Integrating microRNAs into a system biology approach to acute lung injury

  • Tong Zhou
    Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Illinois at Chicago, Chicago, Ill

    Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Ill
    Search for articles by this author
  • Joe G.N. Garcia
    Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Illinois at Chicago, Chicago, Ill

    Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Ill
    Search for articles by this author
  • Wei Zhang
    Reprint requests: Wei Zhang, PhD, Department of Pediatrics, University of Illinois at Chicago, 840 S. Wood Street, 1200 CSB, MC856, Chicago, IL 60612
    Department of Pediatrics, University of Illinois at Chicago, Chicago, Ill

    Institute for Human Genetics, University of Illinois at Chicago, Chicago, Ill
    Search for articles by this author
Published:February 07, 2011DOI:
      Acute lung injury (ALI), including the ventilator-induced lung injury (VILI) and the more severe acute respiratory distress syndrome (ARDS), are common and complex inflammatory lung diseases potentially affected by various genetic and nongenetic factors. Using the candidate gene approach, genetic variants associated with immune response and inflammatory pathways have been identified and implicated in ALI. Because gene expression is an intermediate phenotype that resides between the DNA sequence variation and the higher level cellular or whole-body phenotypes, the illustration of gene expression regulatory networks potentially could enhance understanding of disease susceptibility and the development of inflammatory lung syndromes. MicroRNAs (miRNAs) have emerged as a novel class of gene regulators that play critical roles in complex diseases including ALI. Comparisons of global miRNA profiles in animal models of ALI and VILI identified several miRNAs (eg, miR-146a and miR-155) previously implicated in immune response and inflammatory pathways. Therefore, via regulation of target genes in these biological processes and pathways, miRNAs potentially contribute to the development of ALI. Although this line of inquiry exists at a nascent stage, miRNAs have the potential to be critical components of a comprehensive model for inflammatory lung disease built by a systems biology approach that integrates genetic, genomic, proteomic, epigenetic as well as environmental stimuli information. Given their particularly recognized role in regulation of immune and inflammatory responses, miRNAs also serve as novel therapeutic targets and biomarkers for ALI/ARDS or VILI, thus facilitating the realization of personalized medicine for individuals with acute inflammatory lung disease.


      ACE (angiotensin converting enzyme), ALI (acute lung injury), ARDS (acute respiratory distress syndrome), CNV (copy number variant), HTV (high tidal ventilation), IL (interleukin), LCL (lymphoblastoid cell line sample), LPS (lipopolysaccharide), miRNA (microRNA), PAI-1 (plasminogen activator inhibitor 1), PBEF (pre-B-cell colony enhancing factor), SNP (single nucleotide polymorphism), SOD3 (extracellular superoxide dismutase), TGF-β (transforming growth factor β), THBS1 (thrombospondin 1), TLR (toll-like receptor), VEGF (vascular endothelial growth factor), VILI (ventilator-induced lung injury)
      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 to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Tomlinson L.
        • Bellingan G.J.
        Trauma and acute lung injury.
        Trauma. 2002; 4: 147-157
        • Tsushima K.
        • King L.S.
        • Aggarwal N.R.
        • et al.
        Acute lung injury review.
        Intern Med. 2009; 48: 621-630
        • Rubenfeld G.D.
        • Caldwell E.
        • Peabody E.
        • et al.
        Incidence and outcomes of acute lung injury.
        N Engl J Med. 2005; 353: 1685-1693
        • Bream-Rouwenhorst H.R.
        • Beltz E.A.
        • Ross M.B.
        • Moores K.G.
        Recent developments in the management of acute respiratory distress syndrome in adults.
        Am J Health Syst Pharm. 2008; 65: 29-36
        • Gajic O.
        • Dara S.I.
        • Mendez J.L.
        • et al.
        Ventilator-associated lung injury in patients without acute lung injury at the onset of mechanical ventilation.
        Crit Care Med. 2004; 32: 1817-1824
        • Dhanireddy S.
