PI3K Signaling in Chronic Obstructive Pulmonary Disease: Mechanisms, Targets, and Therapy

Author(s): Flora Pirozzi , Kai Ren , Alessandra Murabito , Alessandra Ghigo* .

Journal Name: Current Medicinal Chemistry

Volume 26 , Issue 16 , 2019

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Chronic Obstructive Pulmonary Disease (COPD) is a progressive respiratory disorder characterized by irreversible chronic inflammation and airflow obstruction. It affects more than 64 million patients worldwide and it is predicted to become the third cause of death in the industrialized world by 2030. Currently available therapies are not able to block disease progression and to reduce mortality, underlying the need for a better understanding of COPD pathophysiological mechanisms to identify new molecular therapeutic targets. Recent studies demonstrated that phosphoinositide 3-kinase (PI3K) signaling is prominently activated in COPD and correlates with an increased susceptibility of patients to lung infections. PI3Ks have thus emerged as promising alternative drug targets for COPD and a wide array of pan-isoform and isoform-selective inhibitors have been tested in preclinical models and are currently being evaluated in clinical studies. Here, we summarize the recent knowledge on the involvement of PI3K enzymes in the pathophysiology of COPD, and we discuss the most recent results arising from the preclinical as well as the clinical testing of PI3K inhibitors as novel therapeutics for COPD.

Keywords: COPD, PI3K, inflammation, targeted therapy, clinical testing, P13K inhibitors.

Vetrano, D.L.; Foebel, A.D.; Marengoni, A.; Brandi, V.; Collamati, A.; Heckman, G.A.; Hirdes, J.; Bernabei, R.; Onder, G. Chronic diseases and geriatric syndromes: The different weight of comorbidity. Eur. J. Intern. Med., 2016, 27, 62-67. [http://dx.doi.org/10.1016/j.ejim.2015.10.025]. [PMID: 26643938].
Gross, N.J.; Barnes, P.J. New therapies for asthma and chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med., 2017, 195(2), 159-166. [http://dx.doi.org/10.1164/rccm.201610-2074PP]. [PMID: 27922751].
Barnes, P.J. Inflammatory mechanisms in patients with chronic obstructive pulmonary disease. J. Allergy Clin. Immunol., 2016, 138(1), 16-27. [http://dx.doi.org/10.1016/j.jaci.2016.05.011]. [PMID: 27373322].
Semenova, T.P.; Bragin, A.G.; Grishchenko, N.I.; Nesterova, I.V.; Vinogradova, O.S.; Gromova, E.A. Compensation for behavioral disorders due to administration of 6-hydroxy-dopamine in transplantation of embryonic locus coeruleus tissue in rats. Neurosci. Behav. Physiol., 1989, 19(5), 359-366. [http://dx.doi.org/10.1007/BF01197864]. [PMID: 2515469].
Decramer, M.; Janssens, W.; Miravitlles, M. Chronic obstructive pulmonary disease. Lancet, 2012, 379(9823), 1341-1351. [http://dx.doi.org/10.1016/S0140-6736(11)60968-9]. [PMID: 22314182].
Barnes, P.J. Identifying molecular targets for new drug development for chronic obstructive pulmonary disease: What does the future hold? Semin. Respir. Crit. Care Med., 2015, 36(4), 508-522. [http://dx.doi.org/10.1055/s-0035-1555611]. [PMID: 26238638].
Yoon, H.K.; Park, Y.B.; Rhee, C.K.; Lee, J.H.; Oh, Y.M. Summary of the chronic obstructive pulmonary disease clinical practice guideline revised in 2014 by the korean academy of tuberculosis and respiratory disease. Tuberc. Respir. Dis. (Seoul), 2017, 80(3), 230-240. [http://dx.doi.org/10.4046/trd.2017.80.3.230]. [PMID: 28747955].
Vogelmeier, C.F.; Criner, G.J.; Martinez, F.J.; Anzueto, A.; Barnes, P.J.; Bourbeau, J.; Celli, B.R.; Chen, R.; Decramer, M.; Fabbri, L.M.; Frith, P.; Halpin, D.M.; López Varela, M.V.; Nishimura, M.; Roche, N.; Rodriguez-Roisin, R.; Sin, D.D.; Singh, D.; Stockley, R.; Vestbo, J.; Wedzicha, J.A.; Agusti, A. Global strategy for the diagnosis, management and prevention of chronic obstructive lung disease 2017 Report: GOLD Executive Summary. Respirology, 2017, 22(3), 575-601. [http://dx.doi.org/10.1111/resp.13012]. [PMID: 28150362].
