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Kamal Dua · Raimar Löbenberg Ângela Cristina Malheiros Luzo Shakti Shukla · Saurabh Satija Editors Targeting Cellular Signalling Pathways in Lung Diseases Targeting Cellular Signalling Pathways in Lung Diseases (cid:129) (cid:129) Kamal Dua Raimar Löbenberg (cid:129) Ângela Cristina Malheiros Luzo (cid:129) Shakti Shukla Saurabh Satija Editors Targeting Cellular Signalling Pathways in Lung Diseases Editors KamalDua RaimarLöbenberg GraduateSchoolofHealth,Discipline DrugDevelopmentandInnovationCentre ofPharmacy UniversityofAlberta UniversityofTechnologySydney Edmonton,AB,Canada Sydney,NSW,Australia ÂngelaCristinaMalheirosLuzo ShaktiShukla HaematologyandHemotherapyCenter GraduateSchoolofHealth,Discipline StateUniversityofCampinas ofPharmacy Campinas,SãoPaulo,Brazil UniversityofTechnologySydney Sydney,NSW,Australia SaurabhSatija SchoolofPharmaceuticalSciences& DivisionofResearch&Development LovelyProfessionalUniversity Phagwara,Punjab,India ISBN978-981-33-6826-2 ISBN978-981-33-6827-9 (eBook) https://doi.org/10.1007/978-981-33-6827-9 #TheEditor(s)(ifapplicable)andTheAuthor(s),underexclusivelicensetoSpringerNatureSingapore PteLtd.2021 Thisworkissubjecttocopyright.AllrightsaresolelyandexclusivelylicensedbythePublisher,whether thewholeorpartofthematerialisconcerned,specificallytherightsoftranslation,reprinting,reuseof illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similarordissimilarmethodologynowknownorhereafterdeveloped. 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The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore Preface Chronic lung diseases are among the leading causes of mortality and morbidity globally and are significantly associated with the economic burden as well as drasticallyreducedqualityoflifeandproductivity.Thecurrentlyavailabletherapies aremostlyeffectiveinmanagingtheaggravatedsymptomsassociatedwiththelung diseases, especially the non-communicable diseases such as asthma and chronic obstructive pulmonary disease (COPD). This warrants consistent rigorous research into discovering novel therapeutic targets that could be then harnessed pharmaco- logicallytoimprovethequalityoflifeofpatients.Thiswouldrequireunderstanding the underlying central/key molecular mechanisms that are generally referred as “disease drivers.” Various molecules that drive the disease are key immune cells, associatedcytokinesorchemokines,disease-associated genes, microRNAs, signal- lingpathways,pathogen/damageassociatemoleculessensingreceptorsanddisease- associatedoxidativestressmolecules/pathways.Anotherkeyaspectofmanagement of lung diseases involves lack of effective drug delivery strategies that could improve the bioavailability and subsequent efficacy of the existing/upcoming therapies. The primary objective of this book, Targeting Cellular Signalling Pathways in Lung Diseases, is to comprehensively provide an overview of various cellular and molecular mechanisms involved in chronic lung diseases and then to suggest the currently available or upcoming therapeutic targets that could be efficacious in managingthesediseases.Thebookadequatelyhighlightsamyriadofdrugdelivery approaches that could be developed and tested before implementing in real-life scenarios for improvingthedrugbioavailabilityandefficacy inlungs and/or target cells/tissues/pathways. Collectively, the book could be immensely informative for readerswhoareinterestedinrecentdevelopmentsinlungdiseasesintermsofnovel mechanisms that could be targeted therapeutically, as well as the innovative drug delivery systems that may become mainstream in coming years for effectively treatingthelungregions/cells/pathwaysthatdemonstrateassociatedpathology. Thebookrightlybeginswithanelaboratedintroductiontothelungdiseasesand then expands to the comprehensive chapters covering the crucial pathological