        • Altemeier W.A.
        • Matute-Bello G.
        • et al.
        Mechanical ventilation induces inflammation, lung injury, and extra-pulmonary organ dysfunction in experimental pneumonia.
        Lab Invest. 2006; 86: 790
        • Altemeier W.A.
        • Matute-Bello G.
        • Frevert C.W.
        • et al.
        Mechanical ventilation with moderate tidal volumes synergistically increases lung cytokine response to systemic endotoxin.
        Am J Physiol Lung Cell Mol Physiol. 2004; 287: L533-L542
        • Bregeon F.
        • Delpierre S.
        • Chetaille B.
        • et al.
        Mechanical ventilation affects lung function and cytokine production in an experimental model of endotoxemia.
        Anesthesiology. 2005; 102: 331-339
        • Wurfel M.M.
        Microarray-based analysis of ventilator-induced lung injury.
        Proc Am Thorac Soc. 2007; 4: 77-84
        • Ware L.B.
        • Matthay M.A.
        The acute respiratory distress syndrome.
        N Engl J Med. 2000; 342: 1334-1349
        • Meyer N.J.
        • Garcia J.G.
        Wading into the genomic pool to unravel acute lung injury genetics.
        Proc Am Thorac Soc. 2007; 4: 69-76
        • Gong M.N.
        • Thompson B.T.
        • Williams P.
        • et al.
        Clinical predictors of and mortality in acute respiratory distress syndrome: potential role of red cell transfusion.
        Crit Care Med. 2005; 33: 1191-1198
        • Moss M.
        • Mannino D.M.
        Race and gender differences in acute respiratory distress syndrome deaths in the United States: an analysis of multiple-cause mortality data (1979-1996).
        Crit Care Med. 2002; 30: 1679-1685
        • Lim L.P.
        • Lau N.C.
        • Garrett-Engele P.
        • et al.
        Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs.
        Nature. 2005; 433: 769-773
        • Zhang W.
        • Dolan M.E.
        Emerging role of microRNAs in drug response.
        Curr Opin Mol Ther. 2010; 12: 695-702
        • Ghosh B.
        • Sharma A.
        • Kumar M.
        • Mabalirajan U.
        • Agrawal A.
        Identification of microRNA involved in il−10 expression and its implication in asthma.
        Am J Respir Crit Care Med. 2009; 179: A2491
        • Tan Z.
        • Randall G.
        • Fan J.
        • et al.
        Allele-specific targeting of microRNAs to HLA-G and risk of asthma.
        Am J Hum Genet. 2007; 81: 829-834
        • Lu T.X.
        • Munitz A.
        • Rothenberg M.E.
        MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression.
        J Immunol. 2009; 182: 4994-5002
        • Chiba Y.
        • Tanabe M.
        • Goto K.
        • Sakai H.
        • Misawa M.
        Down-regulation of miR-133a contributes to up-regulation of Rhoa in bronchial smooth muscle cells.
        Am J Respir Crit Care Med. 2009; 180: 713-719
        • Mattes J.
        • Collison A.
        • Plank M.
        • Phipps S.
        • Foster P.S.
        Antagonism of microRNA-126 suppresses the effector function of TH2 cells and the development of allergic airways disease.
        Proc Natl Acad Sci U S A. 2009; 106: 18704-18709
        • Chiba Y.
        • Misawa M.
        MicroRNAs and their therapeutic potential for human diseases: mir-133a and bronchial smooth muscle hyperresponsiveness in asthma.
        J Pharmacol Sci. 2010; 114: 264-268
        • Mohamed J.S.
        • Lopez M.A.
        • Boriek A.M.
        Mechanical stretch up-regulates microRNA-26a and induces human airway smooth muscle hypertrophy by suppressing glycogen synthase kinase-3beta.
        J Biol Chem. 2010; 285: 29336-29347
        • Polikepahad S.
        • Knight J.M.
        • Naghavi A.O.
        • et al.
