Advertisement

RNAi therapeutic strategies for acute respiratory distress syndrome

      Acute respiratory distress syndrome (ARDS), replacing the clinical term acute lung injury, involves serious pathophysiological lung changes that arise from a variety of pulmonary and nonpulmonary injuries and currently has no pharmacological therapeutics. RNA interference (RNAi) has the potential to generate therapeutic effects that would increase patient survival rates from this condition. It is the purpose of this review to discuss potential targets in treating ARDS with RNAi strategies, as well as to outline the challenges of oligonucleotide delivery to the lung and tactics to circumvent these delivery barriers.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      REFERENCES

        • Ranieri VM
        • Rubenfeld GD
        • Thompson BT
        • et al.
        • ARDS Definition Task Force
        Acute respiratory distress syndrome: the Berlin Definition.
        JAMA. 2012; 307: 2526-2533
        • Ragaller M
        • Richter T
        Acute lung injury and acute respiratory distress syndrome.
        J Emerg Trauma Shock. 2010; 3: 43-51
        • Pan C
        • Liu L
        • Xie JF
        • Qiu HB
        Acute respiratory distress syndrome: challenge for diagnosis and therapy.
        Chin Med J. 2018; 131: 1220-1224
        • Bellani G
        • Laffey JG
        • Pham T
        • et al.
        Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries.
        JAMA. 2016; 315: 788-800
        • Herridge MS
        • Cheung AM
        • Tansey CM
        • et al.
        One-year outcomes in survivors of the acute respiratory distress syndrome.
        N Engl J Med. 2003; 348: 683-693
        • Cheung AM
        • Tansey CM
        • Tomlinson G
        • et al.
        Two-year outcomes, health care use, and costs of survivors of acute respiratory distress syndrome.
        Am J Respir Crit Care Med. 2006; 174: 538-544
        • Puybasset L
        • Cluzel P
        • Chao N
        • et al.
        A computed tomography scan assessment of regional lung volume in acute lung injury.
        Am J Respir Crit Care Med. 1998; 158: 1644-1655
        • Desai SR
        • Wells AU
        • Rubens MB
        • Evans TW
        • Hansell DM
        Acute respiratory distress syndrome: CT abnormalities at long-term follow-up.
        Radiology. 1999; 210: 29-35
        • Desai SR
        • Wells AU
        • Suntharalingam G
        • et al.
        Acute respiratory distress syndrome caused by pulmonary and extrapulmonary injury: a comparative CT study.
        Radiology. 2001; 218: 689-693
        • Wheeler AP
        • Bernard GR
        Acute lung injury and the acute respiratory distress syndrome: a clinical review.
        Lancet. 2007; 369: 1553-1564
        • Perl M
        • Chung C-S
        • Lomas-Neira J
        • et al.
        Silencing of fas, but not Caspase-8, in lung epithelial cells ameliorates pulmonary apoptosis, inflammation, and neutrophil influx after hemorrhagic shock and sepsis.
        Am J Pathol. 2005; 167: 1545-1559
        • Johnson ER
        • Matthay MA
        Acute lung injury: epidemiology, pathogenesis, and treatment.
        J Aerosol Med Pulm Drug Deliv. 2010; 23: 243-252
        • Hudson LD
        • Steinberg KP
        Epidemiology of acute lung injury and ARDS.
        Chest. 1999; 116: 74S-82S
        • Ware LB
        • Matthay MA
        The acute respiratory distress syndrome.
        N Engl J Med. 2000; 342: 1334-1349
        • Orfanos SE
        • Mavrommati I
        • Korovesi I
        • Roussos C
        Pulmonary endothelium in acute lung injury: from basic science to the critically ill.
        Intensive Care Med. 2004; 30: 1702-1714
        • Matthay MA
        • Zimmerman GA.
        Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management.
        Am J Respir Cell Mol Biol. 2005; 33: 319-327
        • Bhattacharya J
        • Matthay MA.
        Regulation and repair of the alveolar-capillary barrier in acute lung injury.
        Annu Rev Physiol. 2013; 75: 593-615
        • Calfee CS
        • Eisner MD
        • Ware LB
        • et al.
        Trauma-associated lung injury differs clinically and biologically from acute lung injury due to other clinical disorders*.
        Crit Care Med. 2007; 35: 2243-2250
        • Glas GJ
        • Van Der Sluijs KF
        • Schultz MJ
        • et al.
        Bronchoalveolar hemostasis in lung injury and acute respiratory distress syndrome.
        J Thromb Haemost. 2013; 11: 17-25
        • Perl M
        • Chung CS
        • Perl U
        • et al.
        Fas-induced pulmonary apoptosis and inflammation during indirect acute lung injury.
        Am J Respir Crit Care Med. 2007; 176: 591-601
        • Ayala A
        • Chung C-S
        • Lomas JL
        • et al.
        Shock-induced neutrophil mediated priming for acute lung injury in mice.
        Am J Pathol. 2002; 161: 2283-2294
        • Matute-Bello G
        • Liles WC
        • Radella F
        • Steinberg KP
        • Ruzinski JT
        • Hudson LD
        • MArtin TR
        Modulation of neutrophil apoptosis by granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor during the course of acute respiratory distress syndrome.
        Crit Care Med. 2000; 28: 1-7
        • Aggarwal A
        • Baker CS
        • evans TW
        • Haslam PL
        G-CSF and IL-8 but not GM-CSF correlate with severity of pulmonary neutrophilia in acute respiratory distress syndrome.
        Eur Respir J. 2000; 15: 895-901
        • Teder P
        • Vandivier RW
        • Jiang D
        • et al.
        Resolution of lung inflammation by CD44.
        Science. 2002; 296: 155-158
        • Fadok VA
        • Bratton DL
        • Konowal A
        • et al.
        Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF.
        J Clin Invest. 1998; 101: 890-898
        • Kitamura Y
        • Hashimoto S
        • Mizuta N
        • et al.
        Fas/FasL-dependent apoptosis of alveolar cells after lipopolysaccharide-induced lung injury in mice.
        Am J Respir Crit Care Med. 2001; 163: 762-769
        • Menezes SL
        • Bozza PT
        • Neto HC
        • et al.
        Pulmonary and extrapulmonary acute lung injury: inflammatory and ultrastructural analyses.
        J Appl Physiol (1985). 2005; 98: 1777-1783
        • Maniatis NA
        • Kotanidou A
        • Catravas JD
        • Orfanos SE
        Endothelial pathomechanisms in acute lung injury.
        Vascul Pharmacol. 2008; 49: 119-133
        • Bachofen H
        • Bachofen M
        • Weibel ER
        Ultrastructural aspects of pulmonary edema.
        J Thorac Imaging. 1988; 3: 1-7
        • Zhao YY
        • Gao XP
        • Zhao YD
        • et al.
        Endothelial cell-restricted disruption of FoxM1 impairs endothelial repair following LPS-induced vascular injury.
