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REVIEW

Novel Anti-Inflammatory Approaches to COPD

ORCID Icon, , &
Pages 1333-1352 | Received 27 Apr 2023, Accepted 20 Jun 2023, Published online: 29 Jun 2023

References

  • Stolz D, Mkorombindo T, Schumann DM, et al. Towards the elimination of chronic obstructive pulmonary disease: a lancet commission. Lancet. 2022;400(10356):921–972. doi:10.1016/S0140-6736(22)01273-9
  • Gamble E, Qiu Y, Wang D, et al. Variability of bronchial inflammation in chronic obstructive pulmonary disease: implications for study design. Eur Respir J. 2006;27(2):293–299. doi:10.1183/09031936.06.00027705
  • Deng F, Zhong S, Yu C, et al. Abnormal neutrophil polarization in chronic obstructive pulmonary disease and how cigarette smoke extracts attract neutrophils. Ann Transl Med. 2022;10(8):472. doi:10.21037/atm-22-1480
  • David B, Bafadhel M, Koenderman L, De Soyza A. Eosinophilic inflammation in COPD: from an inflammatory marker to a treatable trait. Thorax. 2021;76(2):188–195. doi:10.1136/thoraxjnl-2020-215167
  • Burgoyne RA, Fisher AJ, Borthwick LA. The role of epithelial damage in the pulmonary immune response. Cells. 2021;10(10):2763. doi:10.3390/cells10102763
  • Matera MG, Cazzola M, Page C. Prospects for COPD treatment. Curr Opin Pharmacol. 2021;56:74–84. doi:10.1016/j.coph.2020.11.003
  • Cazzola M, Ora J, Calzetta L, Rogliani P, Matera MG. Advances in inhaled corticosteroids for the treatment of chronic obstructive pulmonary disease: what is their value today? Expert Opin Pharmacother. 2022;23(8):917–927. doi:10.1080/14656566.2022.2076592
  • Barnes PJ. Glucocorticosteroids. Handb Exp Pharmacol. 2017;237:93–115. doi:10.1007/164_2016_62
  • Adcock IM, Bhatt SP, Balkissoon R, Wise RA. The use of inhaled corticosteroids for patients with COPD who continue to smoke cigarettes: an evaluation of current practice. Am J Med. 2022;135(3):302–312. doi:10.1016/j.amjmed.2021.09.006
  • Plumb J, Gaffey K, Kane B, et al. Reduced glucocorticoid receptor expression and function in airway neutrophils. Int Immunopharmacol. 2012;12(1):26–33. doi:10.1016/j.intimp.2011.10.006
  • Milara J, Lluch J, Almudever P, Freire J, Xiaozhong Q, Cortijo J. Roflumilast N-oxide reverses corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2014;134(2):314–322. doi:10.1016/j.jaci.2014.02.001
  • Li LB, Leung DY, Martin RJ, Goleva E. Inhibition of histone deacetylase 2 expression by elevated glucocorticoid receptor beta in steroid-resistant asthma. Am J Respir Crit Care Med. 2010;182(7):877–883. doi:10.1164/rccm.201001-0015OC
  • Pavord ID, Lettis S, Anzueto A, Barnes N. Blood eosinophil count and pneumonia risk in patients with chronic obstructive pulmonary disease: a patient-level meta-analysis. Lancet Respir Med. 2016;4(9):731–741. doi:10.1016/S2213-2600(16)30148-5
  • Matera MG, Calzetta L, Annibale R, Russo F, Cazzola M. Classes of drugs that target the cellular components of inflammation under clinical development for COPD. Expert Rev Clin Pharmacol. 2021;14(8):1015–1027. doi:10.1080/17512433.2021.1925537
  • Barnes PJ. 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. doi:10.1055/s-0035-1555611
  • Barnes PJ. Targeting cytokines to treat asthma and chronic obstructive pulmonary disease. Nat Rev Immunol. 2018;18(7):454–466. doi:10.1038/s41577-018-0006-6
  • Cazzola M, Page CP, Calzetta L, Matera MG. Emerging anti-inflammatory strategies for COPD. Eur Respir J. 2012;40(3):724–741. doi:10.1183/09031936.00213711
  • Prenner BM, Bukofzer S, Behm S, Feaheny K, McNutt BE. A randomized, double-blind, placebo-controlled study assessing the safety and tolerability of regadenoson in subjects with asthma or chronic obstructive pulmonary disease. J Nucl Cardiol. 2012;19(4):681–692. doi:10.1007/s12350-012-9547-4
  • Haskó G, Linden J, Cronstein B, Pacher P. Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat Rev Drug Discov. 2008;7(9):759–770. doi:10.1038/nrd2638
  • Mahler DA, Huang S, Tabrizi M, Bell GM. Efficacy and safety of a monoclonal antibody recognizing interleukin-8 in COPD: a pilot study. Chest. 2004;126(3):926–934. doi:10.1378/chest.126.3.926
