Posted on Authorea 2 Jul 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.159373163.39100261 | This a preprint and has not been peer reviewed. Data may be preliminary. E1 ocdeprtr ouei s 1 in volume expiratory forced FEV1: Endothelin-1 ET-1: cells Endothelial ECs: mellitus Diabetes DM: protein C-reactive CRP: disease pulmonary obstructive Chronic COPD: mono-phosphate guanosine Cyclic cGMP: triphosphate adenosine Cellular c-ATP: monophosphate adenosine Cyclic cAMP: II Angiotensin II: Ang dermatitis Atopic AD: 2 enzyme Angiotensin-converting ACE2: enzyme Angiotensin-converting ACE: cyclase Adenylate AC: preventive in-vivo Abbreviations its evaluate to and strategy in this importance confirm great COVID-19. to of ailments; against required be inflammatory efficacy may are airway therapeutic which studies several roflumilast, and clinical of via mitigate further properties action However, to therapeutic a anti-inflammatory COVID-19. NEP-based reported Being its curing proposed previously potentiates the approaches was discusses Roflumilast. probably NEP deeply therapeutic was that review activating effective level, this effects Because the cAMP adverse activity. more enhancing of less by NEP One be with acts increasing to diseases roflumilast COVID-19. agent PDE4i, lung of selective therapeutic inflammatory component highly any neutrophils-associated neutrophilic COVID-19-associated for reduce the for proposed to Thus, mediator block many key investigated greatly the of complications. should be Despite fibrotic to it appear and appropriate, worldwide. Neutrophils thromboembolic yet. disease approved immunopathologic, respiratory been inflammatory has inflammatory medication serious effective most no therapies, the represents COVID-19 Nowadays, Abstract 2020 2, July 2 1 Tabaa COVID-19 El Manar treating in Roflumilast of role (NEP)-dependent pharmacotherapeutic Neprilysin into insights putative New at University Tanta City Sadat of University 1 n aa lTabaa El Maram and 2 1 Posted on Authorea 2 Jul 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.159373163.39100261 | This a preprint and has not been peer reviewed. Data may be preliminary. ettos uha og,trdes uceahs edce oetra ihsmtmsfvradchills and fever sometimes with throat sore pre- headache, respiratory aches, symptomatic typical muscle show tiredness, usually cough, patients COVID-19 as diseases, such airway sentations, severe of one Being 5.28 have COVID-19 than cases more of million and 10.3 manifestations until deaths than Clinical 507,000 more China 2.1 than 2020, 2020). Wuhan, more June (CSSE, in in 30 recovered resulting 2019 respiratory of have territories, of As acute people and end severe million countries 2020). 188 al., the called across et virus at reported (Huang novel recognized been pandemic a first ongoing by an was now caused It being disease (SARS-CoV-2). respiratory coronavirus-2 fatal syndrome contagious a is COVID-19 the challenges review COVID-19 to 2. aim we cascades. COVID-19-associated Thus, fibrotic Tabaa, block El can and significance. al., and roflumilast Tabaa coagulopathy prominent et which (El inflammatory, by therapy a (Graf (Rabe, COVID-19 mechanisms have (NEP) for pharmacological cAMP target may NEP-dependent Neprilysin potential of proposed activity activating new level a by NEP be 2020b). the effect to roflumilast-enhanced supposed anti-inflammatory al., enhancing 2020), lately its via is et NEP the prolong inflammation (Li As exhibits may airway roflumilast 1995). turn therapy. blunting PDE4i, in effective Among and which most 2020). for targeting 2011), al., the (PDE4i) for et inhibitor evok deaths. potency (Bridgewood phosphodiesterase-4 of to beneficial highest anti-inflammatory number need be the huge may urgent using a COVID-19 an that in modulating hypothesizes results is study that there illness a Recently, spread, infectious global its a restricting is For (COVID-19) 2019 disease Coronavirus Introduction 1. protease like chymotrypsin 3 3CLpro: Organization Health World transcription-3 WHO: of activator and transducer Signal STAT-3: 3-kinase phosphoinositide kinases family Src 2 SFK–PI3K: coronavirus syndrome respiratory acute Severe SARS-CoV-2: Roflumilast-N-oxide RNO: arthritis Rheumatic RA: Coagulopathy Intravascular Pulmonary PIC: inhibitor Phosphodiesterase-4 PDE4i, factor activating Patelet PAF: traps extracellular Neutrophils NETs: Neprilysin endopeptidase, Neutral NEP: kinase Janus JAK: Interleukin-6 IL-6: diseases bowel Inflammatory IBD: Hydroxychloroquine HCQ: peptide-1 like Glucagon GLP-1: tract Gastrointestinal GIT: L-leucyl-L-phenylalanine N-formyl-L-methionyl- fMLP: 2 Posted on Authorea 2 Jul 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.159373163.39100261 | This a preprint and has not been peer reviewed. Data may be preliminary. C- a on ob ihyepesdi lelradbocilmmrns ntp Ipemctsand pneumocytes utilizing II of type in evidence membranes, the bronchial and from alveolar ensured in expressed is highly SARS- which be for finding to way entry, viral found main The for was the receptors body. ACE-2 as as enzyme human considered (ACE-2) 2 is the enzyme angiotensin-converting pneumocytes within penetrating replication that showed commonly CoV-2 studies more (3CL several protease 2005). are like present, (Ziebuhr, chymotrypsin which At 3 helicase enzymes, (RdRp), and be polymerase proteolytic protease should RNA of conti- like dependent polyproteins variety papain RNA it replication, as protease), a viral such so For by viruses membranes, survival. 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Data may be preliminary. -ie D)lvl,wihi eotdt eascae ihtesvrt fCVD1 neto n may and infection COVID-19 of severity elevated in the reflected with plasminogen deposits associated of fibrin be increase these to compensatory down a reported break in is to result which fails clots levels, it These (DD) pulmonary progression, 2020). developing D-dimer al., disease for risk in et with the clot) Klok but, increases (fibrin 2020; (fibrinolysin) that thrombus al., thrombosis blood vein et deep of (Cui to formation embolism addition the in demonstrate vessels, victims pulmonary COVID-19 their McGonagle of 2017; vasculopathy studies Poll, anatomical specific der Most pulmonary van a and Levi in 2020). 2003; resulting al., (Aird, activate aggregation; et (PIC) could and IL-6 Coagulopathy Intravascular or adhesion itself Pulmonary their SARS-CoV-2 termed stimulate by responses either and endothelial function platelets cells in (ECs) endothelial the impairment the cells disrupting to endothelial consequence, leading a of produc- As state NO function stress decrease normal oxidative 2010). could dysfunction an al., the turn in et of endothelial interrupt which (Hung induction the to (eNOS) subsequent synthase inducing reported with oxide in also nitric tion interaction was endothelial SARS-CoV-2/ACE-2 the IL-6 inactivating of 2020b), through role al., direct et the (Ghasemi, (Zhang to inflammation; infection COVID-19 addition COVID-19 ocular in In coagulopathy with the and linked promoting dysfunction be in endothelial IL-6-induced involved to 3.2 extremely reported be recently neuro- et to is a (Marinosci found have that dysfunction 2018). olfactory also may conjunctivitis an was SARS-CoV-2 with 2013; causing IL-6 that matching al., pathway Jointly, et olfactory supporting (Henkin 2020). central elements mucosa the al., detected nasal additional invade the anosmia to other of that propensity Besides, inflammation proposing invasive 2007). 