):154. doi:10.1186/s12931-017-0637-328797290
   PubMed Web of Science ®Google Scholar
• KuruvillaME, LeeF, LeeGB. Understanding asthma phenotypes, endotypes, and mechanisms of disease. Clin Rev Allergy Immunol. 2019;56:219–233. doi:10.1007/s12016-018-8712-130206782
   PubMed Web of Science ®Google Scholar
• NelsonRK, BushA, StokesJ, NairP, AkuthotaP. Eosinophilic asthma. J Allergy Clin Immunol Pract. 2020;8(2):465–473. doi:10.1016/j.jaip.2019.11.02431786254
   PubMed Web of Science ®Google Scholar
• CosmiL, AnnunziatoF. ILC2 are the earliest recruiters of eosinophils in lungs of allergic asthmatic patients. Am J Respir Crit Care Med. 2017;196:666–668. doi:10.1164/rccm.201704-0799ED28475847
   PubMed Web of Science ®Google Scholar
• PelaiaC, PaolettiG, PuggioniF, et al. Interleukin-5 in the pathophysiology of severe asthma. Front Physiol. 2019;10:1514. doi:10.3389/fphys.2019.0151431920718
   PubMed Web of Science ®Google Scholar
• PelaiaC, CrimiC, VatrellaA, TinelloC, TerraccianoR, PelaiaG. Molecular targets for biological therapies of severe asthma. Front Immunol. 2020;11:603312. doi:10.3389/fimmu.2020.60331233329598
   PubMed Web of Science ®Google Scholar
• ManeechotesuwanK, XinY, ItoK, et al. Regulation of Th2 cytokine genes by p38 MAPK-mediated phosphorylation of GATA-3. J Immunol. 2007;178:2491–2498. doi:10.4049/jimmunol.178.4.249117277157
   PubMed Web of Science ®Google Scholar
• KabataH, MoroK, KoyashuS. The group 2 innate lymphoid cell (ILC2) regulatory network and its underlying mechanisms. Immunol Rev. 2018;286:37–52. doi:10.1111/imr.1270630294963
   PubMed Web of Science ®Google Scholar
• PetrovaT, PesicJ, PardaliK, GaestelM, ArthurJSC. p38 MAPK signalling regulates cytokine production in IL-33 stimulated type 2 innate lymphoid cells. Sci Rep. 2020;10:3479. doi:10.1038/s41598-020-60089-032103032
   PubMed Web of Science ®Google Scholar
• RayA, KollsJK. Neutrophilic inflammation in asthma and association with disease severity. Trends Immunol. 2017;38(12):942–954. doi:10.1016/j.it.2017.07.00328784414
   PubMed Web of Science ®Google Scholar
• BainesKJ, FrickerM, McdonaldVM, et al. Sputum transcriptomics implicates increased p38 signalling activity in severe asthma. Respirology. 2020;25:709–718. doi:10.1111/resp.1374931808595
   PubMed Web of Science ®Google Scholar
• TamuraDY, MooreEE, JohnsonJL, ZallenG, AiboshiJ, SillimanCC. p38 mitogen-activated protein kinase inhibition attenuates intercellular adhesion molecule-1 up-regulation on human pulmonary microvascular endothelial cells. Surgery. 1998;124:403–407. doi:10.1016/S0039-6060(98)70147-39706165
   PubMed Web of Science ®Google Scholar
• NickJA, YoungSK, BrownKK, et al. Role of p38 mitogen-activated protein kinase in a murine model of pulmonary inflammation. J Immunol. 2000;164(4):2151–2159. doi:10.4049/jimmunol.164.4.215110657669
   PubMed Web of Science ®Google Scholar
• OchayonDE, AliA, AlarconPC, et al. IL-33 promotes type 1 cytokine expression via p38 MAPK in human NK cells. J Leukoc Biol. 2020;107(4):663–671. doi:10.1002/JLB.3A0120-379RR32017227
   PubMed Web of Science ®Google Scholar
• KimDH, GuA, LeeJS, et al. Suppressive effect of S100A8 and S100A9 on neutrophil apoptosis by cytokine release of human bronchial epithelial cells in asthma. Int J Med Sci. 2020;17:498–509. doi:10.7150/ijms.3783332174780
   PubMed Web of Science ®Google Scholar
• JaiswalAK, MakhijaS, StahrN, et al. Dendritic cell-restricted progenitors contribute to obesity-associated airway inflammation via Adam17-p38 MAPK-dependent pathway. Front Immunol. 2020;11:363. doi:10.3389/fimmu.2020.0036332184787
   PubMed Web of Science ®Google Scholar