  • van der Vaart H, Koëter GH, Postma DS, Kauffman HF, ten Hacken NH. First study of infliximab treatment in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005;172(4):465–469. doi:10.1164/rccm.200501-147OC
  • Rennard SI, Fogarty C, Kelsen S, et al. The safety and efficacy of infliximab in moderate to severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175(9):926–934. doi:10.1164/rccm.200607-995OC
  • Aaron SD, Vandemheen KL, Maltais F, et al. TNFα antagonists for acute exacerbations of COPD: a randomised double-blind controlled trial. Thorax. 2013;68(2):142–148. doi:10.1136/thoraxjnl-2012-202432
  • Cazzola M, Ora J, Cavalli F, Rogliani P, Matera MG. An overview of the safety and efficacy of monoclonal antibodies for the chronic obstructive pulmonary disease. Biologics. 2021;15:363–374. doi:10.2147/BTT.S295409
  • Rogliani P, Matera MG, Puxeddu E, et al. Emerging biological therapies for treating chronic obstructive pulmonary disease: a pairwise and network meta-analysis. Pulm Pharmacol Ther. 2018;50:28–37. doi:10.1016/j.pupt.2018.03.004
  • Maurice DH, Ke H, Ahmad F, Wang Y, Chung J, Manganiello VC. Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov. 2014;13(4):290–314. doi:10.1038/nrd4228
  • Jin SL, Goya S, Nakae S, et al. Phosphodiesterase 4B is essential for TH2-cell function and development of airway hyperresponsiveness in allergic asthma. J Allergy Clin Immunol. 2010;126(6):1252–9.e12. doi:10.1016/j.jaci.2010.08.014
  • Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation. 2011;123(20):2263–2273. doi:10.1161/CIRCULATIONAHA.110.981738
  • Lam M, Bourke JE. A new pathway to airway relaxation: targeting the “other” cyclase in asthma. Am J Respir Cell Mol Biol. 2020;62(1):3–4. doi:10.1165/rcmb.2019-0274ED
  • Page CP. Phosphodiesterase inhibitors for the treatment of asthma and chronic obstructive pulmonary disease. Int Arch Allergy Immunol. 2014;165(3):152–164. doi:10.1159/000368800
  • Cazzola M, Calzetta L, Rogliani P, Matera MG. The discovery of roflumilast for the treatment of chronic obstructive pulmonary disease. Expert Opin Drug Discov. 2016;11(7):733–744. doi:10.1080/17460441.2016.1184642
  • Rogliani P, Calzetta L, Cazzola M, Matera MG. Drug safety evaluation of roflumilast for the treatment of COPD: a meta-analysis. Expert Opin Drug Saf. 2016;15(8):1133–1146. doi:10.1080/14740338.2016.1199683
  • Agustí A, Celli BR, Criner GJ, et al. Global Initiative for Chronic Obstructive Lung Disease 2023 report: GOLD executive summary. Am J Respir Crit Care Med. 2023;207(7):819–837. doi:10.1164/rccm.202301-0106PP
  • Matera MG, Rogliani P, Calzetta L, Cazzola M. Phosphodiesterase inhibitors for chronic obstructive pulmonary disease: what does the future hold? Drugs. 2014;74(17):1983–1992. doi:10.1007/s40265-014-0303-8
  • Matera MG, Ora J, Cavalli F, Rogliani P, Cazzola M. New avenues for phosphodiesterase inhibitors in asthma. J Exp Pharmacol. 2021;13:291–302. doi:10.2147/JEP.S242961
  • Phillips JE. Inhaled phosphodiesterase 4 (PDE4) inhibitors for inflammatory respiratory diseases. Front Pharmacol. 2020;11:259. doi:10.3389/fphar.2020.00259
  • Singh D, Emirova A, Francisco C, Santoro D, Govoni M, Nandeuil MA. Efficacy and safety of CHF6001, a novel inhaled PDE4 inhibitor in COPD: the PIONEER study. Respir Res. 2020;21(1):246. doi:10.1186/s12931-020-01512-y
  • Nguyen HO, Salvi V, Tiberio L, et al. The PDE4 inhibitor tanimilast shows distinct immunomodulatory properties associated with a type 2 endotype and CD141 upregulation. J Transl Med. 2022;20(1):203. doi:10.1186/s12967-022-03402-x
  • Li G, He D, Cai X, et al. Advances in the development of phosphodiesterase-4 inhibitors. Eur J Med Chem. 2023;250:115195. doi:10.1016/j.ejmech.2023.115195
  • Paes D, Hermans S, van den Hove D, Vanmierlo T, Prickaerts J, Carlier A. Computational investigation of the dynamic control of cAMP signaling by PDE4 isoform types. Biophys J. 2022;121(14):2693–2711. doi:10.1016/j.bpj.2022.06.019
  • Page C, Cazzola M. Bifunctional drugs for the treatment of respiratory diseases. Handb Exp Pharmacol. 2017;237:197–212. doi:10.1007/164_2016_69
  • Abbott-Banner KH, Page CP. Dual PDE3/4 and PDE4 inhibitors: novel treatments for COPD and other inflammatory airway diseases. Basic Clin Pharmacol Toxicol. 2014;114(5):365–376. doi:10.1111/bcpt.12209