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T1rdcdcM nCOVID-19 in 2016). cAMP al., ET-1-reduced the et 3.6 (Wermuth stimulate development could could which factor- fibrosis 2013), dysfunction growth pulmonary al., endothelial the transforming et driving vascular (Elshazly of (ET-1) The release proliferation endothelin-1 myofibroblastic namely the as peptide, 2020). induce a features al., secreting in fibrotic via et findings extensive consequences post-mortem (George fibrotic of pulmonary prompted pneumonia presence that also the organizing extent revealed be the or may COVID-19 to fibrosis of infection, pulmonary cases COVID-19 during dysfunction, fatal problem endothelial substantial induced a of as evidence reported the Giving sepsis important of TGF- one and 3.5 be dysfunction to 2008). endothelial caused al., documented inflammation, not 2017). was et increased are al., (Schouten dysfunction between et which microvascular hallmarks Mantzarlis crosslink the death, 2001; extensive which (Crowther, even an inflammation in and hyper-coagulopathy, of is result shock, of there a dysfunction, sepsis, as release but During organ subsequent pathogens; multiple invading the the to by in directly lead share could may sepsis itself Developing Sepsis bacterial severe 2019). by about 2005). al., caused of that al., et TNF- rate Franco response mortality and et inflammatory high (IL-6 systemic (Annane its factors of injuries of kind inflammatory a tissue because as of worldwide and recognized attention existence widely infections the the is 2020). attracted emphasized It al., has diagnosis et %. that final 50–80 (Dallan syndrome the lymphopenia a with profound worsening is consistence with further Sepsis in patients is with COVID-19 that neutrophils among 2020a), by shock al., be induced septic may et inflammation a sepsis (Li uncontrolled viral injury systemic COVID-19, tissue in of of established result lymphopenia a progressive as with promoted neutrophilia high to 2010). response In al., et COVID-19 cathepsin (Gernez in tissue and sepsis host proteinase-3 Di- Inflammatory the 3.4 (elastase, 2017; damage as Hong, can such also and (TNF- proteases but (Hyun as only, of degranulation such pathogens arsenal by mediators an followed inflammatory possess recruitment, G), could Neutrophils and which cell-mediated chemotaxis 2020). response adaptive their dangelos, neutrophils of with inflammatory-mediated stimulation the started the facilitate (Dallan be inhibit consequently, virus effectively and the inactivating will response for immune lymphopenia targeted severe antibodies developing specific 2020). the Therefore, al., form killer et to effector natural Remy lymphocyte able and 2020; all which lymphocytes of al., cells, cytotoxic loss B et or to as CD8+ due well including occurs activity, as This antiviral prone cells, essential rate. more the mortality become high possess they of that patients, risk cells COVID-19 the of with count infections lymphocytes abundant secondary in innate for detected most the reduction continual the in the defense of With of One COVID-19 line in first inflammation 2018). the Neutrophils-mediated represent 3.3 al., tissue that extensive et neutrophils to (Chen lead are also disorders COVID-19 an system. may immune play in inflammatory it to assured injury, numerous known or been in infection equilibrium was leukocytes any vascular shown trafficking against the leukocyte as responses shift Although protective damage may the turn, 2003). in structural in (Aird, part several which essential inflammation trafficking, induce more leukocyte could triggering in dysfunction towards resulting endothelial changes Sarıalio˘glu, COVID-19-associated functional and that and (Belen-Apak suggest cascade data cytokine Emerging pro-inflammatory 2020). the al., of et activation Leonard-Lorant with 2020; correlated also be β -nue umnr boi nCOVID-19 in fibrosis pulmonary 1-induced α htcudeetal grvt h xsigiflmain(Molano inflammation existing the aggravate eventually could that ) α n L6,adtxcoiat htd o ilphagocytosed kill not do that oxidants toxic and IL-6), and β (TGF- 1 5 β ) boei yoiemil mlctdin implicated mainly cytokine fibrogenic a 1), Posted on Authorea 2 Jul 2020 — The copyright holder is the author/funder. 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C,ahmnzdmncoa nioyatdb lcigI- eetr,hsbe ugse o COVID- for suggested been has receptors, IL-6 blocking by to acted clinicians antibody pushed monoclonal That humanized complications. a 2020). neutrophilic related TCZ, al., the steroid control et from efficiently (Varga apart can COVID-19 COVID-19 that treatments of with anti-inflammatory representcomponent infected alternative which or be diseases, additional choice to cardiovascular for of search or drug group inappropriate diabetes, susceptible be hypertension, In may most steroids pre-existing the 2005). effects, with adverse al., patients harmful systemic vulnerable et and (Fukakusa for local neutrophilia their COVID-19-associated steroids, to anti-inflammatory due is exaggerate oral addition, CQ paradoxically of use or may 2013). the HCQ they recommends al., however also either have et protocol to Additionally, (Joyce treatment recorded COVID-19 COVID-19 arrhythmias. lately current treat Moreover, is cardiac corti- to HCQ serious FDA systemic of of by use including, authorized risk the drugs However, longer increased other no 2020). to al., with due et anticoagulant combination restrictions Rosenberg and in many 2020; Lopinavir/Ritonavir al., or guidelines, antiviral et international alone Aazithromycin, (Mehra the either Enoxaparin macrolide on utilized (TCZ), Based be Tocilizumab its of 2017). to costeroids, because al., reported therapy et first-line is the (Hu as HCQ effects (HCQ) hydroxychloroquine immunomodulatory of and use anti-inflammatory the involves one commonly inducing most by The been severity have strategies the therapies therapeutic 2020). increasing Current several al., in 4.1 context, et role (Cascella that COVID-19 In airway major control trigger the to al.). can proposed COVID-19 play et that (Zuo neutrophils doubt coagulopathy which no COVID-19-associated towards is in researchers crisis. 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E lohsahg laigant oad oeptn namtr n aocieppie other peptides vasoactive and inflammatory potent atrial some and et (fMLP) towards (Kletsas L-leucyl-L-phenylalanine affinity N-formyl-L-methionyl- fibroblasts (BKs), cleaving and in bradykinins 1998), high including expressed al., ET-1 a be than et to has Maria found inflammatory also (Di been many cells NEP has in muscle NEP as smooth airways, well the 1997), as 1998). 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Data may be preliminary. el,lk etohl,Tlmhcts oiohl,mnctsadbspis(a caky ta. 2005; al., et Schalkwyk (van and basophils inflammatory cells various and muscle in monocytes smooth distributed airway eosinophils, widely cells, be lymphocytes, 2008). epithelial to T Halpin, airway noticed neutrophils, including also like 2014). was lung al., cells, PDE4 cAMP the et regulating (Azevedo within endothelium. for 11) vascular types responsible and pulmonary isoenzyme cell 10, predominant 3, many the 2, represent in (PDE1, to levels cGMP accounted was and it cAMP PDE4, both Regarding for hydrolases hydrolases and cGMP-selective to 9) 8), according and categories and 7 three 6, classified into their (PDE4, (PDE5, grouped hydrolases be cAMP-selective also of could including, be PDEs can specificities duration PDEs substrate properties, Similarly, their pharmacological and 5’ PDE1-PDE11. and namely amplitude inactive distribution families, tissue 11 the their into sequences, acid as into amino well (cGMP) on Based as mono-phosphate sec- 2009). level guanosine of al., intracellular hydrolysis et cyclic the (Hertz their and catalyze signaling regulating that cAMP thus enzymes as of monophosphate; such superfamily large messengers a use ondary are 2011). its (PDEs) (Rabe, which enzymes cAMP to intracellular Phosphodiesterase isoenzyme, of PDE4 level (PDEs) the of enzymes in inhibitor Phosphodiesterase increase long-acting 5.1 an selective with highly accompanied a surely be be will to recorded is Roflumilast this until NEP However, overview on COVID-19. roflumilast Roflumilast be treating relying may in 5. to role roflumilast contributing great that pathways a fundamental predict play potential we to Accordingly, the expected activity. declares is activity. study that NEP drugs no as useful moment, well anti-inflammatory most efficient as the its of level exert can one and cAMP PDE4i, selective enhancing Ayoub highly via a 1995; effect roflumilast, that