• ZhangY, LiX, HeM, et al. The effects of neutralizing anti-murine interleukin-17A monoclonal antibody on ozone-induced inflammation and glucocorticoids insensitivity in a murine model of asthma. Biomed Pharmacother. 2019;114:108786. doi:10.1016/j.biopha.2019.10878630917335
   PubMed Web of Science ®Google Scholar
• SouthworthT, MasonS, BellA, et al. PI3K, p38 and JAK/STAT signalling in bronchial tissue from patients with asthma following allergen challenge. Biomark Res. 2018;6(1):14. doi:10.1186/s40364-018-0128-929651336
   PubMed Web of Science ®Google Scholar
• PelaiaG, CudaG, VatrellaA, et al. Effects of transforming growth factor-β and budesonide on mitogen-activated protein kinase activation and apoptosis in airway epithelial cells. Am J Respir Cell Mol Biol. 2003;29(1):12–18. doi:10.1165/rcmb.2002-0074OC12600835
   PubMed Web of Science ®Google Scholar
• BucchieriF, PuddicombeSM, LordanJL, et al. Asthmatic bronchial epithelium is more susceptible to oxidant-induced apoptosis. Am J Respir Cell Mol Biol. 2002;27(2):179–185. doi:10.1165/ajrcmb.27.2.469912151309
   PubMed Web of Science ®Google Scholar
• TrautmannA, Schmid-GrendelmeierP, KrugerK, et al. T cells and eosinophils cooperate in the induction of bronchial epithelial cell apoptosis in asthma. J Allergy Clin Immunol. 2002;109:329–337. doi:10.1067/mai.2002.12146011842305
   PubMed Web of Science ®Google Scholar
• O’SullivanMP, TynerJW, HoltzmanMJ. Apoptosis in the airways: another balancing act in the epithelial program. Am J Respir Cell Mol Biol. 2003;29(1):3–7. doi:10.1165/rcmb.F27312821445
   PubMed Web of Science ®Google Scholar
• VignolaAM, MirabellaF, CostanzoG, et al. Airway remodeling in asthma. Chest. 2003;123(3 Suppl):417S–422S. doi:10.1378/chest.123.3_suppl.417S
   Web of Science ®Google Scholar
• EliasJA, ZhuZ, ChuppG, HomerRJ. Airway remodeling in asthma. J Clin Invest. 1999;104(8):1001–1006. doi:10.1172/JCI812410525034
   PubMed Web of Science ®Google Scholar
• FitzgeraldSM, LeeSA, HallHK, ChiDS, KrishnaswamyG. Human lung fibroblasts express IL-6 in response to signaling following mast cell contact. Am J Respir Cell Mol Biol. 2004;30:585–593. doi:10.1165/rcmb.2003-0282OC14565941
   PubMed Web of Science ®Google Scholar
• MarumoS, HoshinoY, KiyokawaH, et al. p38 mitogen-activated protein kinase determines the susceptibility to cigarette smoke-induced emphysema in mice. BMC Pulm Med. 2014;14:79. doi:10.1186/1471-2466-14-7924885161
   PubMed Web of Science ®Google Scholar
• WangC, ZhouJ, WangJ, et al. Progress in the mechanism and targeted drug therapy for COPD. Signal Transduct Target Ther. 2020;5:248.33110061
   PubMed Web of Science ®Google Scholar
• RendaT, BaraldoS, PelaiaG, et al. Increased activation of p38 MAPK in COPD. Eur Respir J. 2008;31(1):62–69. doi:10.1183/09031936.0003670717959643
   PubMed Web of Science ®Google Scholar
• GaffeyK, ReynoldsS, PlumbJ, KaurM, SinghD. Increased phosphorylated p38 mitogen-activated protein kinase in COPD lungs. Eur Respir J. 2013;42(1):28–41. doi:10.1183/09031936.0017071123060629
   PubMed Web of Science ®Google Scholar
• HuangC, XieM, HeX, GaoH. Activity of sputum p38 MAPK is correlated with airway inflammation and reduced FEV1 in COPD patients. Med Sci Monitor. 2013;19:1229–1235. doi:10.12659/MSM.889880
   PubMed Web of Science ®Google Scholar
• WatanabeT, JonoH, HanJ, LimDJ, LiJD. Synergistic activation of NF-αB by nontypeable Haemophilus influenzae and tumor necrosis factor. Proc Natl Acad Sci USA. 2004;101:3563–3568. doi:10.1073/pnas.040055710114993593
   PubMed Web of Science ®Google Scholar
• GallelliL, PelaiaG, FrattoD, et al. Effects of budesonide on p38 MAPK activation, apoptosis and IL-8 secretion, induced by TNF-α and Haemophilus influenzae in human bronchial epithelial cells. Int J Immunopathol Pharmacol. 2010;23:471–479. doi:10.1177/03946320100230020920646342