  • Cazzola M, Calzetta L, Rogliani P, Matera MG. Ensifentrine (RPL554): an investigational PDE3/4 inhibitor for the treatment of COPD. Expert Opin Investig Drugs. 2019;28(10):827–833. doi:10.1080/13543784.2019.1661990
  • Barjaktarevic IZ, Rheault T, Bengtsson T, Rickard K. Ensifentrine, a novel dual phosphodiesterase (PDE) 3 and 4 inhibitor, significantly reduces annualized exacerbations and delays the time to first exacerbation in COPD: pooled sub-group analyses of ENHANCE-1 and ENHANCE-2 phase 3 trials. Am J Respir Crit Care Med. 2023;207:A5008. doi:10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A5008
  • Sciurba F, Anzueto A, Rheault T, Bengtsson T, Rickard K. Ensifentrine, a novel dual phosphodiesterase (PDE) 3 and 4 inhibitor, improves lung function, symptoms, quality of life and reduces exacerbation rate and risk in patients with COPD: results from replicate phase 3 trials. Am J Respir Crit Care Med. 2023;207:A5005. doi:10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A5005
  • Anzueto A, Rheault T, Bengtsson T, Rickard K. Treatment with ensifentrine, a dual PDE3 and PDE4 inhibitor, significantly reduced exacerbation rate and risk in subjects with COPD: sub-group results from the phase 3 trial, ENHANCE-2. Am J Respir Crit Care Med. 2023;207:A4998. doi:10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A4998
  • Chapman RW, Phillips JE, Hipkin RW, Curran AK, Lundell D, Fine JS. CXCR2 antagonists for the treatment of pulmonary disease. Pharmacol Ther. 2009;121(1):55–68. doi:10.1016/j.pharmthera.2008.10.005
  • Thatcher TH, McHugh NA, Egan RW, et al. Role of CXCR2 in cigarette smoke-induced lung inflammation. Am J Physiol Lung Cell Mol Physiol. 2005;289(2):L322–L328. doi:10.1152/ajplung.00039.2005
  • Rennard SI, Dale DC, Donohue JF, et al. CXCR2 antagonist MK-7123. A phase 2 proof-of-concept trial for chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;191(9):1001–1011. doi:10.1164/rccm.201405-0992OC
  • Lazaar AL, Miller BE, Donald AC, et al. CXCR2 antagonist for patients with chronic obstructive pulmonary disease with chronic mucus hypersecretion: a phase 2b trial. Respir Res. 2020;21(1):149. doi:10.1186/s12931-020-01401-4
  • Keir HR, Richardson H, Fillmore C, et al. CXCL-8-dependent and -independent neutrophil activation in COPD: experiences from a pilot study of the CXCR2 antagonist danirixin. ERJ Open Res. 2020;6(4):00583–2020. doi:10.1183/23120541.00583-2020
  • Mattos MS, Ferrero MR, Kraemer L, et al. CXCR1 and CXCR2 inhibition by ladarixin improves neutrophil-dependent airway inflammation in mice. Front Immunol. 2020;11:566953. doi:10.3389/fimmu.2020.566953
  • Pelaia C, Vatrella A, Sciacqua A, Terracciano R, Pelaia G. Role of p38-mitogen-activated protein kinase in COPD: pathobiological implications and therapeutic perspectives. Expert Rev Respir Med. 2020;14(5):485–491. doi:10.1080/17476348.2020.1732821
  • Pascoe S, Costa M, Marks-Konczalik J, McKie E, Yang S, Scherbovsky PS. Biological effects of p38 MAPK inhibitor losmapimod does not translate to clinical benefits in COPD. Respir Med. 2017;130:20–26. doi:10.1016/j.rmed.2017.07.002
  • Higham A, Karur P, Jackson N, Cunoosamy DM, Jansson P, Singh D. Differential anti-inflammatory effects of budesonide and a p38 MAPK inhibitor AZD7624 on COPD pulmonary cells. Int J Chron Obstruct Pulmon Dis. 2018;13:1279–1288. doi:10.2147/COPD.S159936
  • Patel NR, Cunoosamy DM, Fagerås M, et al. The development of AZD7624 for prevention of exacerbations in COPD: a randomized controlled trial. Int J Chron Obstruct Pulmon Dis. 2018;13:1009–1019. doi:10.2147/COPD.S150576
  • Charron CE, Russell P, Ito K, et al. RV568, a narrow-spectrum kinase inhibitor with p38 MAPK-α and -γ selectivity, suppresses COPD inflammation. Eur Respir J. 2017;50(4):1700188. doi:10.1183/13993003.00188-2017
  • Strâmbu IR, Kobalava ZD, Magnusson BP, MacKinnon A, Parkin JM. Phase II study of single/repeated doses of acumapimod (BCT197) to treat acute exacerbations of COPD. COPD. 2019;16(5–6):344–353. doi:10.1080/15412555.2019.1682535
  • Wedzicha JA, MacKinnon A, Parkin JM. 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.