mechanisms in non-communicable respiratory diseases, i.e., asthma, chronic obstructive pulmonary disease, lung cancer, and idiopathic pulmonary fibrosis. Thereafter, the book contains comprehensive chapters on microbial infections of v vi Preface thelung,suchastuberculosis,Haemophilusinfluenzae,andviralinfections(including the novel Coronavirus Disease 2019). This section is followed by chapters comprising discussions around the master molecular regulators of lung diseases, including,phosphoinositide3-kinase,thecholinergicsystem,Nrf2-Keap1signalling pathway, Toll-like receptor (TLR). There is a dedicated subsection on the impor- tanceofplant-basedornaturalcompoundsthatcouldbepotentialinthemanagement oflungdiseases.Thefinalsectionofbookexclusivelysummarizestheprospectsand challenges in developing and validating various drug delivery systems for respira- torydiseases.Thechaptersinthebookhaveextensivevisualillustrationsthatmake iteasierforreaderstounderstandthecomplexdiseasemechanisms. We believe that this book will be a valuable resource for academicians, researchers, and industry engaged in the field of respiratory biology. It is also a valuable resource for translational researchers, graduates, and postgraduates (Mas- ter’s,PhD,andPost-DoctoralResearchers)ofvariousdisciplinesincludingPharma- ceuticalSciences,Biotechnology,Immunology,andMedicalandHealthSciences. The editorial team has extensive research experience in the field of respiratory diseases, respiratory infections, lung inflammation, and drug delivery systems for respiratory system. The editors of this book would like to express their sincere gratitude toall the authorsfor their time andfor their valuablecontributions inthe productionofthisbook. Sydney,NSW,Australia KamalDua Edmonton,AB,Canada RaimarLöbenberg Campinas,SãoPaulo,Brazil ÂngelaCristinaMalheirosLuzo Sydney,NSW,Australia ShaktiShukla Phagwara,Punjab,India SaurabhSatija Acknowledgment The publication of this book was finalized during the coronavirus (COVID-19) pandemic. We would like to dedicate this book to all those who were affected by thepandemicand,inparticular, toour health workforce around the world for their dedicationandcareduringthisdifficulttime. vii Contents 1 IntroductiontoLungDiseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 ShivrajPopatJadhav,HimmatSingh,SalmanHussain,RituGilhotra, AnuragMishra,ParteekPrasher,AnandKrishnan,andGauravGupta 2 TargetingMolecularandCellularMechanismsinAsthma. . . . . . . 27 ArchitaRay,SabitaSingh,JoytriDutta,andUlaganathanMabalirajan 3 VariousCellularandMolecularAxisInvolvedinthePathogenesis ofAsthma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 GurjitKaurBhatti,AmitKhurana,DebapriyaGarabadu, PrashantGupta,SnehalSainathJawalekar,JasvinderSinghBhatti, andUmashankerNavik 4 TargetingMolecularandCellularMechanismsin Steroid-ResistantAsthma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 JoytriDutta,SabitaSingh,ArchitaRay,andUlaganathanMabalirajan 5 TargetingMolecularandCellularMechanismsinChronic ObstructivePulmonaryDisease. . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 ShvetankBhatt,JovitaKanoujia,A.N.Nagappa, andK.SreedharaR.Pai 6 ProbingtheCellularandMolecularMechanismsUnderlyingin thePathogenesisofChronicObstructivePulmonaryDisease. . . . . 147 C.SarathChandran,AlanRaj,andT.K.ShahinMuhammed 7 ChronicObstructivePulmonaryDisease:MolecularBasisof PathogenesisandTargetedTherapeuticApproaches. . . . . . . . . . . . 163 SushwetaMahalanobish,SayantaDutta,andParamesC.Sil 8 Exploringthe‘DormancyActivationSwitch’intheTumour MicroenvironmentforMetastaticLungCancer:ThePossible RoleofMicroRNA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 AmnaniAminuddin,SitiFathiahMasre,Sin-YeangTeow, andPeiYuenNg iixx x Contents 9 TherapeuticStrategiesTargetingSignalingPathwaysinLung Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 GurjitKaurBhatti,ParasPahwa,AnshikaGupta,UmashankerNavik, andJasvinderSinghBhatti 10 ModulationofSignalingPathwaysbyImmunotherapeutics inLungCancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 ParamitaMandal,AninditaGoswami,SarmisthaAdhikari, andSubhamSarkar 11 UnderpinningtheCellularandMolecularMechanismswith NanotheranosticsforLungCancer. . . . . . . . . . . . . . . . . . . . . . . . . 