   PubMed Web of Science ®Google Scholar
• ChungKF. Inflammatory mediators in chronic obstructive pulmonary disease. Curr Drug Targets Inflamm Allergy. 2005;4(6):619–625. doi:10.2174/15680100577491280617305518
   PubMedGoogle Scholar
• PelaiaG, CudaG, VatrellaA, et al. Effects of hydrogen peroxide on MAPK activation, IL-8 production and cell viability in primary cultures of human bronchial epithelial cells. J Cell Biochem. 2004;93(1):142–152. doi:10.1002/jcb.2012415352171
   PubMed Web of Science ®Google Scholar
• ShenH, YoshidaH, YanF, et al. Synergistic induction of MUC5AC mucin by nontypeable Haemophilus influenzae and Streptococcus pneumoniae. Biochem Biophys Res Commun. 2008;365:795–800. doi:10.1016/j.bbrc.2007.11.06018037371
   PubMed Web of Science ®Google Scholar
• WedzichaJA, SeemungalTAR. COPD exacerbations: defining their cause and prevention. Lancet. 2007;370(9589):786–796. doi:10.1016/S0140-6736(07)61382-817765528
   PubMed Web of Science ®Google Scholar
• WiehlerS, ProudD. Interleukin-17A modulates human airway epithelial responses to human rhinovirus infection. Am J Physiol Lung Cell Mol Physiol. 2007;293(2):L505–L515.17545490
   PubMed Web of Science ®Google Scholar
• JamiesonKC, TravesSL, KooiC, et al. Rhinovirus and bacteria synergistically induce IL-17C release from human airway epithelial cells to promote neutrophil recruitment. J Immunol. 2019;202(1):160–170. doi:10.4049/jimmunol.180054730504421
   PubMed Web of Science ®Google Scholar
• BathoornE, KerstjensH, PostmaD, TimensW, MacNeeW. Airways inflammation and treatment during acute exacerbations of COPD. Int J Chron Obstruct Pulmon Dis. 2008;3:217–229. doi:10.2147/COPD.S121018686731
   PubMedGoogle Scholar
• BarnesPJ, BakerJ, DonnellyLE. Cellular senescence as a mechanism and target in chronic lung diseases. Am J Respir Crit Care Med. 2019;200(5):556–564. doi:10.1164/rccm.201810-1975TR30860857
   PubMed Web of Science ®Google Scholar
• UnderwoodDC, OsbornRR, KotzerCJ, et al. SB 239063, a potent p38 MAP kinase inhibitor, reduces inflammatory cytokine production, airways eosinophil infiltration, and persistence. J Pharmacol Exp Ther. 2000;293:281–288.10734180
   PubMed Web of Science ®Google Scholar
• MaJY, MedicherlaS, KerrI, MangaduR, ProtterAA, HigginsLS. Selective p38 mitogen-activated protein kinase inhibitor attenuates lung inflammation and fibrosis in IL-13 transgenic mouse model of asthma. J Asthma Allergy. 2008;1:31–44. doi:10.2147/JAA.S419921436983
   PubMedGoogle Scholar
• DuanW, ChanJH, McKayK. Inhaled p38- mitogen-activated protein kinase antisense oligonucleotide attenuates asthma in mice. Am J Respir Crit Care Med. 2005;171:571–578. doi:10.1164/rccm.200408-1006OC15557129
   PubMed Web of Science ®Google Scholar
• RatcliffeMJ, DougallIG. Comparison of the anti-inflammatory effects of cilomilast, budesonide and a p38 mitogen activated protein kinase inhibitor in COPD lung tissue macrophages. BMC Pharmacol Toxicol. 2012;13(1):15. doi:10.1186/2050-6511-13-1523148608
   PubMed Web of Science ®Google Scholar
• NormanP. Investigational p38 inhibitors for the treatment of chronic obstructive pulmonary disease. Expert Opin Investig Drugs. 2015;24(3):383–392. doi:10.1517/13543784.2015.1006358
   PubMed Web of Science ®Google Scholar
• SinghD, SmythL, BorrillZ, SweeneyL, Tal-SingerR. A randomized, placebo-controlled study of the effects of the p38 MAPK inhibitor SB-681323 on blood biomarkers of inflammation in COPD patients. J Clin Pharmacol. 2010;50(1):94–100. doi:10.1177/009127000934787319880675
   PubMed Web of Science ®Google Scholar
• BarnesN, PavordI, MadenC. Evaluation of an oral p38 mitogen activated protein kinase (MAPK) inhibitor SB-681323 in COPD patients. Eur Respir J. 2009;34(Suppl. 53):648s.