        J Clin Invest. 2006; 116: 2333-2343
        • Aird WC.
        Phenotypic heterogeneity of the endothelium: II. Representative vascular beds.
        Circ Res. 2007; 100: 174-190
        • Mehta D
        • Malik AB.
        Signaling mechanisms regulating endothelial permeability.
        Physiol Rev. 2006; 86: 279-367
        • Georgieva GS
        • Kurata S
        • Ikeda S
        • et al.
        Nonischemic lung injury by mediators from unilateral ischemic reperfused lung: ameliorating effect of tumor necrosis factor-alpha-converting enzyme inhibitor.
        Shock. 2007; 27: 84-90
        • Angelini DJ
        • Hyun SW
        • Grigoryev DN
        • et al.
        TNF-alpha increases tyrosine phosphorylation of vascular endothelial cadherin and opens the paracellular pathway through fyn activation in human lung endothelia.
        Am J Physiol Lung Cell Mol Physiol. 2006; 291: L1232-L1245
        • Reutershan J
        • Stockton R
        • Zarbock A
        • et al.
        Blocking p21-activated kinase reduces lipopolysaccharide-induced acute lung injury by preventing polymorphonuclear leukocyte infiltration.
        Am J Respir Crit Care Med. 2007; 175: 1027-1035
        • Alvarez DF
        • King JA
        • Weber D
        • et al.
        Transient receptor potential vanilloid 4-mediated disruption of the alveolar septal barrier: a novel mechanism of acute lung injury.
        Circ Res. 2006; 99: 988-995
        • Maniatis NA
        • Orfanos SE.
        The endothelium in acute lung injury/acute respiratory distress syndrome.
        Curr Opin Crit Care. 2008; 14: 22-30
        • Gao XP
        • Zhu X
        • Fu J
        • et al.
        Blockade of class IA phosphoinositide 3-kinase in neutrophils prevents NADPH oxidase activation- and adhesion-dependent inflammation.
        J Biol Chem. 2007; 282: 6116-6125
        • Martin TR
        • Nakamura M
        • Matute-Bello G
        The role of apoptosis in acute lung injury.
        Crit Care Med. 2003; 31: S184-S188
        • Perl M
        • Chung CS
        • Perl U
        • et al.
        Therapeutic accessibility of caspase-mediated cell death as a key pathomechanism in indirect acute lung injury.
        Crit Care Med. 2010; 38: 1179-1186
        • Vazquez de Lara L
        • Becerril C
        • Montano M
        • et al.
        Surfactant components modulate fibroblast apoptosis and type I collagen and collagenase-1 expression.
        Am J Physiol Lung Cell Mol Physiol. 2000; 279: L950-L957
        • White MK
        • Baireddy V
        • Strayer DS
        Natural protection from apoptosis by surfactant protein A in type II pneumocytes.
        Exp Cell Res. 2001; 263: 183-192
        • Greene KE
        • Wright JR
        • Steinberg KP
        • et al.
        Serial changes in surfactant-associated proteins in lung and serum before and after onset of ARDS.
        Am J Respir Crit Care Med. 1999; 160: 1843-1850
        • Tang PS
        • Mura M
        • Seth R
        • Liu M
        Acute lung injury and cell death: how many ways can cells die?.
        Am J Physiol Lung Cell Mol Physiol. 2008; 294: L632-L641
        • Fine A
        • Anderson NL
        • Rothstein TL
        • Williams MC
        • Gochuico BR
        Fas expression in pulmonary alveolar type II cells.
        Am J Physiol. 1997; 273: L64-L71
        • Hamann KJ
        • Dorscheid DR
        • Ko FD
        • et al.
        Expression of Fas (CD95) and FasL (CD95L) in human airway epithelium.
        Am J Respir Cell Mol Biol. 1998; 19: 537-542
        • Wen LPM
        • Madani K
        • Fahrni JA
        • Duncan SR
        • Rosen GD
        Dexamethasone inhibits lung epithelial cell apoptosis induced by IFN-gamma and Fas.
        Am J Physiol. 1997; 273: L921-L9L9
        • Martin TR
        • Hagimoto N
        • Nakamura M
        • Matute-Bello G
        Apoptosis and epithelial injury in the lungs.
        Proc Am Thorac Soc. 2005; 2: 214-220
        • Matthay MA
        • Zemans RL
        • Zimmerman GA
        • et al.
        Acute respiratory distress syndrome.
        Nature Rev Dis Primers. 2019; 5: 18
        • Agrawal A
        • Matthay MA
        • Kangelaris KN
        • et al.
        Plasma angiopoietin-2 predicts the onset of acute lung injury in critically ill patients.
        Am J Respir Crit Care Med. 2013; 187: 736-742
        • Gajic O
        • Dabbagh O
        • Park PK
        • et al.
        Early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study.
        Am J Respir Crit Care Med. 2011; 183: 462-470
        • Levitt JE
        • Calfee CS
        • Goldstein BA
        • Vojnik R
        • Matthay MA
        Early acute lung injury: criteria for identifying lung injury prior to the need for positive pressure ventilation*.
        Crit Care Med. 2013; 41: 1929-1937
        • Moss M.
        The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults.
        JAMA. 1996; 275: 50-54
        • Moss M
        • Burnham EL
        Chronic alcohol abuse, acute respiratory distress syndrome, and multiple organ dysfunction.
        Crit Care Med. 2003; 31: S207-SS12
        • Calfee CS
        • Matthay MA
        • Eisner MD
        • et al.
        Active and passive cigarette smoking and acute lung injury after severe blunt trauma.
        Am J Respir Crit Care Med. 2011; 183: 1660-1665
        • Calfee CS
        • Matthay MA
        • Kangelaris KN
        • et al.
        Cigarette smoke exposure and the acute respiratory distress syndrome*.
        Crit Care Med. 2015; 43: 1790-1797
        • Ware LB
        • Zhao Z
        • Koyama T
        • et al.
        Long-term ozone exposure increases the risk of developing the acute respiratory distress syndrome.
        Am J Respir Crit Care Med. 2016; 193: 1143-1150
        • Reilly JP
        • Zhao Z
        • Shashaty MGS
        • et al.
        Low to moderate air pollutant exposure and acute respiratory distress syndrome after severe trauma.
        Am J Respir Crit Care Med. 2019; 199: 62-70
        • Ferguson ND
        • Frutos-Vivar F
        • Esteban A
        • et al.
        Clinical risk conditions for acute lung injury in the intensive care unit and hospital ward: a prospective observational study.
        Critical Care. 2007; 11: R96
        • Cortegiani A
        • Madotto F
        • Gregoretti C
        • et al.
        Immunocompromised patients with acute respiratory distress syndrome: secondary analysis of the LUNG SAFE database.
        Crit Care. 2018; 22: 157
        • Sprung CL
        • Caralis PV
        • Marcial EH
        • et al.
        The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study.