  • Yu H, Su X, Lei T, et al. Safety and efficacy of p38 mitogen-activated protein kinase inhibitors (MAPKIs) in COPD. Front Pharmacol. 2022;13:950035. doi:10.3389/fphar.2022.950035
  • Wang C, Zhou J, Wang J, et al. Progress in the mechanism and targeted drug therapy for COPD. Signal Transduct Target Ther. 2020;5(1):248. doi:10.1038/s41392-020-00345-x
  • Onions ST, Ito K, Charron CE, et al. Discovery of narrow spectrum kinase inhibitors: new therapeutic agents for the treatment of COPD and steroid-resistant asthma. J Med Chem. 2016;59(5):1727–1746. doi:10.1021/acs.jmedchem.5b01029
  • Curran A, Charron C, Russell P, Hava D. PUR1800 (RV1162), A novel narrow spectrum kinase inhibitor, but not fluticasone, reduces TNFa-induced cytokine release by primary bronchial epithelial cells from healthy volunteers and COPD patients. Eur Respir J. 2018;52:A5247. doi:10.1183/13993003.congress-2018.PA5247
  • Wasilewski M, Clayton R, Singh D, Perry J, Curran A. Safety and tolerability of PUR1800, an orally inhaled narrow spectrum kinase inhibitor, in patients with stable chronic obstructive pulmonary disease (COPD). J Allergy Clin Immunol. 2023;151(2 suppl):AB10. doi:10.1016/j.jaci.2022.12.062
  • Gupta V, Khan A, Higham A, et al. The effect of phosphatidylinositol-3 kinase inhibition on matrix metalloproteinase-9 and reactive oxygen species release from chronic obstructive pulmonary disease neutrophils. Int Immunopharmacol. 2016;35:155–162. doi:10.1016/j.intimp.2016.03.027
  • Sapey E, Stockley JA, Greenwood H, et al. Behavioral and structural differences in migrating peripheral neutrophils from patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2011;183(9):1176–1186. doi:10.1164/rccm.201008-1285OC
  • Stark AK, Chandra A, Chakraborty K, et al. PI3Kδ hyper-activation promotes development of B cells that exacerbate Streptococcus pneumoniae infection in an antibody-independent manner. Nat Commun. 2018;9(1):3174. doi:10.1038/s41467-018-05674-8
  • Cahn A, Hamblin JN, Robertson J, et al. An inhaled PI3Kδ inhibitor improves recovery in acutely exacerbating COPD patients: a randomized trial. Int J Chron Obstruct Pulmon Dis. 2021;16:1607–1619. doi:10.2147/COPD.S309129
  • Fahy WA, Homayoun-Valiani F, Cahn A, et al. Nemiralisib in patients with an acute exacerbation of COPD: placebo-controlled, dose-ranging study. Int J Chron Obstruct Pulmon Dis. 2021;16:1637–1646. doi:10.2147/COPD.S309320
  • Begg M, Hamblin JN, Jarvis E, et al. Exploring PI3Kδ molecular pathways in stable COPD and following an acute exacerbation, two randomized controlled trials. Int J Chron Obstruct Pulmon Dis. 2021;16:1621–1636. doi:10.2147/COPD.S309303
  • Sadiq MW, Asimus S, Belvisi MG, et al. Characterisation of pharmacokinetics, safety, and tolerability in a first-in-human study for AZD8154, a novel inhaled selective PI3Kγδ dual inhibitor targeting airway inflammatory disease. Br J Clin Pharmacol. 2022;88(1):260–270. doi:10.1111/bcp.14956
  • Di Stefano A, Maestrelli P, Roggeri A, et al. Upregulation of adhesion molecules in the bronchial mucosa of subjects with chronic obstructive bronchitis. Am J Respir Crit Care Med. 1994;149(3 Pt 1):803–810. doi:10.1164/ajrccm.149.3.7509705
  • Blidberg K, Palmberg L, James A, et al. Adhesion molecules in subjects with COPD and healthy non-smokers: a cross sectional parallel group study. Respir Res. 2013;14(1):47. doi:10.1186/1465-9921-14-47
  • Watz H, Bock D, Meyer M, et al. Inhaled pan-selectin antagonist Bimosiamose attenuates airway inflammation in COPD. Pulm Pharmacol Ther. 2013;26(2):265–270. doi:10.1016/j.pupt.2012.12.003