Rodrigo, G.J.; Price, D.; Anzueto, A.; Singh, D.; Altman, P.; Bader, G.; Patalano, F.; Fogel, R.; Kostikas, K. LABA/LAMA combinations versus LAMA monotherapy or LABA/ICS in COPD: a systematic review and meta-analysis. Int. J. Chron. Obstruct. Pulmon. Dis., 2017, 12, 907-922. [http://dx.doi.org/10.2147/COPD.S130482]. [PMID: 28360514].
Barnes, P.J.; Shapiro, S.D.; Pauwels, R.A. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur. Respir. J., 2003, 22(4), 672-688. [http://dx.doi.org/10.1183/09031936.03.00040703]. [PMID: 14582923].
Ito, K.; Caramori, G.; Adcock, I.M. Therapeutic potential of phosphatidylinositol 3-kinase inhibitors in inflammatory respiratory disease. J. Pharmacol. Exp. Ther., 2007, 321(1), 1-8. [http://dx.doi.org/10.1124/jpet.106.111674]. [PMID: 17021257].
Ito, K.; Ito, M.; Elliott, W.M.; Cosio, B.; Caramori, G.; Kon, O.M.; Barczyk, A.; Hayashi, S.; Adcock, I.M.; Hogg, J.C.; Barnes, P.J. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N. Engl. J. Med., 2005, 352(19), 1967-1976. [http://dx.doi.org/10.1056/NEJMoa041892]. [PMID: 15888697].
Reuter, S.; Taube, C. Mast cells and the development of allergic airway disease. J. Occup. Med. Toxicol., 2008, 3(Suppl. 1), S2. [http://dx.doi.org/10.1186/1745-6673-3-S1-S2]. [PMID: 18315833].
Galli, S.J.; Nakae, S.; Tsai, M. Mast cells in the development of adaptive immune responses. Nat. Immunol., 2005, 6(2), 135-142. [http://dx.doi.org/10.1038/ni1158]. [PMID: 15662442].
Mortaz, E.; Folkerts, G.; Redegeld, F. Mast cells and COPD. Pulm. Pharmacol. Ther., 2011, 24(4), 367-372. [http://dx.doi.org/10.1016/j.pupt.2011.03.007]. [PMID: 21463700].
Kalesnikoff, J.; Galli, S.J. New developments in mast cell biology. Nat. Immunol., 2008, 9(11), 1215-1223. [http://dx.doi.org/10.1038/ni.f.216]. [PMID: 18936782].
Mortaz, E.; Givi, M.E.; Da Silva, C.A.; Folkerts, G.; Redegeld, F.A. A relation between TGF-β and mast cell tryptase in experimental emphysema models. Biochim. Biophys. Acta, 2012, 1822(7), 1154-1160. [http://dx.doi.org/10.1016/j.bbadis.2012.03.006]. [PMID: 22481124].
Thakurdas, S.M.; Melicoff, E.; Sansores-Garcia, L.; Moreira, D.C.; Petrova, Y.; Stevens, R.L.; Adachi, R. The mast cell-restricted tryptase mMCP-6 has a critical immunoprotective role in bacterial infections. J. Biol. Chem., 2007, 282(29), 20809-20815. [http://dx.doi.org/10.1074/jbc.M611842200]. [PMID: 17456473].
Kalenderian, R.; Raju, L.; Roth, W.; Schwartz, L.B.; Gruber, B.; Janoff, A. Elevated histamine and tryptase levels in smokers’ bronchoalveolar lavage fluid. Do lung mast cells contribute to smokers’ emphysema? Chest, 1988, 94(1), 119-123. [http://dx.doi.org/10.1378/chest.94.1.119]. [PMID: 2454780].