        N Engl J Med. 1984; 311: 1137-1143
        • Weigelt JA.
        Early steroid therapy for respiratory failure.
        Arch Surg. 1985; 120: 536-540
        • Bone RC
        • Fisher CJ
        • Clemmer TP
        • Slotman GJ
        • Metz CA
        Early methylprednisolone treatment for septic syndrome and the adult respiratory distress syndrome.
        Chest. 1987; 92: 1032-1036
        • Luce JM
        • Montgomery AB
        • Marks JD
        • et al.
        Ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock.
        Am Rev Respir Dis. 1988; 138: 62-68
        • Zapol WM.
        Extracorporeal membrane oxygenation in severe acute respiratory failure.
        JAMA. 1979; 242: 2193-2196
        • Gattinoni L.
        Low-frequency positive-pressure ventilation with extracorporeal CO2 removal in severe acute respiratory failure.
        JAMA. 1986; 256: 881-886
        • Brunet F
        • Belghith M
        • Mira J-P
        • et al.
        Extracorporeal carbon dioxide removal and low-frequency positive-pressure ventilation.
        Chest. 1993; 104: 889-898
        • Morris AH
        • Wallace CJ
        • Menlove RL
        • et al.
        Randomized clinical trial of pressure-controlled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome.
        Am J Respir Crit Care Med. 1994; 149: 295-305
        • Adhikari N
        • Granton JT.
        Inhaled nitric oxide for acute lung injury: no place for NO?.
        JAMA. 2004; 291: 1629-1631
        • Taylor RW
        • Zimmerman JL
        • Dellinger RP
        • et al.
        Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial.
        JAMA. 2004; 291: 1603-1609
        • Troncy E
        • Collet JP
        • Shapiro S
        • et al.
        Inhaled nitric oxide in acute respiratory distress syndrome: a pilot randomized controlled study.
        Am J Respir Crit Care Med. 1998; 157: 1483-1488
        • Kristen AV
        • Ajroud-Driss S
        • Conceição I
        • et al.
        Patisiran, an RNAi therapeutic for the treatment of hereditary transthyretin-mediated amyloidosis.
        Neurodegenerative Dis Manag. 2019; 9: 5-23
        • Ragni MV
        • Georgiev P
        • Mant T
        • et al.
        Fitusiran, an investigational RNAi therapeutic targeting antithrombin for the treatment of Hemophilia: updated results from a phase 1 and phase 1/2 extension study in patients without inhibitors.
        Blood. 2016; 128: 2572
        • Kosmas CE
        • Muñoz Estrella A
        • Sourlas A
        • et al.
        Inclisiran: a new promising agent in the management of hypercholesterolemia.
        Diseases. 2018; 6: 63
        • Balwani M
        • Gouya L
        • Rees D
        • et al.
        GS-14-ENVISION, a phase 3 study to evaluate efficacy and safety of givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1, in acute hepatic porphyria patients.
        J Hepatol. 2019; 70: e81-ee2
        • Frishberg Y
        • Deschenes G
        • Cochat P
        • et al.
        Safety and efficacy study of lumasiran, an investigational rna interference (RNAi) therapeutic, in adult and pediatric patients with primary hyperoxaluria type 1 (PH1).
        J Urol. 2019; 201: e174-e389
        • Fitzgerald K
        • White S
        • Borodovsky A
        • et al.
        A highly durable RNAi therapeutic inhibitor of PCSK9.
        N Engl J Med. 2017; 376: 41-51
        • Fire A
        • Xu S
        • Montgomery MK
        • et al.
        Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans.
        Nature. 1998; 391: 806-811
        • Yu JY
        • DeRuiter SL
        • Turner DL
        RNA interference by expression of short-interfering RNAs and hairpin RNAs in mammalian cells.
        Proc Natl Acad Sci U S A. 2002; 99: 6047-6052
        • Meister G
        • Tuschl T.
        Mechanisms of gene silencing by double-stranded RNA.
        Nature. 2004; 431: 343-349
        • Lippman Z
        • Martienssen R.
        The role of RNA interference in heterochromatic silencing.
        Nature. 2004; 431: 364-370
        • Soutschek J
        • Akinc A
        • Bramlage B
        • et al.
        Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs.
        Nature. 2004; 432: 173-178
        • Carthew RW
        • Sontheimer EJ.
        Origins and mechanisms of miRNAs and siRNAs.
        Cell. 2009; 136: 642-655
        • Geoghegan JC
        • Gilmore BL
        • Davidson BL
        Gene silencing mediated by siRNA-binding fusion proteins is attenuated by double-stranded RNA-binding domain structure.
        Mol Ther Nucleic Acids. 2012; 1: e53
        • Wilson RC
        • Doudna JA.
        Molecular mechanisms of RNA interference.
        Annu Rev Biophys. 2013; 42: 217-239
        • Dana H
        • Chalbatani GM
        • Mahmoodzadeh H
        • et al.
        Molecular mechanisms and biological functions of siRNA.
        Int J Biomed Sci. 2017; 13: 48-57
        • Qiu Y
        • Lam JK
        • Leung SW
        • Liang W
        Delivery of RNAi therapeutics to the airways-from bench to bedside.
        Molecules. 2016; 21: 1249https://doi.org/10.3390/molecules21091249
        • Sugiyama T
        • Cam H
        • Verdel A
        • Moazed D
        • Grewal SI
        RNA-dependent RNA polymerase is an essential component of a self-enforcing loop coupling heterochromatin assembly to siRNA production.
        Proc Natl Acad Sci U S A. 2005; 102: 152-157
        • Orban TI
        • Izaurralde E
        Decay of mRNAs targeted by RISC requires XRN1, the Ski complex, and the exosome.
        RNA. 2005; 11: 459-469
        • Zheng X
        • Vladau C
        • Zhang X
        • et al.
        A novel in vivo siRNA delivery system specifically targeting dendritic cells and silencing CD40 genes for immunomodulation.
        Blood. 2009; 113: 2646
        • Kabelitz D.
        Expression and function of Toll-like receptors in T lymphocytes.
        Curr Opin Immunol. 2007; 19: 39-45
        • Petterson T
        • Månsson A
        • Riesbeck K
        • Cardell LO
        Nucleotide-binding and oligomerization domain-like receptors and retinoic acid inducible gene-like receptors in human tonsillar T lymphocytes.
        Immunology. 2011; 133: 84-93
        • Weiss B
        • Davidkova G
        • Zhou LW
        Antisense RNA gene therapy for studying and modulating biological processes.
        Cell Mol Life Sci. 1999; 55: 334-358
        • Fernandez-Carneado J
        • Kogan MJ
        • Pujals S
        • Giralt E
        Amphipathic peptides and drug delivery.
        Biopolymers. 2004; 76: 196-203
        • Reynolds A
        • Leake D
        • Boese Q
        • et al.
        Rational siRNA design for RNA interference.