and al., declare prolong may et outcome may That turn (Graf in mechanism which anti-inflammatory activity, levels NEP 2008). short-term the enhanced Melzig, increasing cAMP-mediated with that suggesting correlated the 2015). examined; directly Bayan, potentiate been was and also cAMP El-Sayed has intracellular 2015; (-)-Epigallocatechin- PDE4i, of investigative al., Curcumin, an et and Rolipram, Chang Luteolin, with, 2008; its Along (Apigenin, and Melzig, enhancing 2008) products and al., natural (Ayoub expression; et Resveratrol) or (Yao gene and developed 2009)) (androgens pre-clinically 3-gallate al., NEP hormones are et 1991), enhancers up-regulate Gruenert, selective (Xiao may of and estrogen variety (Borson that a (glucocorticoids) 1991), agents drugs (Borson, involving for action its searching promoting and studies activity the to target COVID-19 good Referring with a inflam- neuropeptides associated exhibit associated fibrosis inflammatory may pulmonary their it local and for 2011), coagulopathy regulating al., explanation infection. inflammation, et in airway clear (Wick the a NEP cells counteracting vascular be of for nearby will and activities 1989), microenvironment multiple alveolar Mycoplasma al., within Considering and et corona-virus, and Borson rat (Carpenter cascades. 1988; 1, hypoxia matory type al., 1989), virus al., et parainfluenza et (Jacoby like (Dusser pulmonis pathogens smoking respiratory cigarette or and by 2001) worsening either Stenmark, to activity leading NEP tissues, reducing airway inflammatory Therefore, 1991). on enzymes of effects (Borson, elastase destructive disease activation pathophysiological neutrophil further the of and further exert of release recruitment may to the progression which to permeability, lead G), lead vascular may will Cathepsin chemotaxis in (e.g., NEP Neutrophils processes increase regulating neutrophils. inflammatory an particularly down airway involves cells, or This the destroying alleviating that changes. in ensured 1994). role studies al., Several its et Shimamoto on 1985; emphasize al., et that (Connelly (ANP); peptide natriuretic 8 Posted on Authorea 2 Jul 2020 — The copyright holder is the author/funder. 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Data may be preliminary. 09.Ihbtn D4wl pcfial rvn APdgaain hc ntr ildces airway decrease will turn as in neutrophils Banner, specifically which and cells, degradation, (Press inflammatory of responses cAMP recruitment pro-inflammatory prevent and that activation of specifically demonstrating the myriad preventing findings will a via previous PDE4 inflammation suppress the Inhibiting on will based PDE4 be 2009). of may activity COVID-19 for the PDE4i inhibiting selecting for rationale obesity The infection and/or COVID-19 prediabetes and of with role Roflumilast adults the in 9. to sensitivity high-fat referring attenuate 2012), insulin 2019). could al., improving al., PDE4B et et and in (Vollert (Muo weight deficiency mice reducing a in a that inflammation the in is documented tissue from roflumilast which was adipose secretion it (GLP-1), inhibition, and insulin addition, adiposity peptide-1 PDE4 stimulating glycemic In diet-induced like the for through 2012). glucagon improving agent al., roflumilast, intestinal via insulinotropic et of patients (Wouters potent metabolism, 2 secretion and fat type the incretin (DM) and encourage main mellitus could glucose diabetes Roflumilast in in progression index. 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Meyer-Hoffert, 2006; Pham, 1984; al., et (Wintroub iue3 Figure H ta. 00.Hwvr h rvnieadteaetceffectiveness therapeutic and preventive the However, 2020). al., et (He 12 Posted on Authorea 2 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159373163.39100261 — This a preprint and has not been peer reviewed. Data may be preliminary. ot h uhr r hnflt r mdAdlasu lagr pcaito adooy Mahala view. Cardiology, of of point Specialist clinical his Elnaggar, from Abdelmaksoud suggestions interest Emad and of comments Conflict Dr. helpful sup- his to providing for thankful for Egypt are Egypt Center, University, in Cardiac authors Medicine-Tanta University, The of Pharmacy-Tanta Faculty entries of Institute-University Physiology, Faculty Toxicology, Research port. Medical and & of corresponding Studies Pharmacology Environmental Department of of Egypt; Department members to Egypt; staff City, all Sadat thank hyperlinked of to like would authors are The article PHARMACOL- to Guide this Concise Acknowledgments 2019). the al., in in archived et permanently (Alexander are 2019/2020 PHAR- and ligands to OGY 2018), Guide al., IUPHAR/BPS et the and (Harding from MACOLOGY data for targets portal common the http://www.guidetopharmacology.org, protein Key about ligands confirmation and further physicians targets provide for COVID-19. of may stimulus against consequently, Nomenclature a option and as treatment management serve repurposed cascades ther- COVID-19 novel fibrotic will in NEP-mediated a and roflumilast the hypothesis with coagulopathy of discuss our inflammatory, impact to that the anti- therapeutic one facing hope the first in its we role the COVID-19, prolong its is by and review can driven roflumilast this of roflumilast that properties consideration that apeutic our proposed suppose into is COVID-19. taken which managing we activity, Therefore, for NEP level, target enhancing important via cAMP an properties therapeutic be increasing As other to of display now. and result effect till anti-inflammatory a up compromised effect. and effects as resistance the azithromycin adverse their enhance Additionally, improve corticosteroids, can dangerous and either roflumilast any corticosteroids with inflammation, showing of combination neutrophilic properties without airway in inflammatory the Zinc) safely attenuating and used via E be well, (C, to protocol, for vitamins reported concurrent required the been recommended enzyme to advantages had proteolytic additive it have a also since is may roflumilast which treatment, 3CLpro, COVID-19 Considering of cells. inhibitor been host submitted potential drug the has potent within a roflumilast and replication Furthermore, as selective viral behave most disorders. to the inflammatory be reported airway Among to treatment,recently neutrophils-mediated activities. reported COVID-19 many anti-platelets been of and treating has class anti-inflammatory roflumilast new for effective intriguing PDE4i, exhibit an used to offer clinically thought to the is suggested PDE4 been now. inhibiting has until since PDE4i effectiveness continues, ther- and search neutrophils anti-inflammatory satisfaction the recommended modulating treatment As guidelines, provide on underlying not focus do the should COVID-19 to for COVID-19 According suppression apies of response. with associated management linked their coagulopathy and biologically Therefore, and function inflammation be systemic infection. to increased assumed COVID-19 to is with predisposes progression that component COVID-19 neutrophilic of of risk patient’s the Reducing infection. COVID-19 NEP-mediated Conclusion the counteracting 11. ensuring for towards risk proposed 2016). driven roflumilast be al., highly contribute should of et may of efforts mechanisms Raker which clinical system pharmacotherapeutic 1995; cAMP future immune al., of that level et recommend the we high (Graf improving Accordingly, the roflumilast in maintain of also role effect will anti-inflammatory important NEP long-term an by for ET-1 play via breaking to agent groups, anti-fibrotic underscored COVID-19 as is function cAMP to Because ability TGF- the by thereby, driven and fibrosis activities the fibroblast blocking TGF- the ET-1-induced attenuate the to potential stopping by lungs protect β Dnene l,20;Tg ta. 2009). al., et Togo 2007; al., et (Dunkern 1 β ;esrn h ocp htrflmls a aethe have may roflumilast that concept the ensuring 1; 13 Posted on Authorea 2 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159373163.39100261 — This a preprint and has not been peer reviewed. Data may be preliminary. owl-mt,V,Czoa . n ae ..