Wei, X.M.; Kim, H.S.; Kumar, R.K.; Heywood, G.J.; Hunt, J.E.; McNeil, H.P.; Thomas, P.S. Effects of cigarette smoke on degranulation and NO production by mast cells and epithelial cells. Respir. Res., 2005, 6, 108. [http://dx.doi.org/10.1186/1465-9921-6-108]. [PMID: 16168067].
Beckett, E.L.; Stevens, R.L.; Jarnicki, A.G.; Kim, R.Y.; Hanish, I.; Hansbro, N.G.; Deane, A.; Keely, S.; Horvat, J.C.; Yang, M.; Oliver, B.G.; van Rooijen, N.; Inman, M.D.; Adachi, R.; Soberman, R.J.; Hamadi, S.; Wark, P.A.; Foster, P.S.; Hansbro, P.M. A new short-term mouse model of chronic obstructive pulmonary disease identifies a role for mast cell tryptase in pathogenesis. J. Allergy Clin. Immunol., 2013, 131(3), 752-762. [http://dx.doi.org/10.1016/j.jaci.2012.11.053]. [PMID: 23380220].
van der Strate, B.W.; Postma, D.S.; Brandsma, C.A.; Melgert, B.N.; Luinge, M.A.; Geerlings, M.; Hylkema, M.N.; van den Berg, A.; Timens, W.; Kerstjens, H.A. Cigarette smoke-induced emphysema: A role for the B cell? Am. J. Respir. Crit. Care Med., 2006, 173(7), 751-758. [http://dx.doi.org/10.1164/rccm.200504-594OC]. [PMID: 16399994].
Hogg, J.C.; Chu, F.; Utokaparch, S.; Woods, R.; Elliott, W.M.; Buzatu, L.; Cherniack, R.M.; Rogers, R.M.; Sciurba, F.C.; Coxson, H.O.; Paré, P.D. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N. Engl. J. Med., 2004, 350(26), 2645-2653. [http://dx.doi.org/10.1056/NEJMoa032158]. [PMID: 15215480].
Bracke, K.R.; Verhamme, F.M.; Seys, L.J.; Bantsimba-Malanda, C.; Cunoosamy, D.M.; Herbst, R.; Hammad, H.; Lambrecht, B.N.; Joos, G.F.; Brusselle, G.G. Role of CXCL13 in cigarette smoke-induced lymphoid follicle formation and chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med., 2013, 188(3), 343-355. [http://dx.doi.org/10.1164/rccm.201211-2055OC]. [PMID: 23742729].
Feghali-Bostwick, C.A.; Gadgil, A.S.; Otterbein, L.E.; Pilewski, J.M.; Stoner, M.W.; Csizmadia, E.; Zhang, Y.; Sciurba, F.C.; Duncan, S.R. Autoantibodies in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med., 2008, 177(2), 156-163. [http://dx.doi.org/10.1164/rccm.200701-014OC]. [PMID: 17975205].
Kirkham, P.A.; Caramori, G.; Casolari, P.; Papi, A.A.; Edwards, M.; Shamji, B.; Triantaphyllopoulos, K.; Hussain, F.; Pinart, M.; Khan, Y.; Heinemann, L.; Stevens, L.; Yeadon, M.; Barnes, P.J.; Chung, K.F.; Adcock, I.M. Oxidative stress-induced antibodies to carbonyl-modified protein correlate with severity of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med., 2011, 184(7), 796-802. [http://dx.doi.org/10.1164/rccm.201010-1605OC]. [PMID: 21965015].
Ghigo, A.; Damilano, F.; Braccini, L.; Hirsch, E. PI3K inhibition in inflammation: Toward tailored therapies for specific diseases. BioEssays, 2010, 32(3), 185-196. [http://dx.doi.org/10.1002/bies.200900150]. [PMID: 20162662].
Medina-Tato, D.A.; Ward, S.G.; Watson, M.L. Phosphoinositide 3-kinase signalling in lung disease: leucocytes and beyond. Immunology, 2007, 121(4), 448-461. [http://dx.doi.org/10.1111/j.1365-2567.2007.02663.x]. [PMID: 17614878].
Domin, J.; Waterfield, M.D. Using structure to define the function of phosphoinositide 3-kinase family members. FEBS Lett., 1997, 410(1), 91-95. [http://dx.doi.org/10.1016/S0014-5793(97)00617-0]. [PMID: 9247130].