        Nature Biotechnol. 2004; 22: 326-330
        • Oliveira S
        • Storm G
        • Schiffelers RM
        Targeted delivery of siRNA.
        J Biomed Biotechnol. 2006; 2006: 63675
        • Li CX
        • Parker A
        • Menocal E
        • et al.
        Delivery of RNA interference.
        Cell Cycle. 2006; 5: 2103-2109
        • Lundberg P
        • El-Andaloussi S
        • Sutlu T
        • Johansson H
        • Langel U
        Delivery of short interfering RNA using endosomolytic cell-penetrating peptides.
        FASEB J. 2007; 21: 2664-2671
        • Thomas M
        • Lu JJ
        • Chen J
        • Klibanov AM
        Non-viral siRNA delivery to the lung.
        Adv Drug Deliv Rev. 2007; 59: 124-133
        • Moschos SA
        • Williams AE
        • Lindsay MA
        Cell-penetrating-peptide-mediated siRNA lung delivery.
        Biochem Soc Trans. 2007; 35: 807-810
        • Zhang S
        • Zhao B
        • Jiang H
        • Wang B
        • Ma B
        Cationic lipids and polymers mediated vectors for delivery of siRNA.
        J Control Release. 2007; 123: 1-10
        • Martin ME
        • Rice KG.
        Peptide-guided gene delivery.
        AAPS J. 2007; 9: E18-E29
        • Joanne Lomas-Neira C-SC
        • Ayala Alfred
        RNA interference as a potential therapeutic treatment for inflammation associated lung injury.
        International J Clin Exp Med. 2008; 1: 154-160
        • de Fougerolles AR.
        Delivery vehicles for small interfering RNA in vivo.
        Hum Gene Ther. 2008; 19: 125-132
        • Whitehead KA
        • Langer R
        • Anderson DG
        Knocking down barriers: advances in siRNA delivery.
        Nat Rev Drug Discov. 2009; 8: 129-138
        • Oh YK
        • Park TG.
        siRNA delivery systems for cancer treatment.
        Adv Drug Deliv Rev. 2009; 61: 850-862
        • Wu SY
        • McMillan NA.
        Lipidic systems for in vivo siRNA delivery.
        AAPS J. 2009; 11: 639-652
        • Schroeder A
        • Levins CG
        • Cortez C
        • Langer R
        • Anderson DG
        Lipid-based nanotherapeutics for siRNA delivery.
        J Intern Med. 2010; 267: 9-21
        • Wang J
        • Lu Z
        • Wientjes MG
        • Au JL
        Delivery of siRNA therapeutics: barriers and carriers.
        AAPS J. 2010; 12: 492-503
        • Semple SC
        • Akinc A
        • Chen J
        • et al.
        Rational design of cationic lipids for siRNA delivery.
        Nat Biotechnol. 2010; 28: 172-176
        • Lin X
        • Dean DA.
        Gene therapy for ALI/ARDS.
        Crit Care Clin. 2011; 27: 705-718
        • Krebs MD
        • Alsberg E.
        Localized, targeted, and sustained siRNA delivery.
        Chemistry. 2011; 17: 3054-3062
        • Gunther M
        • Lipka J
        • Malek A
        • et al.
        Polyethylenimines for RNAi-mediated gene targeting in vivo and siRNA delivery to the lung.
        Eur J Pharm Biopharm. 2011; 77: 438-449
        • Merkel OM
        • Kissel T.
        Nonviral pulmonary delivery of siRNA.
        Acc Chem Res. 2012; 45: 961-970
        • Lam JK
        • Liang W
        • Chan HK
        Pulmonary delivery of therapeutic siRNA.
        Adv Drug Deliv Rev. 2012; 64: 1-15
        • Hamasaki T
        • Suzuki H
        • Shirohzu H
        • et al.
        Efficacy of a novel class of RNA interference therapeutic agents.
        PLoS One. 2012; 7: e42655
        • Fujita Y
        • Takeshita F
        • Kuwano K
        • Ochiya T
        RNAi therapeutic platforms for lung diseases.
        Pharmaceuticals. 2013; 6: 223-250
        • Taratula O
        • Kuzmov A
        • Shah M
        • Garbuzenko OB
        • Minko T
        Nanostructured lipid carriers as multifunctional nanomedicine platform for pulmonary co-delivery of anticancer drugs and siRNA.
        J Control Release. 2013; 171: 349-357
        • Merkel OM
        • Rubinstein I
        • Kissel T
        siRNA delivery to the lung: what's new?.
        Adv Drug Deliv Rev. 2014; 75: 112-128
        • Shukla RS
        • Qin B
        • Cheng K
        Peptides used in the delivery of small noncoding RNA.
        Mol Pharm. 2014; 11: 3395-3408
        • Li H
        • Tsui TY
        • Ma W
        Intracellular delivery of molecular cargo using cell-penetrating peptides and the combination strategies.
        Int J Mol Sci. 2015; 16: 19518-19536
        • Welch JJ
        • Swanekamp RJ
        • King C
        • Dean DA
        • Nilsson BL
        Functional delivery of siRNA by disulfide-constrained cyclic amphipathic peptides.
        ACS Med Chem Lett. 2016; 7: 584-589
        • Zaki NM
        • Tirelli N.
        Gateways for the intracellular access of nanocarriers: a review of receptor-mediated endocytosis mechanisms and of strategies in receptor targeting.
        Expert Opin Drug Deliv. 2010; 7: 895-913
        • Gilleron J
        • Querbes W
        • Zeigerer A
        • et al.
        Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape.
        Nat Biotechnol. 2013; 31: 638-646
        • Moschos SA
        • Jones SW
        • Perry MM
        • et al.
        Lung delivery studies using siRNA conjugated to TAT(48-60) and penetratin reveal peptide induced reduction in gene expression and induction of innate immunity.
        Bioconjug Chem. 2007; 18: 1450-1459
        • Patrick GL
        An Introduction to Medicinal Chemistry.
        6 ed. United States of America: Oxford University Press, New York, NY2007: 832 (10016)
        • Zheng M
        • Librizzi D
        • Kilic A
        • et al.
        Enhancing in vivo circulation and siRNA delivery with biodegradable polyethylenimine-graft-polycaprolactone-block-poly(ethylene glycol) copolymers.
        Biomaterials. 2012; 33: 6551-6558
        • Emeritus CPHJ
        • Keen SL
        • Larson A
        • et al.
        Integrated principles of zoology.
        McGraw-Hill Education, 2013
        • Ochs M
        • Nyengaard JR
        • Jung A
        • et al.
        The number of alveoli in the human lung.
        Am J Respir Crit Care Med. 2004; 169: 120-124
        • Gartner LP
        • Hiatt JL.
        Color textbook of histology.
        Saunders Elsevier, Philadelphia2007
        • Thornton DJ
        • Rousseau K
        • McGuckin MA
        Structure and function of the polymeric mucins in airways mucus.