        Proinflammatory role for let-7microRNAS in experimental asthma.
        J Biol Chem. 2010; 285: 30139-30149
        • Christenson S.A.
        • Campbell J.D.
        • Zeskind J.
        • et al.
        MicroRNA as regulators of gene expression changes that occur with the progression of emphysema.
        Am J Respir Crit Care Med. 2010; 181: A2024
        • Sato T.
        • Liu X.
        • Nelson A.
        • et al.
        Reduced miR-146a increases prostaglandin E in chronic obstructive pulmonary disease fibroblasts.
        Am J Respir Crit Care Med. 2010; 182: 1020-1029
        • Oglesby I.K.
        • Bray I.M.
        • Chotirmall S.H.
        • et al.
        miR-126 is downregulated in cystic fibrosis airway epithelial cells and regulates TOM1 expression.
        J Immunol. 2010; 184: 1702-1709
        • Pandit K.V.
        • Corcoran D.
        • Yousef H.
        • et al.
        Inhibition and role of let-7d in idiopathic pulmonary fibrosis.
        Am J Respir Crit Care Med. 2010; 182: 220-229
        • Pottier N.
        • Maurin T.
        • Chevalier B.
        • et al.
        Identification of keratinocyte growth factor as a target of microRNA-155 in lung fibroblasts: implication in epithelial-mesenchymal interactions.
        PLoS One. 2009; 4: e6718
        • Liu G.
        • Friggeri A.
        • Yang Y.
        • et al.
        miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis.
        J Exp Med. 2010; 207: 1589-1597
        • Reddy A.J.
        • Kleeberger S.R.
        Genetic polymorphisms associated with acute lung injury.
        Pharmacogenomics. 2009; 10: 1527-1539
        • Kuba K.
        • Imai Y.
        • Rao S.
        • et al.
        A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury.
        Nat Med. 2005; 11: 875-879
        • Imai Y.
        • Kuba K.
        • Rao S.
        • et al.
        Angiotensin-converting enzyme 2 protects from severe acute lung failure.
        Nature. 2005; 436: 112-116
        • Arcaroli J.J.
        • Hokanson J.E.
        • Abraham E.
        • et al.
        Extracellular superoxide dismutase haplotypes are associated with acute lung injury and mortality.
        Am J Respir Crit Care Med. 2009; 179: 105-112
        • Meyer N.J.
        • Christie J.D.
        Extracellular superoxide dismutase haplotypes and acute lung injury: reading into the genome to understand mortality?.
        Am J Respir Crit Care Med. 2009; 179: 89-91
        • Bersten A.D.
        • Hunt T.
        • Nicholas T.E.
        • Doyle I.R.
        Elevated plasma surfactant protein-B predicts development of acute respiratory distress syndrome in patients with acute respiratory failure.
        Am J Respir Crit Care Med. 2001; 164: 648-652
        • Mora R.
        • Arold S.
        • Marzan Y.
        • Suki B.
        • Ingenito E.P.
        Determinants of surfactant function in acute lung injury and early recovery.
        Am J Physiol Lung Cell Mol Physiol. 2000; 279: L342-L349
        • Christie J.D.
        Interleukin-10, age and acute lung injury genetics: the action is in the interaction.
        Eur Respir J. 2006; 27: 669-670
        • Kono H.
        • Fujii H.
        • Hirai Y.
        • et al.
        The Kupffer cell protects against acute lung injury in a rat peritonitis model: role of IL-10.
        J Leukoc Biol. 2006; 79: 809-817
        • Inoue G.
        Effect of interleukin-10 (IL-10) on experimental LPS-induced acute lung injury.
        J Infect Chemother. 2000; 6: 51-60
        • Abadie Y.
        • Bregeon F.
        • Papazian L.
        • et al.
        Decreased VEGF concentration in lung tissue and vascular injury during ARDS.
        Eur Respir J. 2005; 25: 139-146
        • Medford A.R.
        • Ibrahim N.B.