   PubMed Web of Science ®Google Scholar
• BettsJC, MayerRJ, Tal-SingerR, et al. Gene expression changes caused by the p38 MAPK inhibitor dilmapimod in COPD patients: analysis of blood and sputum samples from a randomized, placebo-controlled clinical trial. Pharmacol Res Perspect. 2015;3(1):e00094. doi:10.1002/prp2.9425692013
   PubMedGoogle Scholar
• WatzH, BarnacleH, HartleyB, ChanRA. Randomised, double-blind, placebo-controlled trial of the efficacy and safety of losmapimod in patients with chronic obstructive pulmonary disease. Lancet Respir Med. 2014;2:63–72. doi:10.1016/S2213-2600(13)70200-524461903
   PubMed Web of Science ®Google Scholar
• Marks-KonczalikJ, CostaM, RobertsonJ, McKieE, YangS, PascoeS. A post-hoc subgroup analysis of data from a six month clinical trial comparing the efficacy and safety of losmapimod in moderate-severe COPD patients with < 2% and > 2% blood eosinophils. Respir Med. 2015;109:860–869. doi:10.1016/j.rmed.2015.05.00326033641
   PubMed Web of Science ®Google Scholar
• LamasDA, LipsonDA, MillerBE, et al. Losmapimod Study Investigators. An oral inhibitor of p38 MAP kinase reduces plasma fibrinogen in patients with chronic obstructive pulmonary disease. J Clin Pharmacol. 2012;52:416–424. doi:10.1177/009127001039705022090363
   PubMed Web of Science ®Google Scholar
• MacNeeW, AllanRJ, JonesI, De SalvoMC, TanLF. Efficacy and safety of the oral p38 inhibitor PH-797804 in chronic obstructive pulmonary disease: a randomized clinical trial. Thorax. 2013;68:738–745.23539534
   PubMed Web of Science ®Google Scholar
• StrambuIR, KobalavaZD, MagnussonBP, MacKinnonA, ParkinJM. Phase II study of single/repeated doses of acumapimod (BCT197) to treat acute exacerbations of COPD. COPD. 2019;16:344–353. doi:10.1080/15412555.2019.168253531682162
   PubMedGoogle Scholar
• WedzichaJA, MacKinnonA, ParkinJM. Effectiveness of acumapimod oral p38 inhibitor in the treatment of acute severe exacerbations of COPD: results of the AETHER phase II trial. Am J Respir Crit Care Med. 2018;197:A7710.