        Annu Rev Physiol. 2008; 70: 459-486
        • Fahy JV
        • Dickey BF.
        Airway mucus function and dysfunction.
        N Engl J Med. 2010; 363: 2233-2247
        • Salathe M.
        Regulation of mammalian ciliary beating.
        Annu Rev Physiol. 2007; 69: 401-422
        • Lai SK
        • Wang YY
        • Hanes J
        Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues.
        Adv Drug Deliv Rev. 2009; 61: 158-171
        • Duncan JE
        • Whitsett JA
        • Horowitz AD
        Pulmonary surfactant inhibits cationic liposome-mediated gene delivery to respiratory epithelial cells in vitro.
        Hum Gene Ther. 1997; 8: 431-438
        • De Backer L
        • Braeckmans K
        • Demeester J
        • De Smedt SC
        • Raemdonck K
        The influence of natural pulmonary surfactant on the efficacy of siRNA-loaded dextran nanogels.
        Nanomedicine. 2013; 8: 1625-1638
        • Paranjpe M
        • Muller-Goymann CC.
        Nanoparticle-mediated pulmonary drug delivery: a review.
        Int J Mol Sci. 2014; 15: 5852-5873
        • Sakagami M
        In vivo, in vitro and ex vivo models to assess pulmonary absorption and disposition of inhaled therapeutics for systemic delivery.
        Adv Drug Deliv Rev. 2006; 58: 1030-1060
        • Patton JS
        • Byron PR.
        Inhaling medicines: delivering drugs to the body through the lungs.
        Nat Rev Drug Discov. 2007; 6: 67-74
        • Macintyre NR
        • Silver RM
        • Miller CW
        • Schuler F
        • Coleman RE
        Aerosol delivery in intubated, mechanically ventilated patients.
        Crit Care Med. 1985; 13: 81-84
        • Dhand R.
        Inhalation therapy with metered-dose inhalers and dry powder inhalers in mechanically ventilated patients.
        Respir Care. 2005; 50: 1331-1334
        • Fink JB
        • Dhand R
        • Duarte AG
        • Jenne JW
        • Tobin MJ
        Aerosol delivery from a metered-dose inhaler during mechanical ventilation. An in vitro model.
        Am J Respir Crit Care Med. 1996; 154: 382-387
        • Fink JB
        • Dhand R
        • Grychowski J
        • Fahey PJ
        • Tobin MJ
        Reconciling in vitro and in vivo measurements of aerosol delivery from a metered-dose inhaler during mechanical ventilation and defining efficiency-enhancing factors.
        Am J Respir Crit Care Med. 1999; 159: 63-68
        • Rau JL
        • Dunlevy CL
        • Hill RL
        A comparison of inline MDI actuators for delivery of a beta agonist and a corticosteroid with a mechanically ventilated lung model.
        Respir Care. 1998; 43: 705-712
        • Ran JL
        • Harwood RJ
        • Groff JL
        Evaluation of a reservoir device for metered-dose bronchodilator delivery to intubated adults: an in Vitro study.
        Chest. 1992; 102: 924-930
        • Taylor RH
        • Lerman J
        • Chambers C
        • Dolovich M
        Dosing efficiency and particle-size characteristics of pressurized metered-dose inhaler aerosols in narrow catheters.
        Chest. 1993; 103: 920-924
      1. Diot P, Morra L, Smaldone G. Albuterol delivery in a model of mechanical ventilation Comparison of metered-dose inhaler and nebulizer efficiency1995;152: 1391–4.

        • Thomas SHL
        • O'Doherty MJ
        • Page CJ
        • Treacher DF
        • Nunan TO
        Delivery of ultrasonic nebulized aerosols to a lung model during mechanical ventilation.
        Am Rev Respir Dis. 1993; 148: 872-877
        • Dhand R
        How should aerosols be delivered during invasive mechanical ventilation?.
        Respir Care. 2017; 62: 1343-1367
        • Ari A
        • Fink JB
        • Dhand R
        Inhalation therapy in patients receiving mechanical ventilation: an update.
        J Aerosol Med Pulm Drug Deliv. 2012; 25: 319-332
        • Schaack J.
        Adenovirus vectors deleted for genes essential for viral DNA replication.
        Front Biosci. 2005; 10: 1146-1155
        • Tal J.
        Adeno-associated virus-based vectors in gene therapy.
        J Biomed Sci. 2000; 7: 279-291
        • Moss RB
        • Rodman D
        • Spencer LT
        • et al.
        Repeated adeno-associated virus serotype 2 aerosol-mediated cystic fibrosis transmembrane regulator gene transfer to the lungs of patients with cystic fibrosis.
        Chest. 2004; 125: 509-521
        • Wu Z
        • Yang H
        • Colosi P
        Effect of genome size on AAV vector packaging.
        Mol Ther. 2010; 18: 80-86
        • Kushwah R
        • Cao H
        • Hu J.
        Potential of helper-dependent adenoviral vectors in modulating airway innate immunity.
        Cell Mol Immunol. 2007; 4: 81-89
        • Engelhardt JF
        • Yankaskas JR
        • Wilson JM
        In vivo retroviral gene transfer into human bronchial epithelia of xenografts.
        J Clin Invest. 1992; 90: 2598-2607
        • Dokka S
        • Toledo D
        • Shi X
        • Castranova V
        • Rojanasakul Y
        Oxygen radical-mediated pulmonary toxicity induced by some cationic liposomes.
        Pharm Res. 2000; 17: 521-525
        • Semple SC
        • Klimuk SK
        • Harasym TO
        • et al.
        Efficient encapsulation of antisense oligonucleotides in lipid vesicles using ionizable aminolipids: formation of novel small multilamellar vesicle structures.
        Biochimica et Biophysica Acta. 2001; 1510: 152-166
        • Mundargi RC
        • Babu VR
        • Rangaswamy V
        • Patel P
        • Aminabhavi TM
        Nano/micro technologies for delivering macromolecular therapeutics using poly(D,L-lactide-co-glycolide) and its derivatives.
        J Control Release. 2008; 125: 193-209
        • Patil ML
        • Zhang M
        • Minko T
        Multifunctional triblock Nanocarrier (PAMAM-PEG-PLL) for the efficient intracellular siRNA delivery and gene silencing.
        ACS Nano. 2011; 5: 1877-1887
        • Dash PR
        • Read ML
        • Fisher KD
        • et al.
        Decreased binding to proteins and cells of polymeric gene delivery vectors surface modified with a multivalent hydrophilic polymer and retargeting through attachment of transferrin.
        J Biol Chem. 2000; 275: 3793-3802
        • Tai W
        • Gao X.
        Functional peptides for siRNA delivery.
        Adv Drug Deliv Rev. 2017; 110–111: 157-168
        • Joseph PM
        • O'Sullivan BP
        • Lapey A
        • et al.
        Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. I. Methods, safety, and clinical implications.