(06.Aepopoiseae4ihbtr utmore just inhibitors 4 phosphodiesterase Are (2006). C.P. Immunol. Page, transformed Physiol. Clin. and in Allergy Mol. J. M., endopeptidase Cell. theophylline? Lung neutral Cazzola, - induce V., Physiol. Glucocorticoids J. Boswell-Smith, Am. (1991). cells. D.C. epithelial Physiol. tracheal Gruenert, Appl. human endopeptidase J. and Neutral infections. D.B., (1989). respiratory J.A. Borson, with Nadel, Physiol. rats and in D.M., Mol. inflammation McDonald, Cell. neurogenic K., Lung Sekizawa, and - J.J., Physiol. Brokaw, J. D.B., Borson, Am. airways. in endopeptidase neutral of 260 Roles (1991). D.B. Borson, Thrombolysis possible Thromb. COVID-19: J. 1–3. in therapy. severe anticoagulant/thrombolytic coagulation : intravascular on of recommendations Pulmonary treatment and the (2020). pathogenesis Sarıalio˘glu, for F. and inhibitor F.B., phosphodiesterase-4 Belen-Apak, T novel P a disease. (daliresp): pulmonary Immunol. (2006). Asthma obstructive Roflumilast Allergy, al. chronic Ann. et (2012). C., asthma. J. Schmid-Wirlitsch, of treatment Baye, P., the Magyar, in P., roflumilast Hofbauer, of U., safety and Harnest, Clin. Efficacy J.L., Allergy Izquierdo, J. E.D., asthma. Bateman, moderate-to-severe with montelukast patients with combined in Roflumilast treatment (2016). add-on Immunol. H. as Watz, alone and montelukast F., versus Richard, U.-M., Goehring, pulmonary E.D., obstructive Bateman, chronic Res. and Clinical asthma Drug in (2014). Prog. inhibitors al. (PDE4) (COPD). 4 et disease Rev. Phosphodiesterase de, Endocr. R.B. (1999). Endopeptidase M.S. (PDEs). Alexandre, Barnette, Neutral phosphodiesterases I., Levy, the on A., of Products Horvath, genetics E., Natural molecular COVID-19 Bimpaki, and Selected F.R., Faucz, of (2020). M.F., Influence Azevedo, al. et (2008). S., M.F. Toom, and Melzig, Activity V., and Dandu, S., S., Immun. Ayoub, Sapozhnikov, Behav. 63–78. N., Brain. pp stroke. Narula, Lancet, as In K., presenting shock. Nalleballe, Septic A., (2005). fibrosis Avula, J.M. pulmonary Cavaillon, NOX4/NADPH idiopathic and P.E., (2010). with Bellissant, Thorax J. P.D., patients myofibroblasts. Boczkowski, Annane, from into and differentiation fibroblasts B., fibroblast pulmonary TGFbeta1-induced Crestani, in mediates R., increased and Muloway, is F., Pharma- (2019). expression Prost, J. oxidase D., al. Br. Goven, et N., receptors. J.A., Amara, protein-coupled Peters, G A., Mathie, 2019/20: PHARMACOLOGY E., col. TO Kelly, the syndrome. A.P., GUIDE dysfunction in Davenport, organ CONCISE multiple endopeptidase A., THE and neutral Christopoulos, sepsis S.P.H., severe of Alexander, in Role endothelium the of (1992). role H.R. Blood The Keiser, (2003). W.C. and Aird, E., Hypertension Golomb, endothelin. J.E., of metabolism no Tate, have Z.A., authors other for Abassi, All responsible manuscript. only submitted the the are in institutions References work their disclose. this and to of authors interests content The of the conflict and interest. support of financial conflict the no declare authors The 176 L212-25. : 101 S21–S141. : 138 3765–3777. : β- 142–149. : mli rdcini KNS el.Pam Biol. Pharm. Cells. SK-N-SH in Production Amyloid 53 193–229. : 20 117 89–95. : 37 1237–1243. : 149–61. : 14 46 425–432. : 35 260 195–233. : L83-9. : 66 2653–2658. : 65 733–738. : 96 679–686. : May Posted on Authorea 2 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159373163.39100261 — This a preprint and has not been peer reviewed. Data may be preliminary. iagls .(00.Nurpi novmn nCvd1.Preprints. Covid-19. case in refractory involvement a Neutrophil in (2020). administration A. Tocilizumab Didangelos, (2020). Agents P. Antimicrob. Tabarsi, J. and Int. A., COVID-19. presentation Saffaei, of shock S.A., Septic Nadji, (2020). Heal. F., C. Adolesc. Sahyoun, Dastan, Child and L., Lancet treatment Lacroix, COVID-19. the S., with in Politi, adolescents J., inhibitors in Siebert, 5 Immunol. F., type Clin. Romano, urology. phosphodiesterase C., from of Dallan, patients lesson role in A possible thromboembolism Any infections? (2020). venous COVID19 U. severe of Livi, of Prevalence and (2020). F., F. Haemost. Moro, Wang, Thromb. Dal and J. S., pneumonia. Liu, coronavirus novel X., severe Li, with S., Chen, 2020. S., June Cui, 30 Retrieved University. Hopkins Johns ArcGIS. Gisanddata.Maps.Arcgis.Com. @ Index JAMA (2020). Research. J.H. Sepsis CSSE, of Challenges Continuing unexplored and (2001). and lethal M.A. potentially Crowther, responses Co-infections: (2020). Microbe Inflammatory J. Lancet O’Grady, A. The and S. COVID-19. (2018). D., U. in Bogaert, Sci. Acad. N., al. Natl. Loman, Proc. M.J., et Cox, peptide. chemotactic Erd J., of and Cleavage Deng, A.R., neutrophils: human Johnson, Z., in W.W., 24.11 Schulz, Zuo, R.A., J., Skidgel, J.C., Fang, Connelly, Brown Oncotarget H., in organs. Cui, inhaled in obstruction of diseases H., airflow Effect inflammation-associated Deng, phase (2007). late L., al. allergen-induced Chen, et Pharmacol. of D., J. Prelusky, resolution (-)-Epigallocatechin-3-gallate Eur. C., and Celly, rats. prevention (2015). J., Norway Richard, the H., al. on Jones, et roflumilast A., Y., expression. House, neprilysin Mo, R.W., sepsis upregulating Chapman, on Q., by roflumilast Hu, mice of model Res. C., Influence disease Cell Yang, Alzheimer’s Exp. Y., (2019). in J.B. Chen, deterioration Sci. cognitive Li, C., Pharmacol. attenuates and Rong, Med. X.Y., X., Rev. Liu, Chang, Eur. J., pathway. Yin, and signaling JAK/STAT Evaluation X.J., the Features, Ma, through (2020). L.F., mice Di Hu, R. X., Napoli, Chang, and S.C., Publishing). Dulebohn, increases (StatPearls Physiol. A., (COVID-19) and Mol. Cuomo, Coronavirus expression Treatment M., Cell. neprilysin Lung Rajnik, lung - M., decreases Physiol. Cascella, J. Hypoxia Efficacy Am. J. (2001). (2020). leak. Eur. K.R. vascular al. study. Stenmark, pulmonary cohort et and retrospective N., T.C., single-centre Boffini, Carpenter, a M., patients: Ripa, COVID-19 De, severe Med. G. in Intern. Luca, tocilizumab pathway G., of signaling JAK/STAT Cavalli, safety of and E., roles Della-Torre, specific The C., (2015). Campochiaro, S. Immunol. phosphodi- Zhang, and A Clin. C., Inflammation Chen, Allergy (2006). sepsis. Y., J. in Luo, al. J., vitro. Cai, et in B., N., airways Cai, Cox, in S., deposition Boustany, protein Q., matrix inhibition Ge, 649–657. inhibits PDE4 M.H., inhibitor of Poniris, 4 use B.G.G., esterase for Rationale Oliver, J.K., (2020). Burgess, L. Pneumonia. Quartuccio, COVID-19 and in K., inflammation severe Sharif, for G., Damiani, C., Bridgewood, 76 334 43–49. : 136–145. : 38 1599–1608. : 571 1 e11. : 215–221. : 106043 :. 323 15 1824–1836. : 9 7204–7218. : s ..(95.Nurlendopeptidase Neutral (1985). E.G. ¨ os, 281 214 286 L941-48. : 108414. : 1894. : 23 1335–1341. : 82 8737–8741. : 118 : Posted on Authorea 2 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159373163.39100261 — This a preprint and has not been peer reviewed. Data may be preliminary. des rgratosb h rnhNtoko hraoiiac etr.Therapies. Centers. Pharmacovigilance cardiac of use Network of “Off-label” French survey (2020). the A al. by COVID-19: et reactions in A., drug chloroquine Granvuillemin, adverse and N., lopinavir-ritonavir Parassol, azithromycin, D., hydroxychloroquine, role Viard, of potential A., the Fresse, COVID-19: S., and Romani, G´erard, fibrosis A., Med. Pulmonary cell Respir. (2020). host Lancet R.G. therapy. from antifibrotic Jenkins, Res. formation for and Cell cAMP A.U., Mol. Extracellular Wells, - P.M., (1988). BBA George, J. cyclase. Wolff, adenylate (2011). and pertussis L.G., al. Bordetella Knipling, by et Res. ATP A., K.J., Respir. Raptis, subjects. Killian, F., an- asthmatic M.L., Gentile, by mild Cˆot´e, Duong, in expression C., inflammation J., interleukin-6 allergen-induced Schmid-Wirlitsch, of attenuates L.P., Induction Roflumilast Hypertension Boulet, (1999). cells. G.M., muscle A. Gauvreau, Takeshita, smooth vascular and rat Oral K., Immunol. in Ito, Clin. (2005). II Allergy giotensin IFN- T., al. J. and