Wymann, M.P.; Zvelebil, M.; Laffargue, M. Phosphoinositide 3-kinase signalling--which way to target? Trends Pharmacol. Sci., 2003, 24(7), 366-376. [http://dx.doi.org/10.1016/S0165-6147(03)00163-9]. [PMID: 12871670].
Ciraolo, E.; Iezzi, M.; Marone, R.; Marengo, S.; Curcio, C.; Costa, C.; Azzolino, O.; Gonella, C.; Rubinetto, C.; Wu, H.; Dastrù, W.; Martin, E.L.; Silengo, L.; Altruda, F.; Turco, E.; Lanzetti, L.; Musiani, P.; Rückle, T.; Rommel, C.; Backer, J.M.; Forni, G.; Wymann, M.P.; Hirsch, E. Phosphoinositide 3-kinase p110beta activity: key role in metabolism and mammary gland cancer but not development. Sci. Signal., 2008, 1(36), ra3. [http://dx.doi.org/10.1126/scisignal.1161577]. [PMID: 18780892].
Fischer, M.; Bockhorst, K.; Hoehn-Berlage, M.; Schmitz, B.; Hossmann, K.A. Imaging of the apparent diffusion coefficient for the evaluation of cerebral metabolic recovery after cardiac arrest. Magn. Reson. Imaging, 1995, 13(6), 781-790. [http://dx.doi.org/10.1016/0730-725X(95)00030-K]. [PMID: 8544649].
Schmid, M.C.; Avraamides, C.J.; Dippold, H.C.; Franco, I.; Foubert, P.; Ellies, L.G.; Acevedo, L.M.; Manglicmot, J.R.; Song, X.; Wrasidlo, W.; Blair, S.L.; Ginsberg, M.H.; Cheresh, D.A.; Hirsch, E.; Field, S.J.; Varner, J.A. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kγ, a single convergent point promoting tumor inflammation and progression. Cancer Cell, 2011, 19(6), 715-727. [http://dx.doi.org/10.1016/j.ccr.2011.04.016]. [PMID: 21665146].
Freund, G.G.; Wittig, J.G.; Mooney, R.A. The PI3-kinase serine kinase phosphorylates its p85 subunit and IRS-1 in PI3-kinase/IRS-1 complexes. Biochem. Biophys. Res. Commun., 1995, 206(1), 272-278. [http://dx.doi.org/10.1006/bbrc.1995.1038]. [PMID: 7818531].
Vanhaesebroeck, B.; Guillermet-Guibert, J.; Graupera, M.; Bilanges, B. The emerging mechanisms of isoform-specific PI3K signalling. Nat. Rev. Mol. Cell Biol., 2010, 11(5), 329-341. [http://dx.doi.org/10.1038/nrm2882]. [PMID: 20379207].
Okkenhaug, K.; Bilancio, A.; Farjot, G.; Priddle, H.; Sancho, S.; Peskett, E.; Pearce, W.; Meek, S.E.; Salpekar, A.; Waterfield, M.D.; Smith, A.J.; Vanhaesebroeck, B. Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science, 2002, 297(5583), 1031-1034. [http://dx.doi.org/10.1126/science.1073560]. [PMID: 12130661].
Hirsch, E.; Katanaev, V.L.; Garlanda, C.; Azzolino, O.; Pirola, L.; Silengo, L.; Sozzani, S.; Mantovani, A.; Altruda, F.; Wymann, M.P. Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation. Science, 2000, 287(5455), 1049-1053. [http://dx.doi.org/10.1126/science.287.5455.1049]. [PMID: 10669418].
Sadhu, C.; Masinovsky, B.; Dick, K.; Sowell, C.G.; Staunton, D.E. Essential role of phosphoinositide 3-kinase delta in neutrophil directional movement. J. Immunol., 2003, 170(5), 2647-2654. [http://dx.doi.org/10.4049/jimmunol.170.5.2647]. [PMID: 12594293].
Ferreira, A.M.; Isaacs, H.; Hayflick, J.S.; Rogers, K.A.; Sandig, M. The p110delta isoform of PI3K differentially regulates beta1 and beta2 integrin-mediated monocyte adhesion and spreading and modulates diapedesis. Microcirculation, 2006, 13(6), 439-456. [http://dx.doi.org/10.1080/10739680600776062]. [PMID: 16864411].