  • Tvaroška I, Selvaraj C, Koča J. Selectins - The two Dr. Jekyll and Mr. Hyde faces of adhesion molecules - A review. Molecules. 2020;25(12):2835. doi:10.3390/molecules25122835
  • Matera MG, Calzetta L, Cazzola M, Ora J, Rogliani P. Biologic therapies for chronic obstructive pulmonary disease. Expert Opin Biol Ther. 2023;23(2):163–173. doi:10.1080/14712598.2022.2160238
  • Higham A, Beech A, Wolosianka S, et al. Type 2 inflammation in eosinophilic chronic obstructive pulmonary disease. Allergy. 2021;76(6):1861–1864. doi:10.1111/all.14661
  • Eich A, Urban V, Jutel M, et al. A randomized, placebo-controlled phase 2 trial of CNTO 6785 in chronic obstructive pulmonary disease. COPD. 2017;14(5):476–483. doi:10.1080/15412555.2017.1335697
  • Murugaiah V, Tsolaki AG, Kishore U. Collectins: innate Immune pattern recognition molecules. Adv Exp Med Biol. 2020;1204:75–127. doi:10.1007/978-981-15-1580-4_4
  • Watson A, Madsen J, Clark HW. SP-A and SP-D: dual functioning immune molecules with antiviral and immunomodulatory properties. Front Immunol. 2021;11:622598. doi:10.3389/fimmu.2020.622598
  • Pilecki B, Wulf-Johansson H, Støttrup C, et al. Surfactant protein D deficiency aggravates cigarette smoke-induced lung inflammation by upregulation of ceramide synthesis. Front Immunol. 2018;9:3013. doi:10.3389/fimmu.2018.03013
  • Bafadhel M, Saha S, Siva R, et al. Sputum IL-5 concentration is associated with a sputum eosinophilia and attenuated by corticosteroid therapy in COPD. Respiration. 2009;78(3):256–262. doi:10.1159/000221902
  • Eltboli O, Mistry V, Barker B, Brightling CE. Relationship between blood and bronchial submucosal eosinophilia and reticular basement membrane thickening in chronic obstructive pulmonary disease. Respirology. 2015;20(4):667–670. doi:10.1111/resp.12475
  • Caramori G, Adcock IM, Di Stefano A, Chung KF. Cytokine inhibition in the treatment of COPD. Int J Chron Obstruct Pulmon Dis. 2014;9:397–412. doi:10.2147/COPD.S42544
  • Pavord ID, Chapman KR, Bafadhel M, et al. Mepolizumab for eosinophil-associated COPD: analysis of METREX and METREO. Int J Chron Obstruct Pulmon Dis. 2021;16:1755–1770. doi:10.2147/COPD.S294333
  • Criner GJ, Celli BR, Singh D, et al. Predicting response to benralizumab in chronic obstructive pulmonary disease: analyses of GALATHEA and TERRANOVA studies. Lancet Respir Med. 2020;8(2):158–170. doi:10.1016/S2213-2600(19)30338-8
  • Brightling CE, Bleecker ER, Panettieri RA, et al. Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir Med. 2014;2(11):891–901. doi:10.1016/S2213-2600(14)70187-0
  • Mesnil C, Raulier S, Paulissen G, et al. Lung-resident eosinophils represent a distinct regulatory eosinophil subset. J Clin Invest. 2016;126(9):3279–3295. doi:10.1172/JCI85664
  • Lange P, Ahmed E, Lahmar ZM, Martinez FJ, Bourdin A. Natural history, and mechanisms of COPD. Respirology. 2021;26(4):298–321. doi:10.1111/resp.14007
  • Sun J, Liu T, Yan Y, et al. The role of Th1/Th2 cytokines played in regulation of specific CD4+ Th1 cell conversion and activation during inflammatory reaction of chronic obstructive pulmonary disease. Scand J Immunol. 2018;88(1):e12674. doi:10.1111/sji.12674
  • Bhatt SP, Rabe KF, Hanania NA, et al. Dupilumab for COPD with type 2 inflammation indicated by eosinophil counts. N Engl J Med. 2023. doi:10.1056/NEJMoa2303951
  • Zhang K, Shan L, Rahman MS, Unruh H, Halayko AJ, Gounni AS. Constitutive and inducible thymic stromal lymphopoietin expression in human airway smooth muscle cells: role in chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol. 2007;293(2):L375–L382. doi:10.1152/ajplung.00045.2007