   Web of Science ®Google Scholar
• AgyemangA, FarrellC, MooreW, ParkinJ. A physiologically based pharmacokinetic model to predict potential drug-drug interactions and inform dosing of acumopimod, an oral p38 MAPK inhibitor. CPT Pharmacometrics Syst Pharmacol. 2021;10:30–39. doi:10.1002/psp4.1256533107218
   PubMedGoogle Scholar
• RamosFL, CrinerGJ. Use of long-term macrolide therapy in chronic obstructive pulmonary disease. Curr Opin Pulm Med. 2014;20(2):153–158. doi:10.1097/MCP.000000000000002824378875
   PubMed Web of Science ®Google Scholar
• PatelNR, CunoosamyDM, FagerasM, et al. The development of AZD7624 for prevention of exacerbations in COPD: a randomized controlled trial. Int J COPD. 2018;13:1009–1019. doi:10.2147/COPD.S150576
   Google Scholar
• HighamA, KarurP, JacksonN, CunnoosamyDM, JanssonP, SinghD. Differential anti-inflammatory effects of budesonide and a p38 MAPK inhibitor on COPD pulmonary cells. Int J COPD. 2018;13:1279–1288. doi:10.2147/COPD.S159936
   Google Scholar
• CharronCE, RussellP, ItoK, et al. RV568, a narrow-spectrum kinase inhibitor with p38 MAPK-α and -selectivity, suppresses COPD inflammation. Eur Respir J. 2017;50:1700188. doi:10.1183/13993003.00188-201729074542
   PubMed Web of Science ®Google Scholar
• MillanDS, BunnageME, BurrowsJL, et al. Design and synthesis of inhaled p38 inhibitors for the treatment of chronic obstructive pulmonary disease. J Med Chem. 2011;54(22):7797–7814. doi:10.1021/jm200677b21888439
   PubMed Web of Science ®Google Scholar
• MeiD, TanWSD, WongWSF. Pharmacological strategies to regain steroid sensitivity in severe asthma and COPD. Curr Opin Pharmacol. 2019;46:73–81. doi:10.1016/j.coph.2019.04.01031078066
   PubMed Web of Science ®Google Scholar
• PelaiaG, VatrellaA, BuscetiMT, et al. Molecular and cellular mechanisms underlying the therapeutic effects of budesonide in asthma. Pulm Pharmacol Ther. 2016;40:15–21. doi:10.1016/j.pupt.2016.07.00127381656
   PubMed Web of Science ®Google Scholar
• BhavsarP, HewM, KhorasaniN, et al. Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared to non-severe asthma. Thorax. 2008;63:784–790. doi:10.1136/thx.2007.09002718492738
   PubMed Web of Science ®Google Scholar
• BarnesPJ. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2013;131:636–645. doi:10.1016/j.jaci.2012.12.156423360759
   PubMed Web of Science ®Google Scholar
• LeaS, LiJ, PlumbJ, et al. p38 MAPK and glucocorticoid receptor crosstalk in bronchial epithelial cells. J Mol Med. 2020;98(3):361–374. doi:10.1007/s00109-020-01873-331974640
   PubMed Web of Science ®Google Scholar
• KhalafRM, LeaSR, MetcalfeHJ, SinghD. Mechanisms of corticosteroid insensitivity in COPD alveolar macrophages exposed to NTHi. Respir Res. 2017;18(1):61. doi:10.1186/s12931-017-0539-428420398
   PubMed Web of Science ®Google Scholar
• HighamA, SinghD. Dexamethasone and p38 MAPK inhibition of cytokine production from human lung fibroblasts. Fundam Clin Pharmacol. 2021.
   Web of Science ®Google Scholar
• GoldsteinDM, KuglstatterA, LouY, SothMJ. Selective p38α inhibitors evaluated for the treatment of chronic inflammatory disorders. J Med Chem. 2010;53:2345–2353. doi:10.1021/jm901290619950901
   PubMed Web of Science ®Google Scholar
• KhorasaniN, BakerJ, JohnsonM, ChungKF, BhavsarPK. Reversal of corticosteroid insensitivity by p38 MAPK inhibition in peripheral blood mononuclear cells from COPD. Int J COPD. 2015;10:283–291.
   Google Scholar
• Saba-El-LeilMK, FreminC, MelocheS. Redundancy in the world MAP kinases: all for one. Front Cell Dev Biol. 2016;4:31. doi:10.3389/fcell.2016.0006727148533
   PubMed Web of Science ®Google Scholar
• HammakerD, FiresteinGS. “Go upstream, young man”: lessons learned from the p38 saga. Annals Rheum Dis. 2010;69:177–182. doi:10.1136/ard.2009.119479
   Web of Science ®Google Scholar
• ChopraP, KanojeV, SemwalA, RayA. Therapeutic potential of inhaled p38 mitogen-activated protein kinase inhibitors for inflammatory pulmonary diseases. Expert Opin Investig Drugs. 2008;17(10):1411–1425. doi:10.1517/13543784.17.10.1411
   PubMed Web of Science ®Google Scholar