Ichiki, et mucosa. IL-8, (2010). Y., airway M., neutrophil, Funakoshi, asthmatic Laviolette, increase in al. but Al, expression expression O. et 10 chemokine Dewachi, protein D.D.J., CC P.O., A. inducible and Fiset, S. Myers, eosinophil U. M.K., M., decrease Tulic, Sci. corticosteroids Monestier, C., Acad. Bergeron, D., Natl. M., Schatzberg, Fukakusa, Proc. thrombosis. D., promote COVID-19? Duerschmied, severe traps new for DNA A., treatment Extracellular a effective Brill, an T.A., be Inflammaging: could Fuchs, tocilizumab Why (2018). (2020). A. Med. H. Transl. Wei, Santoro, J. and and Endocrinol. X., Xu, Rev. C., B., Fu, Nat. Giuliani, diseases. J. P., age-related Parini, for Respir. viewpoint P., immune–metabolic Eur. Garagnani, C., pigs. methyl- Franceschi, not guinea but in Roflumilast inflammation (2006). pulmonary R. Beume, Dis. smoke-induced Suppl. and cigarette Dev. L., Wollin, Cardiovasc. inhibited A.E., J. McAulay, prednisolone D., Signalling. Spicer, cAMP M.F., PDE4-Mediated Fitzgerald, (2018). Investig. polymicrobial G.S.B. reverses Lab. and Roflumilast A., mice. (2017). Bracy in al. Fertig, et inflammation Q., of inhibiting Zhong, by Assessment Z., Tuberc. damage Zou, (2013). Y., liver Dis. Cheng, N. sepsis-induced Chest H., Wang, Okasha, J. J., and Chen, Egypt. H., K., Feng, fibrosis. Elkaffas, pulmonary A., idiopathic Zakaria, Biol. in H., path- dysfunction Med. Abdel-Hafiz, Neprilysin endothelial Exp. and H., Hosny, Estradiol Adv. targeting M., disease. Resveratrol Elshazly, Alzheimer of of role model Possible Lipopolysaccharide bronchocon- (2015). in induces Y. ways pig. Bayan, smoke guinea Invest. and Cigarette the Clin. N.S., in El-Sayed, J. (1989). endopeptidase radicals. neutral J.A. airway free Nadel, inactivates of and role and P Possible (2019). D.B., substance to Borson, hyperresponsiveness al. T.D., strictor Obstructive et Biol. Djokic, Chronic P.J., Mol. in D.J., Migration Cell Barnes, Dusser, Neutrophil Respir. H., on J. Tullett, Roflumilast Am. Inhibitor C.M., PDE4 Disease. Davies, the Pulmonary of P.S., Effect Fenwick, Inhibitory TGF- T., Direct Kawamatawong, of of activators Inhibition A.E., and (2007). Pharmacol. Dunne, drugs J. A. inhibiting Hatzelmann, Eur. phosphodiesterase and by cyclase. conversion guanylyl F., myofibroblast Car- soluble Sabatini, to (2020). G.A., fibroblast al. lung Rossi, COVID-19 et induced D., the Feurstein, G., During T.R., Biondi-Zoccai, Systems Dunkern, J., Health Laracy, Cardiol. and Workers, Coll. T., Am. Care Chuich, J. Health B., Pandemic. Patients, Bikdeli, for V., Considerations M. diovascular Madhavan, E., Driggin, 18 164. : 75 2352–2371. : 84 572 900–906. : 12–22. : 16 60 445–453. : 34 118–125. : 971 63–71. : 14 97 107 822 576–590. : 1008–1019. : 15880–15885. : 107–118. : 62 115 589–592. : 280–286. : 12 140. : 5 8. : γ- β Posted on Authorea 2 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159373163.39100261 — This a preprint and has not been peer reviewed. Data may be preliminary. ne,PA,Mra,F,Ykym,U,Rmn,S,Yn . rw,L,e l 21) APadEa in Epac and CAMP (2012). al. et Pharmacol. L., J. Brown, Br. H., Biol. fibrosis. Yun, Leukoc. tissue S., J. of Romano, organs. regulation U., various Yokoyama, the in F., Murray, trafficking P.A., neutrophil Insel, into insight Deep (2017). C. 102 Hong, and Y., Hypertens. Hyun, caveolin-1 J. stabilized infected to cells. patients binding endothelial endothelial synthase inhibits of vascular oxide Interleukin-6 features nitric human (2010). endothelial J.H.S. Clinical in increases Pang, (2020). and and activation H.T., al. synthase Wu, oxide et M.Y., nitric Hung, Y., W.J., Hu, Cherng, Lancet M.J., J., China. Hung, Zhao, Wuhan, L., in coronavirus Ren, SARS-CoV-2 novel X., against 2019 Li, inhibitors with Y., commercially Wang, potential C., of Huang, Prepr. Prediction ArXiv (2020). P. model. Yin, deep multi-task and by Chem. J., Med. Jiang, Curr. Activities F., Therapeutic Diseases. Hu, and Related Mechanisms and Pharmacological The Rheumatic (2017). Elevated in C. Wen, (2009). Hydroxychloroquine macrophages. and of J.-P., al. Wan, monocyte-derived L., et human Lu, A., C., in Hu, Aderem, expression P.S., chemokine Sci. Amieux, induce Acad. M., inhibition Natl. Gilchrist, PDE4 Proc. K.C., and Smith, AMP Neck Head A.T., cyclic - Bender, Otolaryngol. A.L., JAMA hyposmia. Hertz, in 3C-like 6 coronavirus Interleukin (2013). of I. Potential Velicu, Surg. (2020). and L., protease al. Schmidt, of et R.I., structures 106055. Henkin, Y., from Agents Wang, Insights Antimicrob. drugs: Z., J. anti-SARS-CoV-2 Zhang, Int. new inhibitors. C., of development and Wang, the X., for Huang, precli- inhibitors protease L., The chronic (2010). Hu, for al. J., development et He, in Ther. R., inhibitor Pharmacol. Beume, 4 Pulm. S., phosphodiesterase disease. The Sanjar, oral pulmonary (2018). selective, S., obstructive roflumilast–a Adnot, al. of G., guide et pharmacology Lungarella, new nical E.J., S., the Morcillo, Ireland, encompass A., to A.J., Hatzelmann, expansion Pawson, Res. and Acids C., updates Nucleic Tissue 2018: Southan, IMMUNOPHARMACOLOGY. in (2004). to E., PHARMACOLOGY understanding van Faccenda, to in H. Guide step J.L., IUPHAR/BPS first Goor, Sharman, A and S.D., coronavirus. G.J., SARS Harding, Navis, for receptor Pathol. A.T., functional J. Lely, pathogenesis. the M.L.C., SARS protein, Bulthuis, ACE2 of W., distribution Timens, I., of COPD. Hamming, Dis. in treatment activity Pulmon. differential the Obstruct. and interaction Chron. in family: J. Aging phosphodiesterase bronchodilators Int. the and of of Drugs ABCD prescribing. (2008). effects D.M.G. for Halpin, adverse Recommendations Potential people: older (2008). in M.S. obstruction O’Mahony, airways Res. and Respir. Phosphodiesterase cells. P., (2006). muscle J. Gupta, smooth Wharton, artery and pulmonary human K.H., in Banner, effects S., 7 anti-proliferative Afzal, and expression X., 4 Ren, type K.G., Spink, cells. E.J., endothelial Growcott, human in activity endopeptidase neutral enhance Peptides Inflamm. Gr inhibition Immunol. phosphodiesterase M., Ocul. and Zhang, Review. cyclase A K., Inflammation: Kunkel, Ocular K., in Graf, IL-6 of diseases: Roles J. airway (2018). Respir. inflammatory H. Eur. chronic Ghasemi, how? in and Neutrophils them (2010). P. target Chanez, we and Can R., Tirouvanziam, Y., Gernez, :. 617–629. : 139 16 728–734. : 1273–1278. : 106 21978–21983. : 203 631–637. : f,M,Shlz . cut . ta.(95.Atvto fadenylate of Activation (1995). al. et C., Schudt, K., Schultz, M., ¨ afe, 3 543–561. : 2003.00728 35 467–469. : 28 166 17 : 940–951. : 46 395 447–456. : 23 1091–1106. : 497–506. : 235–256. : 24 2241–2249. : 25 415–443. : 26 37–50. : Posted on Authorea 2 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159373163.39100261 — This a preprint and has not been peer reviewed. Data may be preliminary. umnr moimi OI-9Ptet nC nigah n eainhpt -ie Levels. D-Dimer to Acute Relationship (2020). and al. Angiography et CT O., Collange, on C., Patients Pauzet, 2 201561. COVID-19 J., coronavirus Radiology Helms, in syndrome F., Embolism respiratory Severac, Pulmonary X., acute Delabranche, severe carrier Infect. I., Asymptomatic to Immunol. Leonard-Lorant, (2020). Microbiol. due al. J. et pneumonia myths. of M.Y., and and Yen, Inhibition Facts S.C., disease, (SARS-CoV-2): Hsueh, (2003). respiratory Y.H., al. Wang, acute Pharmacol. C.Y., et Wang, state, J. Y.H., M., asthma. Liu, Yang, chronic C.C., murine Lai, R., in Beume, dexamethasone L., and Wollin, Ther. roflumilast P.S., Exp. by remodeling Thomas, and C., inflammation treatments Herbert, 4-targeted R.K., Phosphodiesterase (2013). Kumar, A.B. Med. Gottlieb, converting BMC and angiotensin diseases. N., of autoimmune role Kim, for crucial Med. A.M., A Nat. Goldminz, (2005). injury. al. N., lung et Exp. Kumar, B., coronavirus-induced Guan, Ther. SARS F., in Immunol. Guo, (ACE2) H., Arch. Gao, 2 S., sepsis. enzyme Rao, Y., and Imai, K., response Kuba, inflammatory in endothelin- of antagonists role The receptor (2015). Res. (Warsz). A. Thromb. endothelin Goraca, COVID-19. and and with B., Skibska, 