  • Calvén J, Yudina Y, Hallgren O, et al. Viral stimuli trigger exaggerated thymic stromal lymphopoietin expression by chronic obstructive pulmonary disease epithelium: role of endosomal TLR3 and cytosolic RIG-I-like helicases. J Innate Immun. 2012;4(1):86–99. doi:10.1159/000329131
  • Elder MJ, Webster SJ, Williams DL, Gaston JS, Goodall JC. TSLP production by dendritic cells is modulated by IL-1β and components of the endoplasmic reticulum stress response. Eur J Immunol. 2016;46(2):455–463. doi:10.1002/eji.201545537
  • Cohen ES, Scott IC, Majithiya JB, et al. Oxidation of the alarmin IL-33 regulates ST2-dependent inflammation. Nat Commun. 2015;6(1):8327. doi:10.1038/ncomms9327
  • Cayrol C. IL-33, an Alarmin of the IL-1 Family involved in allergic and non allergic inflammation: focus on the mechanisms of regulation of its activity. Cells. 2021;11(1):107. doi:10.3390/cells11010107
  • Gabryelska A, Kuna P, Antczak A, Białasiewicz P, Panek M. IL-33 mediated inflammation in chronic respiratory diseases-understanding the role of the member of IL-1 superfamily. Front Immunol. 2019;10:692. doi:10.3389/fimmu.2019.00692
  • Tworek D, Majewski S, Szewczyk K, et al. The association between airway eosinophilic inflammation and IL-33 in stable non-atopic COPD. Respir Res. 2018;19(1):108. doi:10.1186/s12931-018-0807-y
  • Rabe KF, Celli BR, Wechsler ME, et al. Safety and efficacy of itepekimab in patients with moderate-to-severe COPD: a genetic association study and randomised, double-blind, phase 2a trial. Lancet Respir Med. 2021;9(11):1288–1298. doi:10.1016/S2213-2600(21)00167-3
  • Yousuf AJ, Mohammed S, Carr L, et al. Astegolimab, an anti-ST2, in chronic obstructive pulmonary disease (COPD-ST2OP): a phase 2a, placebo-controlled trial. Lancet Respir Med. 2022;10(5):469–477. doi:10.1016/S2213-2600(21)00556-7
  • Cazzola M, Rogliani P, Calzetta L, Matera MG. Tozorakimab. Anti-IL-33 monoclonal antibody, Treatment of COPD and asthma, Treatment of atopic dermatitis, Treatment of diabetic kidney disease. Drugs Future. 2023;48(2):101–109. doi:10.1358/dof.2023.48.2.3474010
  • Scott IC, England E, Rees DG, et al. Tozorakimab: a dual-pharmacology anti-IL-33 antibody that inhibits IL-33 signalling via ST2 and RAGE/EGFR to reduce inflammation and epithelial dysfunction. Eur Respir J. 2022;60:2467. doi:10.1183/13993003.congress-2022.246
  • Christopoulou ME, Papakonstantinou E, Stolz D. Matrix metalloproteinases in chronic obstructive pulmonary disease. Int J Mol Sci. 2023;24(4):3786. doi:10.3390/ijms24043786
  • Fingleton B. Matrix metalloproteinases as regulators of inflammatory processes. Biochim Biophys Acta Mol Cell Res. 2017;1864(11 Pt A):2036–2042. doi:10.1016/j.bbamcr.2017.05.010
  • Gharib SA, Manicone AM, Parks WC. Matrix metalloproteinases in emphysema. Matrix Biol. 2018;73:34–51. doi:10.1016/j.matbio.2018.01.018
  • Dahl R, Titlestad I, Lindqvist A, et al. Effects of an oral MMP-9 and −12 inhibitor, AZD1236, on biomarkers in moderate/severe COPD: a randomised controlled trial. Pulm Pharmacol Ther. 2012;25(2):169–177. doi:10.1016/j.pupt.2011.12.011
  • Baggio C, Velazquez JV, Fragai M, Nordgren TM, Pellecchia M. Therapeutic targeting of MMP-12 for the treatment of chronic obstructive pulmonary disease. J Med Chem. 2020;63(21):12911–12920. doi:10.1021/acs.jmedchem.0c01285
  • Li H, Ezra DG, Burton MJ, Bailly M. Doxycycline prevents matrix remodeling and contraction by trichiasis-derived conjunctival fibroblasts. Invest Ophthalmol Vis Sci. 2013;54(7):4675–4682. doi:10.1167/iovs.13-11787