        Hum Gene Ther. 2001; 12: 1369-1382
        • Chetty C
        • Bhoopathi P
        • Joseph P
        • et al.
        Adenovirus-mediated small interfering RNA against matrix metalloproteinase-2 suppresses tumor growth and lung metastasis in mice.
        Mol Cancer Ther. 2006; 5: 2289-2299
        • Sun L
        • Gao H
        • Sarma VJ
        • Guo RF
        • Ward PA
        Adenovirus-mediated in vivo silencing of anaphylatoxin receptor C5aR.
        J Biomed Biotechnol. 2006; 2006: 28945
        • Huber-Lang MS
        • Riedeman NC
        • Sarma JV
        • et al.
        Protection of innate immunity by C5aR antagonist in septic mice.
        FASEB J. 2002; 16: 1567-1574
        • Conway JE
        • Zolotukhin S
        • Muzyczka N
        • Howard GS
        • Byrne BJ
        Recombinant adeno-associated virus type 2 replication and packagin is entirely support by a herpes simplex virus type 1 amplicon expressing rep and cap.
        J Virol. 1997; 71: 8780-8789
        • Tomar RS
        • Matta H
        • Chaudhary PM
        Use of adeno-associated viral vector for delivery of small interfering RNA.
        Oncogene. 2003; 22: 5712-5715
        • Wu CJ
        • Huang WC
        • Chen LC
        • Shen CR
        • Kuo ML
        Pseudotyped adeno-associated virus 2/9-delivered CCL11 shRNA alleviates lung inflammation in an allergen-sensitized mouse model.
        Hum Gene Ther. 2012; 23: 1156-1165
        • Goldman MJ
        • Lee PS
        • Yang JS
        • Wilson JM
        Lentiviral vectors for gene therapy of cystic fibrosis.
        Hum Gene Ther. 1997; 8: 2261-2268
        • Wilson AA
        • Kwok LW
        • Porter EL
        • et al.
        Lentiviral delivery of RNAi for in vivo lineage-specific modulation of gene expression in mouse lung macrophages.
        Mol Ther. 2013; 21: 825-833
        • Chen YS
        • Li HR
        • Miao Y
        • et al.
        Local injection of lentivirus-delivered livinshRNA suppresses lung adenocarcinoma growth by inducing a G0/G1 phase cell cycle arrest.
        Int J Clin Exp Pathol. 2012; 5: 796-805
        • Hattori Y
        • Nakamura M
        • Takeuchi N
        • et al.
        Effect of cationic lipid in cationic liposomes on siRNA delivery into the lung by intravenous injection of cationic lipoplex.
        J Drug Target. 2019; 27: 217-227
        • Alton E
        • Stern M
        • Farley R
        • et al.
        Cationic lipid-mediated CFTR gene transfer to the lungs and nose of patients with cystic fibrosis: a double-blind placebo-controlled trial.
        Lancet. 1999; 353: 947-954
        • Ruiz FE
        • Clancy JP
        • Perricone MA
        • et al.
        A clinical inflammatory syndrome attributable to aerosolized lipid-DNA administration in cystic fibrosis.
        Hum Gene Ther. 2001; 12: 751-761
        • Griesenbach U
        • Kitson C
        • Escudero Garcia S
        • et al.
        Inefficient cationic lipid-mediated siRNA and antisense oligonucleotide transfer to airway epithelial cells in vivo.
        Respir Res. 2006; 7: 26
        • Boussif O
        • Lezoualc'h F
        • Zanta MA
        • et al.
        A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine.
        Proc Natl Acad Sci. 1995; 92: 7297-7301
        • Howard KA
        • Rahbek UL
        • Liu X
        • et al.
        RNA interference in vitro and in vivo using a novel chitosan/siRNA nanoparticle system.
        Mol Ther. 2006; 14: 476-484
        • Liu X
        • Howard KA
        • Dong M
        • et al.
        The influence of polymeric properties on chitosan/siRNA nanoparticle formulation and gene silencing.
        Biomaterials. 2007; 28: 1280-1288
        • Nielsen EJ
        • Nielsen JM
        • Becker D
        • et al.
        Pulmonary gene silencing in transgenic EGFP mice using aerosolised chitosan/siRNA nanoparticles.
        Pharm Res. 2010; 27: 2520-2527
        • Makadia HK
        • Siegel SJ
        Poly Lactic-co-Glycolic Acid (PLGA) as biodegradable controlled drug delivery carrier.
        Polymers. 2011; 3: 1377-1397
        • Panyam J
        • Labhasetwar V
        Biodegradable nanoparticles for drug and gene delivery to cells and tissue.
        Adv Drug Deliv Rev. 2003; 55: 329-347
        • Zheng C
        • Niu L
        • Yan J
        • et al.
        Structure and stability of the complex formed by oligonucleotides.
        Phys Chem Chem Phys. 2012; 14: 7352-7359
        • Pooga M
        • Hallbrink M
        • Zorko M
        • Langel U
        Cell penetration by transportin.
        FASEB J. 1998; 12: 67-77
        • Elliott G
        • O'Hare P.
        Intercellular trafficking and protein delivery by a herpesvirus structural protein.
        Cell. 1997; 88: 223-233
        • Oehlke J
        • Scheller A
        • Wiesner B
        • et al.
        Cellular uptake of an α-helical amphipathic model peptide with the potential to deliver polar compounds into the cell interior non-endocytically.
        Biochimica Biophysica Acta. 1998; 1414: 127-139
        • Koren E
        • Torchilin VP.
        Cell-penetrating peptides: breaking through to the other side.
        Trends Mol Med. 2012; 18: 385-393
        • Futaki S
        • Suzuki T
        • Ohashi W.
        • Yagami T.
        • Tanaka S.
        • Ueda K.
        • Sugiura Y
        Arginine-rich peptides. An abundant source of membrane-permeable peptides having potential as carriers for intracellular protein delivery.
        J Biol Chem. 2001; 276: 5836-5840
        • Reynolds F
        • Weissleder R
        • Josephson L
        Protamine as an efficient membrane-translocating peptide.
        Bioconjug Chem. 2005; 16: 1240-1245
        • Davidson TJ
        • Harel S
        • Arboleda VA
        • et al.
        Highly efficient small interfering RNA delivery to primary mammalian neurons induces MicroRNA-like effects before mRNA degradation.
        J Neurosci. 2004; 24: 10040-10046
        • Daniels DS
        • Schepartz A.
        Intrinsically cell-permeable miniature proteins based on a minimal cationic PPII motif.
        J Am Chem Soc. 2007; 129: 14578-14579
        • De Coupade C
        • Fittipaldi A
        • Chagnas V
        • et al.
        Novel human-derived cell-penetrating peptides for specific subcellular delivery of therapeutic biomolecules.
        Biochem J. 2005; 390: 407-418
        • Simeoni F
        • Morris MC
        • Heitz F
        • Divita G
        Insight into the mechanism of the peptide-based gene delivery system MPG: implications for delivery of siRNA into mammalian cells.