1 patients al. M., ICU et Kolodziejczyk, P., ill K.M., Kleniewska, Kant, critically A., D.A.M.P.J., Kowalczyk, in Gommers, complications M.S., thrombotic Arbous, Ageing der, of van Incidence Mech. N.J.M. (2020). Meer, ageing. M.J.H.A., Neutral and Kruip, Venous (1998). F.A., development Klok, E. in during Ottaviani, NETs and fibroblasts of C., human Franceschi, Role in D., Dev. Emerging Stathakos, activity D., The (NEP) Barbieri, (2016). endopeptidase-24.11 E., P.K. Caselgrandi, Henke, D., Kletsas, and J.A., Immunol. Front. Diaz, Immunothrombosis. and A.T., Thrombosis That Obi, Protein Immunol. Front. Iron-Binding A.S., an Bacteria. Kimball, Lactoferrin, and of Viruses Biology Against The (2020). Defend E. Help Pretorius, Can and E.L., diseases. Heyden, airway D.B., in in Kell, inhibitor, Cytokines 4 to phosphodiesterase selective Dis. Relationship a Thorac. Its roflumilast, J. of and Roles (2017). Signaling T. Kawamatawong, Receptor Biotechnol. Estrogen Biomed. J. (2010). rapidly Erythematosus. P. Lupus Acute a Moutsatsou, Systemic J. as and Hear. presenting E., Eur. cardiotoxicity Kassi, review. Hydroxychloroquine literature and (2013). features N. Care diagnostic Cardiovasc. Mahon, Key cardiomyopathy: and phosphodiesterase biventricular selective A., Ther. evolving Patients of Fabre, Pharmacol. in effect Pulm. E., The Differences vitro. Joyce, (2005). Gender in C.P. function (2020). Page, neutrophil al. and on R., et inhibition Lever, D.-M., isoenzyme V., Han, Heal. Boswell-Smith, Public X.-F., N.A., Front. Liu, Mortality. Jones, and F., Severity Wu, on W., Focus He, COVID-19: P., With Bai, J.-M., Jin, Shock Disease. Lung Inflammatory and (ACE2) 2 46 hyperre- Enzyme Angiotensin-Converting airway Pulmonary causes (2016). infection H. Physiol. peripheral Jia, Influenza Appl. in (1988). J. J.A. IL-6 enkephalinase. Nadel, Longev. of decreasing and Cell. by secretion D.B., Med. sponsiveness Borson, the Oxid. J., inhibits patients. Tamaoki, and diabetic D.B., Jacoby, 2 species type oxygen from reactive cells of mononuclear blood generation the activates cAMP Borges, C.A., Isoni, 239–248. : 102 15–23. : 63 307 41–52. : 9 349–355. : 1144. : 2 77–83. : .. eoo .. ats .. hvs .. n ouiaMcao ..(2009). J.A. Nogueira-Machado, and M.M., Chaves, R.T., Mattos, C.A., Veloso, E.A., ´ 11 96. : 18 7 236. : 64 2653–2658. : 53 11 404. : 1221. : 8 11 152. : 875–879. : 18 2 93–101. : 317–321. : Posted on Authorea 2 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159373163.39100261 — This a preprint and has not been peer reviewed. Data may be preliminary. iaa . oclo . olo,D,Tnr . n otj,J 21a.Rflmls rvnstemetabolic One the PLoS prevents Roflumilast model. (2015a). murine J. a Cortijo, in and fibrosis H., bleomycin-induced Tenor, of D., Front. effects Monleon, E., responses. Morcillo, immune J., innate Milara, modulate Lancet. proteases analysis. serine registry with Neutrophil-derived multinational Biosci. chloroquine a or (2009). Hydroxychloroquine COVID-19: U. of (2020). Meyer-Hoffert, treatment A.N. for Patel, macrolide and a F., without of Ruschitzka, mechanisms or S.S., Immune Desai, (2020). Rheumatol. M.R., C. Lancet Mehra, Bridgewood, pneumonia. and COVID-19 P., in Emery, coagulopathy K., intravascular uncontrolled Sharif, pulmonary Lancet disease J.S., trial. pulmonary O’Donnell, controlled D., obstructive Effect randomised McGonagle, chronic multicentre (2015). severe a K.F. with (REACT): Rabe, patients therapy and in combination L.M., by Fabbri, exacerbations M., on sniffing Brose, roflumilast U.-M., COVID-19: of Goehring, and P.M.A., anosmia Calverley, between F.J., Oto-Rhino-Laryngology link Martinez, Arch. Possible by Eur. (2020). inflammation of A. truth. neurogenic Calmy, Manifestations the airway and out Neurologic of B.N., Landis, Regulation (2020). A., (1998). Marinosci, J. P. al. Respir. Geppetti, et Eur. and C., S., endopeptidase. Neurol. Hong, neutral Bellofiore, JAMA J., Di, China. Chang, Wuhan, G.U. in Q., Maria, 2019 He, Disease Dys- S., Coronavirus Mitochondrial With Chen, Longev. Patients and M., Hospitalized Stress Cell. Wang, Oxidative Med. of L., Oxid. Role Mao, Therapies. (2017). Potential and E. Sepsis Zakynthinos, Biomembr. in and (2019). Bioenerg. function V., J. al. Tsolaki, action. et K., P., in nicotine Mantzarlis, Patalas-Krawczyk, COVID-19 for of M., target rates Prill, possible lower a K., on as Drabik, Reflection Mitochondria B., (2020). Hypotheses Michalska, Q. Med. Chen, M.R., protection? Wieckowski, and Mali´nska, unexpected Y., D., offer Li, immunizations R., Cao, childhood J., Does Dong, children: T., Miao, J., Lyu, otolaryngology: Laryngorhinootologie. Sci. and to? Life pandemic down COVID-19 China indexes comes The Sci. biochemical it injury. (2020). and What O. lung Clinical Guntinas-Lichius, (2020c). and and al. loads J.P., et viral Klumann, Lu¨ers, J., to J.C., Yuan, monitoring linked F., in Wang, patients IL-6 F., infected of Huang, role 2019-nCoV C., potential from Zhang, The Y., (2020b). Yang, al. Y., et MedRxiv. Liu, J., 2019. Zhang, disease Z., women coronavirus Li, pregnant of H., are Ma, case Why Y., severe (2020a). Yang, Immunol. J., A.H. Zhang, Reprod. Liao, inflammatory T., J. and Liu, of viewpoint. G., immunological Mor, treatment An J., the COVID-19? Kwak-Kim, for S.J., to Zhao, susceptible inhibitors L.L., Wang, Phosphodiesterase-4 H., (2018). (COVID-19): Liu, W. 2019 Tang, disease and Coronavirus Pharmacol. Front. (2020b). J., diseases. C.K. Zuo, Agents Tang, Antimicrob. H., and J. Li, Int. S.L., perspectives. Tang, future X.H., and observations Yu, status sepsis: S.M., viral current and Liu, SARS-CoV-2 (2020a). H., al. Li, et N., Tang, H., Dai, Lancet J., (nepri- hypotheses. Xu, endopeptidase D., and neutral Zhang, L., rat Liu, of H., expression Li, Tissue-specific Chem. (1995). Biol. Res. L.B. J. Thromb. Hersh, mRNAs. sepsis. and lysin) and R.M., Coagulation Booze, (2017). C., der Li, van T. Poll, and M., Levi, 14 3409–3418. : 395 1517–1520. : 9 270 :. 5723–5728. : 12 1454–62. : 99 277 287–291. : 19 2149–2150. : 55 10 105951. : e0133453. : 149 139 51 38–44. : 259–276. : 103122. : 385 143 77 857–866. : 63 683–690. : 109842. : 364–374. : Posted on Authorea 2 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159373163.39100261 — This a preprint and has not been peer reviewed. Data may be preliminary. h ucinlatvt,culn ffiinyadsrcua raiaino amla O1APsynthase. ATP FOF1 regulates mammalian CAMP (2016). of S. organization Papa, structural and P., and Lattanzio, efficiency A., coupling Signorile, activity, A., functional Santeramo, the L., Micelli, De, Rheumatol. evaluation D. Arthritis An Rasmo, therapy. (2015). tocilizumab al. during et events J.M., cardiovascular Bathon, adverse aggregation J.T., major 372–380. Giles, platelet for D., factors human Musselman, risk M., causes of Klearman, (paf) Med. A., Pavlov, Leukot. factor V.U., Prostaglandins, activating Rao, modulation. Platelet membrane of (1982). mechanism J.G. the White, through and autoimmune in G.H.R., target Rao, therapeutic as pathway Immunol. cAMP Front. The diseases. (2016). inflammatory K. Anti-inflammatory Steinbrink, and and (2018). C., placebo- al. Becker, randomised, V.K., et 16-week, Raker, N., a chronic Med. (ROBERT): Bagul, Respir. disease D., of pulmonary Lancet Biondini, treatment obstructive trial. F., chronic controlled the Pedersen, in for roflumilast S., of Baraldo, inhibitor effects H., 4 Watz, K.F., phosphodiesterase Rabe, a Pharmacol. J. roflumilast, Br. Chem. on disease. Med. pulmonary Update Prog. obstructive Field. (2011). Current the K.F. of Review Rabe, A - Inhibitors PDE4 2 (2009). 47 K.H. Immunol. Banner, Rev. and Nat. N.J., inflammation. Press, of regulators Specific proteases: airway serine 6 in Neutrophil Biol. dexamethasone (2006). Mol. of C.T.N. Cell effect Pham, Roflumilast Respir. antiinflammatory (2017). J. al. the Am. et enhances cells. B.G., muscle on Oliver, formoterol F.S.