  • Ham J, Kim J, Ko YG, Kim HY. The dynamic contribution of neutrophils in the chronic respiratory diseases. Allergy Asthma Immunol Res. 2022;14(4):361–378. doi:10.4168/aair.2022.14.4.361
  • Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science. 1997;277(5334):2002–2004. doi:10.1126/science.277.5334.2002
  • Kuna P, Jenkins M, O’Brien CD, Fahy WA. AZD9668, a neutrophil elastase inhibitor, plus ongoing budesonide/formoterol in patients with COPD. Respir Med. 2012;106(4):531–539. doi:10.1016/j.rmed.2011.10.020
  • Vogelmeier C, Aquino TO, O’Brien CD, Perrett J, Gunawardena KA. A randomised, placebo-controlled, dose-finding study of AZD9668, an oral inhibitor of neutrophil elastase, in patients with chronic obstructive pulmonary disease treated with tiotropium. COPD. 2012;9(2):111–120. doi:10.3109/15412555.2011.641803
  • Voynow JA, Zheng S, Kummarapurugu AB. Glycosaminoglycans as multifunctional anti-elastase and anti-inflammatory drugs in cystic fibrosis lung disease. Front Pharmacol. 2020;11:1011. doi:10.3389/fphar.2020.01011
  • Voynow JA, Shinbashi M. Neutrophil elastase and chronic lung disease. Biomolecules. 2021;11(8):1065. doi:10.3390/biom11081065
  • Shute JK, Calzetta L, Cardaci V, Di Toro S, Page CP, Cazzola M. Inhaled nebulised unfractionated heparin improves lung function in moderate to very severe COPD: a pilot study. Pulm Pharmacol Ther. 2018;48:88–96. doi:10.1016/j.pupt.2017.10.001
  • Margaroli C, Madison MC, Viera L, et al. An in vivo model for extracellular vesicle-induced emphysema. JCI Insight. 2022;7(4):e153560. doi:10.1172/jci.insight.153560
  • Crocetti L, Quinn MT, Schepetkin IA, Giovannoni MP. A patenting perspective on human neutrophil elastase (HNE) inhibitors (2014–2018) and their therapeutic applications. Expert Opin Ther Pat. 2019;29(7):555–578. doi:10.1080/13543776.2019.1630379
  • Palmér R, Mäenpää J, Jauhiainen A, et al. Dipeptidyl peptidase 1 inhibitor AZD7986 induces a sustained, exposure-dependent reduction in neutrophil elastase activity in healthy subjects. Clin Pharmacol Ther. 2018;104(6):1155–1164. doi:10.1002/cpt.1053
  • Miller BE, Mayer RJ, Goyal N, et al. Epithelial desquamation observed in a Phase I study of an oral cathepsin C inhibitor (GSK2793660). Br J Clin Pharmacol. 2017;83(12):2813–2820. doi:10.1111/bcp.13398
  • Chalmers JD, Haworth CS, Metersky ML, et al. Phase 2 trial of the DPP-1 inhibitor brensocatib in bronchiectasis. N Engl J Med. 2020;383(22):2127–2137. doi:10.1056/NEJMoa2021713
  • Long MB, Chalmers JD. Treating neutrophilic inflammation in airways diseases. Arch Bronconeumol. 2022;58(6):463–465. doi:10.1016/j.arbres.2021.11.003
  • Kim WD, Chi HS, Choe KH, Kim WS, Hogg JC, Sin DD. The role of granzyme B containing cells in the progression of chronic obstructive pulmonary disease. Tuberc Respir Dis. 2020;83(Supple 1):S25–S33. doi:10.4046/trd.2020.0089
  • Afonina IS, Tynan GA, Logue SE, et al. Granzyme B-dependent proteolysis acts as a switch to enhance the proinflammatory activity of IL-1α. Mol Cell. 2011;44(2):265–278. doi:10.1016/j.molcel.2011.07.037
  • Aslam MS, Yuan L. Serpina3n: potential drug and challenges, mini review. J Drug Target. 2020;28(4):368–378. doi:10.1080/1061186X.2019.1693576
  • Marcet-Palacios M, Ewen C, Pittman E, et al. Design and characterization of a novel human Granzyme B inhibitor. Protein Eng Des Sel. 2015;28(1):9–17. doi:10.1093/protein/gzu052
  • Shen Y, Zeglinski MR, Turner CT, et al. Topical small molecule granzyme B inhibitor improves remodeling in a murine model of impaired burn wound healing. Exp Mol Med. 2018;50(5):1–11. doi:10.1038/s12276-018-0095-0