        • Millar A.B.
        Vascular endothelial growth factor receptor and coreceptor expression in human acute respiratory distress syndrome.
        J Crit Care. 2009; 24: 236-242
        • Medford A.R.
        • Millar A.B.
        Vascular endothelial growth factor (VEGF) in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS): paradox or paradigm?.
        Thorax. 2006; 61: 621-626
        • Tsangaris I.
        • Tsantes A.
        • Bonovas S.
        • et al.
        The impact of the PAI-1 4G/5G polymorphism on the outcome of patients with ALI/ARDS.
        Thromb Res. 2009; 123: 832-836
        • Liu A.
        • Mosher D.F.
        • Murphy-Ullrich J.E.
        • Goldblum S.E.
        The counteradhesive proteins, thrombospondin 1 and SPARC/osteonectin, open the tyrosine phosphorylation-responsive paracellular pathway in pulmonary vascular endothelia.
        Microvasc Res. 2009; 77: 13-20
        • Dhainaut J.F.
        • Charpentier J.
        • Chiche J.D.
        Transforming growth factor-beta: a mediator of cell regulation in acute respiratory distress syndrome.
        Crit Care Med. 2003; 31: S258-S264
        • Gao L.
        • Flores C.
        • Fan-Ma S.
        • et al.
        Macrophage migration inhibitory factor in acute lung injury: expression, biomarker, and associations.
        Transl Res. 2007; 150: 18-29
        • Flores C.
        • Ma S.F.
        • Maresso K.
        • et al.
        IL6 gene-wide haplotype is associated with susceptibility to acute lung injury.
        Transl Res. 2008; 152: 11-17
        • Grigoryev D.N.
        • Ma S.F.
        • Irizarry R.A.
        • et al.
        Orthologous gene-expression profiling in multi-species models: search for candidate genes.
        Genome Biol. 2004; 5: R34
        • Flores C.
        • Perez-Mendez L.
        • Maca-Meyer N.
        • et al.
        A common haplotype of the LBP gene predisposes to severe sepsis.
        Crit Care Med. 2009; 37: 2759-2766
        • Christie J.D.
        • Ma S.F.
        • Aplenc R.
        • et al.
        Variation in the myosin light chain kinase gene is associated with development of acute lung injury after major trauma.
        Crit Care Med. 2008; 36: 2794-2800
        • Christie J.D.
        • Ma S.F.
        • Aplenc R.
        • et al.
        Variation in the MYLK gene is associated with development of acute lung injury after major trauma.
        Crit Care Med. 2008 Aug 28; ([Epub ahead of print])
        • Flores C.
        • Ma S.F.
        • Maresso K.
        • Ober C.
        • Garcia J.G.
        A variant of the myosin light chain kinase gene is associated with severe asthma in African Americans.
        Genet Epidemiol. 2007; 31: 296-305
        • Gao L.
        • Grant A.
        • Halder I.
        • et al.
        Novel polymorphisms in the myosin light chain kinase gene confer risk for acute lung injury.
        Am J Respir Cell Mol Biol. 2006; 34: 487-495
        • Hong S.B.
        • Huang Y.
        • Moreno-Vinasco L.
        • et al.
        Essential role of pre-B-cell colony enhancing factor in ventilator-induced lung injury.
        Am J Respir Crit Care Med. 2008; 178: 605-617
        • Ye S.Q.
        • Simon B.A.
        • Maloney J.P.
        • et al.
        Pre-B-cell colony-enhancing factor as a potential novel biomarker in acute lung injury.
        Am J Respir Crit Care Med. 2005; 171: 361-370
        • Meyer N.J.
        • Huang Y.
        • Singleton P.A.
        • et al.
        GADD45a is a novel candidate gene in inflammatory lung injury via influences on Akt signaling.
        Faseb J. 2009; 23: 1325-1337
        • Marshall R.P.
        • Webb S.
        • Bellingan G.J.
        • et al.
        Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome.