Tkaczyk, C.; Beaven, M.A.; Brachman, S.M.; Metcalfe, D.D.; Gilfillan, A.M. The phospholipase C gamma 1-dependent pathway of Fc epsilon RI-mediated mast cell activation is regulated independently of phosphatidylinositol 3-kinase. J. Biol. Chem., 2003, 278(48), 48474-48484. [http://dx.doi.org/10.1074/jbc.M301350200]. [PMID: 13129935].
Ali, K.; Bilancio, A.; Thomas, M.; Pearce, W.; Gilfillan, A.M.; Tkaczyk, C.; Kuehn, N.; Gray, A.; Giddings, J.; Peskett, E.; Fox, R.; Bruce, I.; Walker, C.; Sawyer, C.; Okkenhaug, K.; Finan, P.; Vanhaesebroeck, B. Essential role for the p110delta phosphoinositide 3-kinase in the allergic response. Nature, 2004, 431(7011), 1007-1011. [http://dx.doi.org/10.1038/nature02991]. [PMID: 15496927].
Ali, K.; Camps, M.; Pearce, W.P.; Ji, H.; Rückle, T.; Kuehn, N.; Pasquali, C.; Chabert, C.; Rommel, C.; Vanhaesebroeck, B. Isoform-specific functions of phosphoinositide 3-kinases: p110 delta but not p110 gamma promotes optimal allergic responses in vivo. J. Immunol., 2008, 180(4), 2538-2544. [http://dx.doi.org/10.4049/jimmunol.180.4.2538]. [PMID: 18250464].
Laffargue, M.; Calvez, R.; Finan, P.; Trifilieff, A.; Barbier, M.; Altruda, F.; Hirsch, E.; Wymann, M.P. Phosphoinositide 3-kinase gamma is an essential amplifier of mast cell function. Immunity, 2002, 16(3), 441-451. [http://dx.doi.org/10.1016/S1074-7613(02)00282-0]. [PMID: 11911828].
Yanagisawa, S.; Baker, J.R.; Vuppusetty, C.; Fenwick, P.; Donnelly, L.E.; Ito, K.; Barnes, P.J. Decreased phosphatase PTEN amplifies PI3K signaling and enhances proinflammatory cytokine release in COPD. Am. J. Physiol. Lung Cell. Mol. Physiol., 2017, 313(2), L230-L239. [http://dx.doi.org/10.1152/ajplung.00382.2016]. [PMID: 28522564].
Liu, A.; Wu, J.; Li, A.; Bi, W.; Liu, T.; Cao, L.; Liu, Y.; Dong, L. The inhibitory mechanism of Cordyceps sinensis on cigarette smoke extract-induced senescence in human bronchial epithelial cells. Int. J. Chron. Obstruct. Pulmon. Dis., 2016, 11, 1721-1731. [http://dx.doi.org/10.2147/COPD.S107396]. [PMID: 27555762].
Baker, J.R.; Vuppusetty, C.; Colley, T.; Papaioannou, A.I.; Fenwick, P.; Donnelly, L.; Ito, K.; Barnes, P.J. Oxidative stress dependent microRNA-34a activation via PI3Kα reduces the expression of sirtuin-1 and sirtuin-6 in epithelial cells. Sci. Rep., 2016, 6, 35871. [http://dx.doi.org/10.1038/srep35871]. [PMID: 27767101].
Hsu, A.C.; Starkey, M.R.; Hanish, I.; Parsons, K.; Haw, T.J.; Howland, L.J.; Barr, I.; Mahony, J.B.; Foster, P.S.; Knight, D.A.; Wark, P.A.; Hansbro, P.M. Targeting PI3K-p110α suppresses influenza virus infection in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med., 2015, 191(9), 1012-1023. [http://dx.doi.org/10.1164/rccm.201501-0188OC]. [PMID: 25751541].
Gustafson, A.M.; Soldi, R.; Anderlind, C.; Scholand, M.B.; Qian, J.; Zhang, X.; Cooper, K.; Walker, D.; McWilliams, A.; Liu, G.; Szabo, E.; Brody, J.; Massion, P.P.; Lenburg, M.E.; Lam, S.; Bild, A.H.; Spira, A. Airway PI3K pathway activation is an early and reversible event in lung cancer development. Sci. Transl. Med., 2010, 2(26)26ra25 [http://dx.doi.org/10.1126/scitranslmed.3000251]. [PMID: 20375364].