-M., smooth focus with Tang, combination D., infections: Xenaki, in viral G., N-oxide and Baehring, M.M., Macrolides non- 106053. Rahman, (2020). Agents B.S., completely Antimicrob. F. Patel, it J. Scaglione, Int. and is pathology. A., COVID-19 infection: in Romandini, Covid-19 azithromycin M., in Lauriola, A., use platelet- Pani, Lopinavir/ritonavir stimulates Infect. (2020). Endothelin Immunol. O.T. Microbiol. (1995). J. Owa, beneficial? M.S. and Hepatology Olson, A.B., cells. and kupffer Owa, rat S.A.K., cultured Harvey, by synthesis C.R., factor Ther. activating Targets Gandhi, Early age- Obes. involve (2019). S.B., Syndr. overweight/obesity al. Metab. Mustafa, and Diabetes, et study. prediabetes P.E., exploratory with Martinez, an adults A.M., of in 743. loss–results Gharib, sensitivity mass S.-J., insulin fat Park, on associated R., roflumilast Madan, of S.D., effects role MacDonald, Pathophysiological adults. disease: I.M., bowel ill Muo, inflammatory Dis. critically in Bowel and signaling in Inflamm. Il-6 relevance. X., sepsis (2007). clinical Nuvials, M.F. of and Neurath, N.G., diagnosis and J., Oleas, the Mudter, Montero for concentration M., Rev. interleukin-6 Syst. Figuls, Database Plasma I Roqu´e Dis. Cochrane (2019). I., Pulm. J. Arevalo-Rodriguez, Obstr. Zamora, D., Chronic transition J. Franco, mesenchymal COPD Molano to increases epithelial vitro. Simvastatin in smoke-induced (2015c). cells cigarette al. epithelial inhibit et 327–338. bronchial H., to improves Tenor, human N-oxide J., well-differentiated Roflumilast Aparicio, roflumilast in E., (2015b). of Artigues, ability A., al. Serrano, the et Respir. T., Peiro, X., agonist. J., 3 Qian, Milara, receptor J., like toll Freire, with C., stimulated cells Sanz, Res. epithelial B., bronchial COPD Ballester, resistance A., corticosteroid Morell, J., Milara, 541–550. : 37–74. : 16 12. : 4 CD011811. : 6 827–836. : 13 7 123. : 1016–1023. : 163 56 20 53–67. : 532–538. : 21 545–553. : 9 459–472. : 12 12 67 : : : Posted on Authorea 2 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159373163.39100261 — This a preprint and has not been peer reviewed. Data may be preliminary. tri-vru oseodtetdPtet ihAoi sha m .Rsi.Cl o.Biol. disease. vascular and Mol. dysfunction vascular Cell in cytokines Inflammatory Pharmacol. Respir. (2009). Biochem. R.A. J. from et Khalil, Biopsies and L.N.A., A.H., Am. in Willems, Sprague, Epithelium C.R., Airway Asthma. in Atopic Apap, (NEP) with A.C., Endopeptidase Patients 549–556. Roldaan, Neutral Nonsteroid-treated Van, as of versus diarrhoea Expression H.C.J. induced Steroid- Enhanced Klink, SARS-CoV-2 Van, (1997). (2020). J.H.J.M. al. al. Krieken, et J., J.K., Gut Xia, Sont, J., COVID-19. Zhang, with Y.L., patient Pediatr. Chu, in J. X.L., symptom Indian Shi, onset P., (COVID-19). Liu, Disease-2019 Il). Tocilizumab-induced Y., Coronavirus (Northfield. Song, of (2020). Review Med. R. A Clin. Singh, (2020). endopeptidase arthritis. and T. Biol. rheumatoid neutral Singhal, e T., with of Medicas patient Rajakulenthiran, mechanisms a Pesqui. J., in Bras. natriuretic Moorcroft, fibrosis Rev. The R., pulmonary Res. Amarasena, Biol. (1994). S., Sci. Silva, Med. O. roflumilast J. Med. Iimura, Brazilian of J. and rats. Effect in N., Ir. inhibitor (2018). Ura, meta-analysis. W.-F. K., and Lu, Shimamoto, review and systematic Z.-X., a Fang, Q., disease: Yang, 731–738. pulmonary W.-Y., obstructive Chen, chronic (2001). X.-D., on al. Lv, Res. et L.-F., Surg. L.L., Shen, J. Reznikov, interleukin-10. C.H., and of Selzman, independent endothelium, E.J., and Inflammation, Pulido, level factor necrosis (2008). D.D., tumor der Bensard, of Suppression van R.C., McIntyre, T. B.D., Poll, Shames, Biol. and Leukoc. M., J. sepsis. Levi, in (2005). W.J., coagulation al. Wiersinga, et M., C., reacti- Schouten, Schmid-Wirlitsch, asthmatic Immunol. S., allergen-induced attenuates Clin. Leichtl, inhibitor, Allergy L., 4 J. Venter, phosphodiesterase ons. Z., once-daily Williams, N- oral, an K., of Roflumilast, Strydom, Mechanisms van, Molecular Biol. E. Cell. (2013). Schalkwyk, Mol. Y. Dispensable. Kanaho, Neu- Is Mouse and D in Y., Phospholipase Degranulation Funakoshi, trophils: and M., Generation Sakamoto, Superoxide T., Formyl-Methionyl-Leucyl-Phenylalanine-Induced microvascular Hongu, and T., molecules Roflu- Sato, adhesion (2007). al. of et Pharmacol. expression J. B., interactions, Br. Burgbacher, cell permeability. E., Cerd´a-Nicol´as, leukocyte-endothelial Schatton, M.A., Assoc. Asso- inhibits M., Taha, Med. milast J., (2020). Am. Cortijo, al. with J. M.J., Patients et - Sanz, in JAMA J., Mortality Tesoriero, State. In-Hospital York J., with New Kumar, Azithromycin in or L.A., COVID-19 Hydroxychloroquine Wilberschied, with T., Treatment of Udo, ciation E.M., pulmonary obstructive Dufort, (2020). chronic E.S., in Rosenberg, al. inhibitors Med. phosphodiesterase-4 et Intern. of G., J. Role Korean Med. (2020). Monneret, D.K. disease. Respir. C.S., M. Kim, Lancet. and Deutschman, during C.K., sepsis. regulation T., Rhee, from immune Daix, learned in lessons B., IL-10 COVID-19: Francois, for of S.C., Immunotherapies role Brakenridge, The K.E., Remy, (2011). A. Immunol. Mucosal O’garra, Dis. infection. and Pulmon. tuberculosis P.J., Obstruct. Murray, Chron. P.S., J. Redford, Int. COPD. in Receptor Sensitivity 125–134. Glucocorticoid Dexamethasone (2020). : Restore R.C. Reddy, to and Ability A., milast’s Banno, S.P., Lakshmi, A.T., Reddy, Bioenerg. - Acta Biophys. Biochim. 78 539–552. : 116 35 152 276–283. : 292–298. : 1857 α 481–492. : 83 rdcinb APi ua ooye:Dsoito ihmRNA with Dissociation monocytes: human in cAMP by production 536–545. : 4 350–358. : 261–270. : 69 1143–1144. : 21 99 187–193. : 33 136–145. : 27 1965–1973. : 20 α s57–s57. : eitsRoflu- Mediates 87 281–286. : 187 16 15 : : Posted on Authorea 2 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159373163.39100261 — This a preprint and has not been peer reviewed. Data may be preliminary. ffc ftepopoiseae4ihbtrrflmls nguoemtbls nptet ihtreatment- with Metab. patients Endocrinol. in Clin. metabolism J. glucose mellitus. on diabetes 2 roflumilast type inhibitor diagnosed 4 newly phosphodiesterase naive, the of I Effect Dermatol. Angiotensin Bredenbr Invest. (1984). J. E.F.M., L.B. proteinases. Wouters, Schwartz, chymotryptic and Respir. rat C.E., and J. Kaempfer, human G.S., by Am. Lazarus, conversion N.B., disease. Schechter, Decreased B.U., pulmonary (2011). Wintroub, obstructive al. chronic et in M.R., Med. Zamora, Care remodeling C.D., vascular Crit. Cool, Pharma- pulmonary Z.L., Loomis, Clin. and C.A., J. neprilysin Wehling, E.J., Br. P-450A Buesing, dirithromycin. cytochrome M.J., Wick, and with azithromycin interactions clarithromycin, drug on relevant focused clinically col. update Induced An Growth - Transforming 3A4: Macrolide (CYP) of Stimulation (2000). J.F. One Westphal, (2016). PLoS S.A. ET-1. of potential Jimenez, Effect as and Profibrotic Novel inhibitors F.A., Mendoza, phosphodiesterase nucleotide Z., Factor- cyclic Li, P.J., Selective Toxicol. Wermuth, Pharmacol. (1977). Rev. action Annu. W.N. anti-inflammatory Res. Impaired agents. Hait, Respir. therapeutic (2016). and asthma. al. steroid-resistant B., et with Q., Weiss, patients Yang, from Y., Feng, neutrophil Y., in Chen, glucocorticoid glucose- X., Diabetologia of The Wu, P., mice. (2012). Gao, db/db M., al. in Wang, et roflumilast-N-oxide D., and Relat. Knaack, roflumilast A., inhibitors 2779–2788. Scler. Dieckmann, PDE4 : G., the Mult. Hanauer, of A., effects COVID-19. Heuser, lowering in N., Kaessner, (2020). groups S., high-risk Vollert, al. Rethinking et (2020). A.S., M. Zinkernagel, Levy, Disord. R., and Lancet Andermatt, A., COVID-19. M., Vishnevetsky, in Haberecker, endotheliitis P., and infection Steiger, cell A.J., Endothelial Flammer, Z., leukocytes inhibits Roflumilast Varga, polymorphonuclear Haemost. (2016). of Thromb. al. functions et J. prothrombotic N., monocytes. Martelli, the A., and prevents Piccoli, and G., Dell’Elba, interactions Di, leukocyte–platelet A. Santo, C., roflumilast Amore, inhibitors L., Totani, PDE4 (2009). TGF- al. of et S., inhibition Physiol. Kawasaki, K., PGE2 Mol. Kamio, augment H., rolipram Sugiura, atopic X., and and and Wang, normal X., theophylline Liu, from of S., eosinophils Effects Togo, human (1996). of J.K. Pharmacol. chemotaxis Shute, J. and Br. synthesis and (LTC4) subjects. C., C4 Schudt, leukotriene A M.K., on Church, rolipram COVID-19: A., immunity, of Hatzelmann, COVID-19: H., of prognosis trinity Tenor, Immunol. poor The Rev. (2020). a L.F.P. Nat. Ng, intervention. for and and predictor P.A., inflammation MacAry, Rev. R´enia, a L., C.M., Res. as Poh, Clin. M.Z., Tay, Obesity Syndr. Metab. (2020). Diabetes D.L. review. Tahapary, COVID-19: systematic powerful and against A., system Tamara, immune powerful Hypotheses The Med. hope (2020). hypothesis. new H. A potential Akbari, A and 114057. pathways: F., (NEP) Pharmacol. Taghizadeh-Hesary, Neprilysin Biochem. Targeting (Basel). ghost. (2020). Genes COVID-19 El defeat disorders. M.M. Tabaa, to age-related and and El, aging M.M. of Tabaa, basis mitochondrial The (2017). S. Srivastava, 50 285–295. : β 42 -nue nohla-oMsnhmlTasto n iseFboi yEdtei- E-) A (ET-1): Endothelin-1 by Fibrosis Tissue and Transition Endothelial-To-Mesenchymal 1-Induced 102139. : 296 183 L959-69. : 330–340. : kr . ecmn,P,Boe . ae .. abi .. ta.