        Am J Respir Crit Care Med. 2002; 166: 646-650
        • Wosten-van Asperen R.M.
        • Lutter R.
        • Haitsma J.J.
        • et al.
        ACE mediates ventilator-induced lung injury in rats via angiotensin II but not bradykinin.
        Eur Respir J. 2008; 31: 363-371
        • Jiang J.S.
        • Wang L.F.
        • Chou H.C.
        • Chen C.M.
        Angiotensin-converting enzyme inhibitor captopril attenuates ventilator-induced lung injury in rats.
        J Appl Physiol. 2007; 102: 2098-2103
        • Chen C.M.
        • Chou H.C.
        • Wang L.F.
        • Lang Y.D.
        Captopril decreases plasminogen activator inhibitor-1 in rats with ventilator-induced lung injury.
        Crit Care Med. 2008; 36: 1880-1885
        • Sapru A.
        • Curley M.A.
        • Brady S.
        • Matthay M.A.
        • Flori H.
        Elevated PAI-1 is associated with poor clinical outcomes in pediatric patients with acute lung injury.
        Intensive Care Med. 2010; 36: 157-163
        • Prabhakaran P.
        • Ware L.B.
        • White K.E.
        • et al.
        Elevated levels of plasminogen activator inhibitor-1 in pulmonary edema fluid are associated with mortality in acute lung injury.
        Am J Physiol Lung Cell Mol Physiol. 2003; 285: L20-L28
        • Garzon R.
        • Calin G.A.
        • Croce C.M.
        MicroRNAs in cancer.
        Annu Rev Med. 2009; 60: 167-179
        • Zhang W.
        • Dolan M.E.
        Use of cell lines in the investigation of pharmacogenetic loci.
        Curr Pharm Des. 2009; 15: 3782-3795
        • Simon B.A.
        • Easley R.B.
        • Grigoryev D.N.
        • et al.
        Microarray analysis of regional cellular responses to local mechanical stress in acute lung injury.
        Am J Physiol Lung Cell Mol Physiol. 2006; 291: L851-L861
        • Garcia J.G.
        Searching for candidate genes in acute lung injury: SNPs, Chips and PBEF.
        Trans Am Clin Climatol Assoc. 2005; 116: 205-219
        • Zhang W.
        • Ratain M.J.
        • Dolan M.E.
        The HapMap resource is providing new insights into ourselves and its application to pharmacogenomics.
        Bioinform Biol Insights. 2008; 2: 15-23
        • Duan S.
        • Huang R.S.
        • Zhang W.
        • et al.
        Genetic architecture of transcript-level variation in humans.
        Am J Hum Genet. 2008; 82: 1101-1113
        • The International HapMap Consortium
        The international HapMap project.
        Nature. 2003; 426: 789-796
        • The International HapMap Consortium
        A haplotype map of the human genome.
        Nature. 2005; 437: 1299-1320
        • Cheung V.G.
        • Conlin L.K.
        • Weber T.M.
        • et al.
        Natural variation in human gene expression assessed in lymphoblastoid cells.
        Nat Genet. 2003; 33: 422-425
        • Morley M.
        • Molony C.M.
        • Weber T.M.
        • et al.
        Genetic analysis of genome-wide variation in human gene expression.
        Nature. 2004; 430: 743-747
        • Stranger B.E.
        • Forrest M.S.
        • Clark A.G.
        • et al.
        Genome-wide associations of gene expression variation in humans.
        PLoS Genet. 2005; 1: e78
        • Zhang W.
        • Duan S.
        • Kistner E.O.
        • et al.
        Evaluation of genetic variation contributing to differences in gene expression between populations.
        Am J Hum Genet. 2008; 82: 631-640
        • Stranger B.E.
        • Forrest M.S.
        • Dunning M.
        • et al.
        Relative impact of nucleotide and copy number variation on gene expression phenotypes.
        Science. 2007; 315: 848-853
        • Stranger B.E.
        • Nica A.C.
        • Forrest M.S.