263 AsiyaMahtab,MonikaYadav,KarishmaNiveria, andAnitaKamraVerma 12 TargetingMolecularandCellularMechanismsinIdiopathic PulmonaryFibrosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 BanudeviSivananthamandVijayageethaBose 13 ARefinedApproachtoTargettheMolecularandCellular MechanismsinPulmonaryFibrosis. . . . . . . . . . . . . . . . . . . . . . . . . 311 SabitaSingh,JoytriDutta,ArchitaRay,AshishJaiswal, andUlaganathanMabalirajan 14 TargetingMolecularandCellularMechanismsinTuberculosis. . . 337 LubhanSingh,KamalDua,SokindraKumar,DeepakKumar, andSagarikaMajhi 15 CellularandMolecularMechanismsofRepurposedAntidiabetic DrugasanAdjunctiveTreatmentforTuberculosis. . . . . . . . . . . . . 355 RupeshK.Gautam,RituMishra,KanikaSharma,andManjuSharma 16 TargetingHostandBacterialSignalingPathwaysinTuberculosis: AnEffectiveStrategyfortheDevelopmentofNovel Anti-tubercularTherapies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373 SamreenFatima,BhavyaBhardwaj,andVedPrakashDwivedi 17 TargetingMolecularandCellularMechanismsinPulmonary Hypertension. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395 StephenA.Adefegha,OlorunfemiR.Molehin, andAderonkeE.Fakayode 18 TargetingMolecularandCellularMechanismsofPulmonary ArterialHypertension. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407 MdKhademAli,JayC.Horvat,andEddaF.Spiekerkoetter Contents xi 19 PotentialCellularTargetsAssociatedwiththeSignalingofthe PulmonaryHypertension. .. . . . .. . . . .. . . . .. . . . .. . . . .. . . . .. 435 MeemanshaSharma,ThakurUttamSingh, MadhuCholanhalliLingaraju,andSubhashreeParida 20 TargetingMolecularandCellularMechanismofInfluenza AVirus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447 GayathriGopal,ShibiMuralidar,andSenthilVisagaAmbi 21 UnderstandingtheBiologyofNon-typeableHaemophilusinfluenzae inChronicObstructivePulmonaryDiseaseThroughtheLensof Genomics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471 RajendraKCandRonanF.O’Toole 22 TargetingMolecularandCellularMechanisminRhinovirus Infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485 ManjuandPranavKumarPrabhakar 23 TargetingMolecularandCellularMechanismsinRespiratory SyncytialVirus(RSV)Infection. . . . . . . . . . . . . . . . . . . . . . . . . . . 501 PoojaMittal,RamitKapoor,AnjaliSaharan,andRupeshK.Gautam 24 TargetingMolecularandCellularMechanismsin SARS-CoV-2NovelCoronavirusDisease2019(COVID-19). . . . . . 517 SagarikaMajhi,KamalDua,ParteekPrasher, HarlokeshNarayanYadav,andLubhanSingh 25 UnderpinningtheRudimentary/UnderlyingMechanisms InvolvedinthePathogenesisofSARS-CoV-2(COVID-19) inHumanLungCells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537 ArnabGhosh,ChandrikaBhattacharyya,NidhanK.Biswas, andAmlanDas 26 TargetingMolecularandCellularMechanismsin SARS-CoV-2NovelCorona(COVID-19)VirusInfection. . . . . . . . 559 NabanitaRoyChattopadhyay,NilanjanaDas, andTathagataChoudhuri 27 SpecialFeaturesofHumanLungACE2Sensitivityto SARS-CoV-2SpikeGlycoprotein. . . . . . . . . . . . . . . . . . . . . . . . . . 583 DipannitaSantra,AmritaBanerjee,andSmarajitMaiti 28 ImplicationsofPhosphoinositide3-Kinase(PI3K)Signallingin CellularandMolecularMechanismsofRespiratoryDiseases. . . . . 601 BiswarupBasu,SandipGhosh,SouvikDas,andAmlanDas 29 TheRoleoftheCholinergicSysteminLungDiseases. . . . . . . . . . . 625 VedranMilankovicandTamaraLazarevic-Pasti 30 TheKeap1-Nrf2SignalingPathwayinLungCancer. . . . . . . . . . . . 661 AzhwarRaghunath,RajuNagarajan,andKiruthikaSundarraj