(2012). al. et L.M., Fabbri, K.F., Rabe, M., Brose, P., Teichmann, D., ¨ oker, 118 1727–1735. : 140 109762. : 14 191–204. : 11 e0161988. : β -tmltdfirbat.A.J hso.-Ln Cell. Lung - Physiol. J. Am. fibroblasts. 1-stimulated 20 22 17 363–374. : 441–477. : 14 655–659. : 395 1417–1418. : 97 83 E1720–E1725. : 336–339. : 17 1–9. : 8 398. : 55 Posted on Authorea 2 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159373163.39100261 — This a preprint and has not been peer reviewed. Data may be preliminary. oeEffect L nM 1–1000 10 Dose infection. COVID-19 and smoking Tobacco (2020). F.T. 1: Table Leone, 1451–1454. and traps Med. G., extracellular Neutrophil Respir. Richards, Lancet al. van, et R.N. H., Shi, Zyl-Smit, J.A., MedRxiv. Madison, COVID-19. K., in Gockman, Immunol. thrombosis S., Yalavarthi, and Microbiol. mortality M., Top. for Zuo, factors Curr. Y., risk Lancet Zuo, and replicase. study. course coronavirus of Clinical cohort The damage retrospective (2020). the (2005). a al. of J. China: et understanding Ziebuhr, Wuhan, Z., in New Liu, COVID-19 Y., (2020b). with Liu, inpatients G., al. Fan, adult R., et of Du, J., Pharmacother. T., Yu, Xu, Biomed. F., C., Zhou, system. Xu, respiratory Q., the Li, outside Y., infection Tan, SARS-CoV-2 X., Care Geng, Intensive Y., 2 target. enzyme Zhang, therapeutic Angiotensin-converting potential (2020a). and A.S. mechanisms Slutsky, molecular and Med. receptor: N., SARS-CoV-2 Zhong, a Y., as Li, (ACE2) J.M., neprilysin Penninger, regulate H., Androgens (2008). Zhang, critically C.J. Pike, of and reducing outcomes M., in and Ramsden, Role E.R., course Rosario, expression: observational Clinical V., retrospective, (2020). T.V. Nguyen, single-centered, al. M., Yao, a et H., China: Wuhan, Liu, Med. in J., Respir. pneumonia Xia, Lancet study. H., SARS-CoV-2 of Shu, with characteristics J., patients Transcriptomic Xu, ill (2020). Y., Yu, al. X., et Microbes Yang, Emerg. A., patients. Jiang, COVID-19 in M., cells Guo, mononuclear D., blood Infect. Wang, peripheral L., and gene fluid neprilysin Cao, lavage the bronchoalveolar Y., of Liu, regulation Estrogen Y., Neurosci. (2009). Xiong, of J. Mol. Huang, Findings J. and element. Ocular J.J., hormone-responsive of Zhang, a Y.M., Characteristics through Liu, (2020). Ophthalmol. L., al. Sun, JAMA Z.M., et China. Xiao, L., Province, Liang, Hubei in X., (COVID-19) Qu, 2019 Q., 575–578. Disease Liu, Coronavirus C., with Luo, Patients F., Duan, P., Wu, -9 10 – 46 9 -6 761–770. : 586–590. : utpepamclgclpoete froflumilast of properties pharmacological Multiple niiinof Inhibition M 1 MNs and PMNs of functions prothrombotic the of Inhibition function neutrophils 8 β- 475–481. : mli ees .Neurochem. J. levels. amyloid cinMdlReferences MNs in expression factor tissue suppressed and NETs of release Model the Inhibited MMP-9 and NE MPO, of release the Suppressed action of mechanisms molecular Main 23 39 . 22–26. : 105 2477–2488. : n PMNs and PLTs Human HUVECs to adhesion Neutrophils 127 287 110195. : 57–94. : 395 2016) al., et (Totani 2005) al., et (Jones 1054–1062. : 138 : Posted on Authorea 2 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159373163.39100261 — This a preprint and has not been peer reviewed. Data may be preliminary. 10 solution methylcellulose 4% glycol polyethylene 2.5% in suspended mg/kg/d, 5 DMSO in dissolved μολ/Λ 1 μ ανδ μολ/Λ 100 ν ανδ 10, 1, body mg/kg 1.0 – 0.3 Anti- ug/d 500 Effect Anti- ug/d 500 Dose -9 10 – -6 Anti- M effects proliferative remodeling airway of Inhibition remodeling airway of Inhibition sepsis polymicrobial of Prevention effects inflammatory effects inflammatory MMP-9) and (MMP-2 of production and proliferation cell Attenuated epithelium airway of thickening and cells, inflammatory chronic of accumulation the Reduced remodeling airway thereby, and deposition protein ECM Inhibited ΣΤΑΤ3 ανδ ΜΑΠΚ π38 ΝΦ-κΒ, συππρεσσεδ ανδ ΤΝΦ-αλπηα ανδ ΙΛ-6 μαινλψ ςψτοκινες ινφλαμματορψ προ- οφ εξπρεσσιον ινηιβιτεδ λοαδ, βαςτεριαλ Reduced ECP and neutrophils eosinophils, sputum allergen-induced Inhibited References mediators inflammatory decreased and COPD with associated inflammation Model systemic the targets that enzyme 4 phosphodiesterase- Inhibited action of mechanisms molecular Main 24 sepsis puncture-induced and ligation cecal with Mice patients COPD PASMCs human Distal asthma model mice BALB/c cells ASM Human patients asthmatic Allergic of chronic Fn ta. 2017) al., et (Feng 2015) al., et (Martinez 2006) al., et (Growcott 2003) al., et (Kumar 2006) al., et (Burgess 2016) al., et Bateman 2011; al., et (Gauvreau Posted on Authorea 2 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159373163.39100261 — This a preprint and has not been peer reviewed. Data may be preliminary. cytes, OVA; oxidase, kinase, protein Mitogen-activated protein, mellitus, Diabetes ASM; Anti- ug/d 500 10 Effect fibrotic Anti- mg/kg/day 5 Dose -6 10 – PLTs; iwysot muscle smooth Airway Ovalbumin NE; GLP-1; -7 Anti-fibrotic M etohlelastase, Neutrophil Platelets lcgnlk peptide-1, like glucagon PASMCs; , DMSO; STAT3; , effects hyperglycemic effects effects iehlsulfoxide, Dimethyl COPD; , umnr reysot ucecells muscle smooth artery Pulmonary inltasue n ciao ftasrpin3 transcription of activator and transducer Signal MMP-9 NETs; hoi btutv umnr disease pulmonary obstructive Chronic etohletaellrtraps, extracellular Neutrophil arxmetalloproteinase-9, Matrix ; HUVECs; GLP-1, intestinal of secretion Enhanced TGF-beta1 by stimulated fibroblasts of activity profibrotic the Antagonized activation) synthesis collagen and References response inflammatory strong a equilibrium, oxidative the in alterations Model (like fibrosis pulmonary to related effects metabolic Antagonized action of mechanisms molecular Main effect insulinotropic potent with incretin ECM; 25 a ua miia enedteilcells, endothelial vein umbilical Human main xrclua matrix Extracellular nmice in Fibrosis Induced Bleomycin- ellines cell fibroblast lung human Adult yeII type DM diagnosed newly with patients yr. 35–70 PMNs; , MN; ΝΦ-κΒ· Monocytes CS; , ECP; , oyopoula leuko- Polymorphonuclear ula atrkpaB factor-kappa Nuclear iaet smoke Cigarette oiohlcationic Eosinophil MPO; , 2015a) al., et (Milara Tg ta. 2009) al., et (Togo 2012) al., et (Wouters Myeloper- MAPK; DM; , , Posted on Authorea 2 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159373163.39100261 — This a preprint and has not been peer reviewed. Data may be preliminary. 26 Posted on Authorea 2 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159373163.39100261 — This a preprint and has not been peer reviewed. Data may be preliminary. 27 Posted on Authorea 2 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159373163.39100261 — This a preprint and has not been peer reviewed. Data may be preliminary. treating-covid-19 insights-into-neprilysin-nep-dependent-pharmacotherapeutic-role-of-roflumilast-in- Table.docx file Hosted vial at available https://authorea.com/users/339038/articles/465335-new-putative- 28