Angulo, I.; Vadas, O.; Garçon, F.; Banham-Hall, E.; Plagnol, V.; Leahy, T.R.; Baxendale, H.; Coulter, T.; Curtis, J.; Wu, C.; Blake-Palmer, K.; Perisic, O.; Smyth, D.; Maes, M.; Fiddler, C.; Juss, J.; Cilliers, D.; Markelj, G.; Chandra, A.; Farmer, G.; Kielkowska, A.; Clark, J.; Kracker, S.; Debré, M.; Picard, C.; Pellier, I.; Jabado, N.; Morris, J.A.; Barcenas-Morales, G.; Fischer, A.; Stephens, L.; Hawkins, P.; Barrett, J.C.; Abinun, M.; Clatworthy, M.; Durandy, A.; Doffinger, R.; Chilvers, E.R.; Cant, A.J.; Kumararatne, D.; Okkenhaug, K.; Williams, R.L.; Condliffe, A.; Nejentsev, S. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science, 2013, 342(6160), 866-871. [http://dx.doi.org/10.1126/science.1243292]. [PMID: 24136356].
Gao, X.P.; Zhu, X.; Fu, J.; Liu, Q.; Frey, R.S.; Malik, A.B. Blockade of class IA phosphoinositide 3-kinase in neutrophils prevents NADPH oxidase activation- and adhesion-dependent inflammation. J. Biol. Chem., 2007, 282(9), 6116-6125. [http://dx.doi.org/10.1074/jbc.M610248200]. [PMID: 17197441].
Thomas, M.J.; Smith, A.; Head, D.H.; Milne, L.; Nicholls, A.; Pearce, W.; Vanhaesebroeck, B.; Wymann, M.P.; Hirsch, E.; Trifilieff, A.; Walker, C.; Finan, P.; Westwick, J. Airway inflammation: chemokine-induced neutrophilia and the class I phosphoinositide 3-kinases. Eur. J. Immunol., 2005, 35(4), 1283-1291. [http://dx.doi.org/10.1002/eji.200425634]. [PMID: 15739165].
Jones, G.E.; Prigmore, E.; Calvez, R.; Hogan, C.; Dunn, G.A.; Hirsch, E.; Wymann, M.P.; Ridley, A.J. Requirement for PI 3-kinase gamma in macrophage migration to MCP-1 and CSF-1. Exp. Cell Res., 2003, 290(1), 120-131. [http://dx.doi.org/10.1016/S0014-4827(03)00318-5]. [PMID: 14516793].
Bonnans, C.; Fukunaga, K.; Keledjian, R.; Petasis, N.A.; Levy, B.D. Regulation of phosphatidylinositol 3-kinase by polyisoprenyl phosphates in neutrophil-mediated tissue injury. J. Exp. Med., 2006, 203(4), 857-863. [http://dx.doi.org/10.1084/jem.20052143]. [PMID: 16567384].
Yum, H.K.; Arcaroli, J.; Kupfner, J.; Shenkar, R.; Penninger, J.M.; Sasaki, T.; Yang, K.Y.; Park, J.S.; Abraham, E. Involvement of phosphoinositide 3-kinases in neutrophil activation and the development of acute lung injury. J. Immunol., 2001, 167(11), 6601-6608. [http://dx.doi.org/10.4049/jimmunol.167.11.6601]. [PMID: 11714830].
Doukas, J.; Eide, L.; Stebbins, K.; Racanelli-Layton, A.; Dellamary, L.; Martin, M.; Dneprovskaia, E.; Noronha, G.; Soll, R.; Wrasidlo, W.; Acevedo, L.M.; Cheresh, D.A. Aerosolized phosphoinositide 3-kinase gamma/delta inhibitor TG100-115 [3-[2,4-diamino-6-(3-hydroxyphenyl)pteridin-7-yl]phenol] as a therapeutic candidate for asthma and chronic obstructive pulmonary disease. J. Pharmacol. Exp. Ther., 2009, 328(3), 758-765. [http://dx.doi.org/10.1124/jpet.108.144311]. [PMID: 19056934].