  • Hirst CE, Buzza MS, Bird CH, et al. The intracellular granzyme B inhibitor, proteinase inhibitor 9, is up-regulated during accessory cell maturation and effector cell degranulation, and its overexpression enhances CTL potency. J Immunol. 2003;170(2):805–815. doi:10.4049/jimmunol.170.2.805
  • Du W, Mohammadpour H, O’Neill RE, et al. Serine protease inhibitor 6 protects alloreactive T cells from Granzyme B-mediated mitochondrial damage without affecting graft-versus-tumor effect. Oncoimmunology. 2017;7(3):e1397247. doi:10.1080/2162402X.2017.1397247
  • Ikram S, Ahmad J, Durdagi S. Screening of FDA approved drugs for finding potential inhibitors against Granzyme B as a potent drug-repurposing target. J Mol Graph Model. 2020;95:107462. doi:10.1016/j.jmgm.2019.107462
  • Cazzola M, Stolz D, Rogliani P, Matera MG. α1-Antitrypsin deficiency and chronic respiratory disorders. Eur Respir Rev. 2020;29(155):190073. doi:10.1183/16000617.0073-2019
  • Stolk J, Tov N, Chapman KR, et al. Efficacy and safety of inhaled α1-antitrypsin in patients with severe α1-antitrypsin deficiency and frequent exacerbations of COPD. Eur Respir J. 2019;54(5):1900673. doi:10.1183/13993003.00673-2019
  • Tumpara S, Martinez-Delgado B, Gomez-Mariano G, et al. The delivery of α1-antitrypsin therapy through transepidermal route: worthwhile to explore. Front Pharmacol. 2020;11:983. doi:10.3389/fphar.2020.00983
  • Remih K, Amzou S, Strnad P. Alpha1-antitrypsin deficiency: new therapies on the horizon. Curr Opin Pharmacol. 2021;59:149–156. doi:10.1016/j.coph.2021.06.001
  • Zou Y, Chen X, He B, et al. Neutrophil extracellular traps induced by cigarette smoke contribute to airway inflammation in mice. Exp Cell Res. 2020;389(1):111888. doi:10.1016/j.yexcr.2020.111888
  • Trivedi A, Khan MA, Bade G, Talwar A. Orchestration of neutrophil extracellular traps (NETs), a unique innate immune function during chronic obstructive pulmonary disease (COPD) development. Biomedicines. 2021;9(1):53. doi:10.3390/biomedicines9010053
  • Grabcanovic-Musija F, Obermayer A, Stoiber W, et al. Neutrophil extracellular trap (NET) formation characterises stable and exacerbated COPD and correlates with airflow limitation. Respir Res. 2015;16(1):59. doi:10.1186/s12931-015-0221-7
  • Keir HR, Chalmers JD. Neutrophil extracellular traps in chronic lung disease: implications for pathogenesis and therapy. Eur Respir Rev. 2022;31(163):210241. doi:10.1183/16000617.0241-2021
  • Tanner L, Single AB. Animal Models Reflecting chronic obstructive pulmonary disease and related respiratory disorders: translating pre-clinical data into clinical relevance. J Innate Immun. 2020;12(3):203–225. doi:10.1159/000502489
  • Segreti A, Stirpe E, Rogliani P, Cazzola M. Defining phenotypes in COPD: an aid to personalized healthcare. Mol Diagn Ther. 2014;18(4):381–388. doi:10.1007/s40291-014-0100-9
  • Xu X, Huang K, Dong F, et al. The heterogeneity of inflammatory response and emphysema in chronic obstructive pulmonary disease. Front Physiol. 2021;12:783396. doi:10.3389/fphys.2021.783396
  • Calzetta L, Aiello M, Frizzelli A, et al. Stem cell-based regenerative therapy and derived products in COPD: a systematic review and meta-analysis. Cells. 2022;11(11):1797. doi:10.3390/cells11111797
  • Martinez-Garcia MA, Sierra-Párraga JM, Quintana E, López-Campos JL. CFTR dysfunction and targeted therapies: a vision from non-cystic fibrosis bronchiectasis and COPD. J Cyst Fibros. 2022;21(5):741–744. doi:10.1016/j.jcf.2022.04.018