        Nucleic Acid Res. 2003; 31: 2717-2724
        • Unnamalai N
        • Kang BG
        • Lee WS
        Cationic oligopeptide-mediated delivery of dsRNA for post-transcriptional gene silencing in plant cells.
        FEBS Lett. 2004; 566: 307-310
        • Nakase I
        • Hirose H
        • Tanaka G
        • et al.
        Cell-surface accumulation of flock house virus-derived peptide leads to efficient internalization via macropinocytosis.
        Mol Ther. 2009; 17: 1868-1876
        • Godet AN
        • Guergnon J
        • Croset A
        • et al.
        PP2A1 binding, cell transducing and apoptotic properties of Vpr(77-92): a new functional domain of HIV-1 Vpr proteins.
        PLoS One. 2010; 5: e13760
        • Noguchi H
        • Matsushita M
        • Matsumoto S
        • et al.
        Mechanism of PDX-1 protein transduction.
        Biochem Biophys Res Commun. 2005; 332: 68-74
        • Langedijk JPM
        • Olijhoek T
        • Meloen RH
        Application, efficiency and cargo-dependence of transport peptides.
        Int Congress Ser. 2005; 1277: 95-107
        • Wang YF
        • Xu X
        • Fan X
        • et al.
        A cell-penetrating peptide suppresses inflammation by inhibiting NF-kappaB signaling.
        Mol Ther. 2011; 19: 1849-1857
        • Johansson HJ
        • El-Andaloussi S
        • Holm T
        • et al.
        Characterization of a novel cytotoxic cell‐penetrating peptide derived from p14ARF protein.
        Mol Ther. 2008; 16: 115-123
        • El-Andaloussi S
        • Johansson HJ
        • Holm T
        • Langel U
        A novel cell-penetrating peptide, M918, for efficient delivery of proteins and peptide nucleic acids.
        Mol Ther. 2007; 15: 1820-1826
        • Elmquist A
        • Lindgren M
        • Bartfai T
        • Langel U
        VE-cadherin-derived cell-penetrating peptide, pVEC, with carrier functions.
        Exp Cell Res. 2001; 269: 237-244
        • Nakayama F
        • Yasuda T
        • Umeda S
        • et al.
        Fibroblast growth factor-12 (FGF12) translocation into intestinal epithelial cells is dependent on a novel cell-penetrating peptide domain: involvement of internalization in the in vivo role of exogenous FGF12.
        J Biol Chem. 2011; 286: 25823-25834
        • Zhang W
        • Song J
        • Zhang B
        • et al.
        Design of acid-activated cell penetrating peptide for delivery of active molecules into cancer cells.
        Bioconjug Chem. 2011; 22: 1410-1415
        • Delaroche D
        • Aussedat B
        • Aubry S
        • et al.
        Tracking a new cell-penetrating (W/R) nonapeptide, through an enzyme-stable mass spectrometry reporter tag.
        Anal Chem. 2007; 79: 1932-1938
        • Oehlke J
        • Krause E
        • Wiesner B
        • Beyermann M
        • Bienert M
        Extensive cellular uptake into endothelial cells of an amphipathic β-sheet forming peptide.
        FEBS Lett. 1997; 415: 196-199
        • Sadler K
        • Eom KD
        • Yang J-L
        • Dimitrova Y
        • Tam JP
        Translocating proline-rich peptides from the antimicrobial peptide bactenecin 7†.
        Biochemistry. 2002; 41: 14150-14157
        • Milletti F.
        Cell-penetrating peptides: classes, origin, and current landscape.
        Drug Discov Today. 2012; 17: 850-860
        • El-Sayed A
        • Masuda T
        • Khalil I
        • Akita H
        • Harashima H
        Enhanced gene expression by a novel stearylated INF7 peptide derivative through fusion independent endosomal escape.
        J Control Release. 2009; 138: 160-167
        • Konate K
        • Crombez L
        • Deshayes S
        • et al.
        Insight into the cellular uptake mechanism of a secondary amphipathic cell-penetrating peptide for siRNA delivery.
        Biochemistry. 2010; 49: 3393-3402
        • Rhee M
        • Davis P.
        Mechanism of uptake of C105Y, a novel cell-penetrating peptide.
        J Biol Chem. 2006; 281: 1233-1240
        • Gao C
        • Mao S
        • Ditzel HJ
        • et al.
        A cell-penetrating peptide from a novel pVII–pIX phage-displayed random peptide library.
        Bioorg Med Chem. 2002; 10: 4057-4065
        • Smaldone G
        • Falanga A
        • Capasso D
        • et al.
        gH625 is a viral derived peptide for effective delivery of intrinsically disordered proteins.
        Int J Nanomedicine. 2013; 8: 2555-2565
        • Wray C
        • Mao Y
        • Pan J
        • et al.
        Claudin-4 augments alveolar epithelial barrier function and is induced in acute lung injury.
        Am J Physiol Lung Cell Mol Physiol. 2009; 297: L219-L227
        • Van Itallie C
        • Rahner C
        • Anderson JM
        Regulated expression of claudin-4 decreases paracellular conductance through a selective decrease in sodium permeability.
        J Clin Invest. 2001; 107: 1319-1327
        • Gallagher DC
        • Parikh SM
        • Balonov K
        • et al.
        Circulating angiopoietin 2 correlates with mortality in a surgical population with acute lung injury/adult respiratory distress syndrome.
        Shock. 2008; 29: 656-661
        • Roviezzo F
        • Tsigkos S
        • Kotanidou A
        • et al.
        Angiopoietin-2 causes inflammation in vivo by promoting vascular leakage.
        J Pharmacol Exp Ther. 2005; 314: 738-744
        • Parikh SM
        • Mammoto T
        • Schultz A
        • et al.
        Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans.
        PLoS Med. 2006; 3: e46
        • Tinsley JH
        • Teasdale NR
        • Yuan SY
        Myosin light chain phosphorylation and pulmonary endothelial cell hyperpermeability in burns.
        Am J Physiol Lung Cell Mol Physiol. 2004; 286: L841-L847
        • Lee J
        • Cacalano G
        • Camerato T
        • Toy K
        • Moore MW
        • Wood WI
        Chemokine binding and activities mediated by the mouse IL-8 receptor.
        J Immunol. 1995; 155: 2158-2164
        • Lomas-Neira JL
        • Chung CS
        • Wesche DE
        • Perl M
        • Ayala A
        In vivo gene silencing (with siRNA) of pulmonary expression of MIP-2 versus KC results in divergent effects on hemorrhage-induced, neutrophil-mediated septic acute lung injury.
        J Leukoc Biol. 2005; 77: 846-853
        • Lomas JL
        • Chung CS
        • Grutkoski PS
        • LeBlanc BW
        • Lavigne L
        • Reichner J
        • Gregory SH
        • Doughty LA
        • Cioffi WG
        • Ayala A
        Differential effects of macrophage inflammatory chemokine-2 and keratinocyte-derived chemokine on hemorrhage-induced neutrophil priming for lung inflammation: assessment by adoptive cells transfer in mice.