Ghorani, V.; Boskabady, M.H.; Khazdair, M.R.; Kianmeher, M. Experimental animal models for COPD: a methodological review. Tob. Induc. Dis., 2017, 15, 25. [http://dx.doi.org/10.1186/s12971-017-0130-2]. [PMID: 28469539].
Wright, J.L.; Cosio, M.; Churg, A. Animal models of chronic obstructive pulmonary disease. Am. J. Physiol. Lung Cell. Mol. Physiol., 2008, 295(1), L1-L15. [http://dx.doi.org/10.1152/ajplung.90200.2008]. [PMID: 18456796].
Galluzzo, M.; Ciraolo, E.; Lucattelli, M.; Hoxha, E.; Ulrich, M.; Campa, C.C.; Lungarella, G.; Doring, G.; Zhou-Suckow, Z.; Mall, M.; Hirsch, E.; De Rose, V. Genetic deletion and pharmacological inhibition of PI3K γ reduces neutrophilic airway inflammation and lung damage in mice with Cystic Fibrosis-Like Lung Disease. Mediators Inflamm., 2015, 2015545417 [http://dx.doi.org/10.1155/2015/545417]. [PMID: 26185363].
Norman, P. Evaluation of WO2013136076: two crystalline forms of the phosphatidylinositol 3-kinase-δ inhibitor RV-1729. Expert Opin. Ther. Pat., 2014, 24(4), 471-475. [http://dx.doi.org/10.1517/13543776.2014.865725]. [PMID: 24283201].
Marwick, J.A.; Caramori, G.; Casolari, P.; Mazzoni, F.; Kirkham, P.A.; Adcock, I.M.; Chung, K.F.; Papi, A. A role for phosphoinositol 3-kinase delta in the impairment of glucocorticoid responsiveness in patients with chronic obstructive pulmonary disease. J. Allergy Clin. Immunol., 2010, 125(5), 1146-1153. [http://dx.doi.org/10.1016/j.jaci.2010.02.003]. [PMID: 20381852].
Marwick, J.A.; Caramori, G.; Stevenson, C.S.; Casolari, P.; Jazrawi, E.; Barnes, P.J.; Ito, K.; Adcock, I.M.; Kirkham, P.A.; Papi, A. Inhibition of PI3Kdelta restores glucocorticoid function in smoking-induced airway inflammation in mice. Am. J. Respir. Crit. Care Med., 2009, 179(7), 542-548. [http://dx.doi.org/10.1164/rccm.200810-1570OC]. [PMID: 19164702].
To, Y.; Ito, K.; Kizawa, Y.; Failla, M.; Ito, M.; Kusama, T.; Elliott, W.M.; Hogg, J.C.; Adcock, I.M.; Barnes, P.J. Targeting phosphoinositide-3-kinase-delta with theophylline reverses corticosteroid insensitivity in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med., 2010, 182(7), 897-904. [http://dx.doi.org/10.1164/rccm.200906-0937OC]. [PMID: 20224070].
Horiguchi, M.; Oiso, Y.; Sakai, H.; Motomura, T.; Yamashita, C. Pulmonary administration of phosphoinositide 3-kinase inhibitor is a curative treatment for chronic obstructive pulmonary disease by alveolar regeneration. J. Control. Release, 2015, 213, 112-119. [http://dx.doi.org/10.1016/j.jconrel.2015.07.004]. [PMID: 26160307].
Cahn, A.; Hamblin, J.N.; Begg, M.; Wilson, R.; Dunsire, L.; Sriskantharajah, S.; Montembault, M.; Leemereise, C.N.; Galinanes-Garcia, L.; Watz, H.; Kirsten, A.M.; Fuhr, R.; Hessel, E.M. Safety, pharmacokinetics and dose-response characteristics of GSK2269557, an inhaled PI3Kδ inhibitor under development for the treatment of COPD. Pulm. Pharmacol. Ther., 2017, 46, 69-77. [http://dx.doi.org/10.1016/j.pupt.2017.08.008]. [PMID: 28823947].

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Article Details

Year: 2019
Page: [2791 - 2800]
Pages: 10
DOI: 10.2174/0929867325666180320120054
Price: $58

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