        • et al.
        Population genomics of human gene expression.
        Nat Genet. 2007; 39: 1217-1224
        • Spielman R.S.
        • Bastone L.A.
        • Burdick J.T.
        • et al.
        Common genetic variants account for differences in gene expression among ethnic groups.
        Nat Genet. 2007; 39: 226-231
        • Idaghdour Y.
        • Storey J.D.
        • Jadallah S.J.
        • Gibson G.
        A genome-wide gene expression signature of environmental geography in leukocytes of Moroccan Amazighs.
        PLoS Genet. 2008; 4: e1000052
        • Zhang X.
        • Richards E.J.
        • Borevitz J.O.
        Genetic and epigenetic dissection of cis regulatory variation.
        Curr Opin Plant Biol. 2007; 10: 142-148
        • Lau N.C.
        • Lim L.P.
        • Weinstein E.G.
        • Bartel D.P.
        An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans.
        Science. 2001; 294: 858-862
        • He L.
        • Hannon G.J.
        MicroRNAs: small RNAs with a big role in gene regulation.
        Nat Rev Genet. 2004; 5: 522-531
        • Lee C.T.
        • Risom T.
        • Strauss W.M.
        Evolutionary conservation of microRNA regulatory circuits: an examination of microRNA gene complexity and conserved microRNA-target interactions through metazoan phylogeny.
        DNA Cell Biol. 2007; 26: 209-218
        • Griffiths-Jones S.
        • Grocock R.J.
        • van Dongen S.
        • Bateman A.
        • Enright A.J.
        miRBase: microRNA sequences, targets and gene nomenclature.
        Nucleic Acids Res. 2006; 34: D140-D144
        • Griffiths-Jones S.
        • Saini H.K.
        • van Dongen S.
        • Enright A.J.
        miRBase: tools for microRNA genomics.
        Nucleic Acids Res. 2008; 36: D154-D158
        • Griffiths-Jones S.
        The microRNA registry.
        Nucleic Acids Res. 2004; 32: D109-D111
        • Bentwich I.
        • Avniel A.
        • Karov Y.
        • et al.
        Identification of hundreds of conserved and nonconserved human microRNAs.
        Nat Genet. 2005; 37: 766-770
        • Enright A.J.
        • John B.
        • Gaul U.
        • Tuschl T.
        • Sander C.
        • Marks D.S.
        MicroRNA targets in Drosophila.
        Genome Biol. 2003; 5: R1
        • He L.
        • Gregory J.H.
        MicroRNAs: small RNAs with a big role in gene regulation.
        Nat Rev Genet. 2004; 5: 522-531
        • Friedman R.C.
        • Farh K.K.
        • Burge C.B.
        • Bartel D.P.
        Most mammalian mRNAs are conserved targets of microRNAs.
        Genome Res. 2009; 19: 92-105
        • Gatt M.E.
        • Zhao J.J.
        • Ebert M.S.
        • et al.
        MicroRNAs 15a/16-1 function as tumor suppressor genes in multiple myeloma.
        Blood. 2010 Oct 20; ([Epub ahead of print])
        • Burchard J.
        • Zhang C.
        • Liu A.M.
        • et al.
        MicroRNA-122 as a regulator of mitochondrial metabolic gene network in hepatocellular carcinoma.
        Mol Syst Biol. 2010; 6: 402
        • Liu C.
        • Yu J.
        • Yu S.
        • et al.
        MicroRNA-21 acts as an oncomir through multiple targets in human hepatocellular carcinoma.
        J Hepatol. 2010; 53: 98-107
        • Hennessy E.
        • O’Driscoll L.
        Molecular medicine of microRNAs: structure, function and implications for diabetes.
        Expert Rev Mol Med. 2008; 10: e24
        • Lovis P.
        • Roggli E.
        • Laybutt D.R.
        • et al.
        Alterations in microRNA expression contribute to fatty acid-induced pancreatic beta-cell dysfunction.