        Shock. 2003; 19: 358-365
        • Lomas-Neira JL
        • Chung CS
        • Grutkoski PS
        • Miller EJ
        • Ayala A
        CXCR2 inhibition suppresses hemorrhage-induced priming for acute lung injury in mice.
        J Leukoc Biol. 2004; 76: 58-64
        • Yuan B
        • Xiong LL
        • Wen MD
        • et al.
        Interleukin6 RNA knockdown ameliorates acute lung injury induced by intestinal ischemia reperfusion in rats by upregulating interleukin10 expression.
        Mol Med Rep. 2017; 16: 2529-2537
        • Gubernatorova EO
        • Perez-Chanona E
        • Koroleva EP
        • Jobin C
        • Tumanov AV
        Murine model of intestinal ischemia-reperfusion injury.
        J Vis Exp. 2016; 111: 53881
        • Rey C
        • Soubeyran I
        • Mahouche I
        • et al.
        HIPK1 drives p53 activation to limit colorectal cancer cell growth.
        Cell Cycle. 2013; 12: 1879-1891
        • Choi CY
        • Kim YH
        • Kim YO
        • et al.
        Phosphorylation by the DHIPK2 protein kinase modulates the corepressor activity of Groucho.
        J Biol Chem. 2005; 280: 21427-21436
        • Kim YH
        • Choi CY
        • Lee SJ
        • Conti MA
        • Kim Y
        Homeodomain-interacting protein kinases, a novel family of co-repressors for homeodomain transcription factors.
        J Biol Chem. 1998; 273: 25875-25879
        • Oh B
        • Lee M.
        Combined delivery of HMGB-1 box A peptide and S1PLyase siRNA in animal models of acute lung injury.
        J Control Release. 2014; 175: 25-35
        • Huang W
        • Tang Y
        • Li L
        HMGB1, a potent proinflammatory cytokine in sepsis.
        Cytokine. 2010; 51: 119-126
        • Ueno H
        • Matsuda T
        • Hashimoto S
        • et al.
        Contributions of high mobility group box protein in experimental and clinical acute lung injury.
        Am J Respir Crit Care Med. 2004; 170: 1310-1316
        • Lin X
        • Yang H
        • Sakuragi T
        • et al.
        Alpha-chemokine receptor blockade reduces high mobility group box 1 protein-induced lung inflammation and injury and improves survival in sepsis.
        Am J Physiol Lung Cell Mol Physiol. 2005; 289: L583-L590
        • Kim HA
        • Park JH
        • Cho SH
        • Lee M
        Lung epithelial binding peptide-linked high mobility group box-1 A box for lung epithelial cell-specific delivery of DNA.
        J Drug Target. 2011; 19: 589-596
        • Yin X
        • Krikorian P
        • Logan T
        • Csizmadia V
        Induction of RIP-2 kinase by proinflammatory cytokines is mediated via NF-kappaB signaling pathways and involves a novel feed-forward regulatory mechanism.
        Mol Cell Biochem. 2010; 333: 251-259
        • Singh D
        • Fox SM
        • Tal-Singer R
        • et al.
        Induced sputum genes associated with spirometric and radiological disease severity in COPD ex-smokers.
        Thorax. 2011; 66: 489-495
        • Dong J
        • Liao W
        • Tan LH
        • et al.
        Gene silencing of receptor-interacting protein 2 protects against cigarette smoke-induced acute lung injury.
        Pharmacol Res. 2019; 139: 560-568
        • Jin LY
        • Li CF
        • Zhu GF
        • et al.
        Effect of siRNA against NF-kappaB on sepsisinduced acute lung injury in a mouse model.
        Mol Med Rep. 2014; 10: 631-637
        • Dong J
        • Liao W
        • Peh HY
        • et al.
        Ribosomal protein S3 gene silencing protects against cigarette smoke-induced acute lung injury.
        Mol Ther Nucleic Acids. 2018; 12: 370-380
        • Wan F
        • Anderson DE
        • Barnitz RA
        • et al.
        Ribosomal protein S3: a KH domain subunit in NF-kappaB complexes that mediates selective gene regulation.
        Cell. 2007; 131: 927-939
        • Wan F
        • Lenardo MJ.
        The nuclear signaling of NF-kappaB: current knowledge, new insights, and future perspectives.
        Cell Res. 2010; 20: 24-33
        • Nadon AM
        • Perez MJ
        • Hernandez-Saavedra D
        • et al.
        Rtp801 suppression of epithelial mTORC1 augments endotoxin-induced lung inflammation.
        Am J Pathol. 2014; 184: 2382-2389
        • Fielhaber JA
        • Carroll SF
        • Dydensborg AB
        • et al.
        Inhibition of mammalian target of rapamycin augments lipopolysaccharide-induced lung injury and apoptosis.
        J Immunol. 2012; 188: 4535-4542
        • Hu Y
        • Lou J
        • Mao YY
        • et al.
        Activation of MTOR in pulmonary epithelium promotes LPS-induced acute lung injury.
        Autophagy. 2016; 12: 2286-2299
        • Dan HC
        • Cooper MJ
        • Cogswell PC
        • et al.
        Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK.
        Genes Dev. 2008; 22: 1490-1500
        • Weichhart T
        • Costantino G
        • Poglitsch M
        • et al.
        The TSC-mTOR signaling pathway regulates the innate inflammatory response.
        Immunity. 2008; 29: 565-577
        • Schmidt EP
        • Tuder RM.
        Role of apoptosis in amplifying inflammatory responses in lung diseases.
        J Cell Death. 2010; 2010: 41-53
        • D'Alessio FR
        • Tsushima K
        • Aggarwal NR
        • et al.
        CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury.
        J Clin Invest. 2009; 119: 2898-2913
        • Weirather J
        • Hofmann UDW
        • Beyersdorf N
        • et al.
        Foxp3+CD4+ T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation.
        Circ Res. 2014; 115: 55-67
        • Arpaia N
        • Green JA
        • Moltedo B
        • et al.
        A distinct function of regulatory T Cells in tissue protection.
        Cell. 2015; 162: 1078-1089
        • Baecher-Allan C
        • Brown JA
        • Freeman GJ
        • Hafler DA
        CD4+CD25high regulatory cells in human peripheral blood.
        J Immunol. 2001; 167: 1245
        • Ng WF
        • Duggan PJ
        • Ponchel F
        • et al.
        Human CD4+CD25+ cells: a naturally occurring population of regulatory T cells.
        Blood. 2001; 98: 2736
        • Noack M
        • Miossec P.
        Th17 and regulatory T cell balance in autoimmune and inflammatory diseases.
        Autoimmun Rev. 2014; 13: 668-677