        Diabetes. 2008; 57: 2728-2736
        • Small E.M.
        • Frost R.J.
        • Olson E.N.
        MicroRNAs add a new dimension to cardiovascular disease.
        Circulation. 2010; 121: 1022-1032
        • Lu Y.
        • Zhang Y.
        • Shan H.
        • et al.
        MicroRNA-1 downregulation by propranolol in a rat model of myocardial infarction: a new mechanism for ischaemic cardioprotection.
        Cardiovasc Res. 2009; 84: 434-441
        • Voellenkle C.
        • van Rooij J.
        • Cappuzzello C.
        • et al.
        MicroRNA signatures in peripheral blood mononuclear cells of chronic heart failure patients.
        Physiol Genomics. 2010; 42: 420-426
        • Matkovich S.J.
        • Wang W.
        • Tu Y.
        • et al.
        MicroRNA-133a protects against myocardial fibrosis and modulates electrical repolarization without affecting hypertrophy in pressure-overloaded adult hearts.
        Circ Res. 2010; 106: 166-175
        • Naga Prasad S.V.
        • Duan Z.H.
        • Gupta M.K.
        • et al.
        Unique microRNA profile in end-stage heart failure indicates alterations in specific cardiovascular signaling networks.
        J Biol Chem. 2009; 284: 27487-27499
        • Mishra P.J.
        • Mishra P.J.
        • Banerjee D.
        • Bertino J.R.
        miRSNPs or miR-polymorphisms, new players in microRNA mediated regulation of the cell: introducing microRNA pharmacogenomics.
        Cell Cycle. 2008; 7: 853-858
        • Mishra P.J.
        • Song B.
        • Mishra P.J.
        • et al.
        miR-24 tumor suppressor activity is regulated independent of p53 and through a target site polymorphism.
        PLoS One. 2009; 4: e8445
        • Mishra P.J.
        • Humeniuk R.
        • Mishra P.J.
        • et al.
        A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance.
        Proc Natl Acad Sci U S A. 2007; 104: 13513-13518
        • Duan S.
        • Mi S.
        • Zhang W.
        • Dolan M.E.
        Comprehensive analysis of the impact of SNPs and CNVs on human microRNAs and their regulatory genes.
        RNA Biol. 2009; 6: 412-425
        • Lindsay M.A.
        MicroRNAs and the immune response.
        Trends Immunol. 2008; 29: 343-351
        • Wang S.
        • Aurora A.B.
        • Johnson B.A.
        • et al.
        The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis.
        Dev Cell. 2008; 15: 261-271
        • Moschos S.A.
        • Williams A.E.
        • Perry M.M.
        • et al.
        Expression profiling in vivo demonstrates rapid changes in lung microRNA levels following lipopolysaccharide-induced inflammation but not in the anti-inflammatory action of glucocorticoids.
        BMC Genomics. 2007; 8: 240
      1. Pino-Yanes M, Tejera P, Corrales A, et al. Common variants of the interleukin-1 receptor-associated kinase 3 gene are associated with susceptibility to sepsis induced-acute lung injury. In press.

        • Taganov K.D.
        • Boldin M.P.
        • Chang K.J.
        • Baltimore D.
        NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses.
        Proc Natl Acad Sci U S A. 2006; 103: 12481-12486
        • Nahid M.A.
        • Pauley K.M.
        • Satoh M.
        • Chan E.K.
        miR-146a is critical for endotoxin-induced tolerance: implication in innate immunity.
        J Biol Chem. 2009; 284: 34590-34599
        • Bazzoni F.
        • Rossato M.
        • Fabbri M.
        • et al.
        Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signals.
        Proc Natl Acad Sci U S A. 2009; 106: 5282-5287
        • Liu X.
        • Zhan Z.
        • Xu L.
        • et al.
        MicroRNA-148/152 impair innate response and antigen presentation of TLR-triggered dendritic cells by targeting CaMKIIalpha.
        J Immunol. 2010; 185: 7244-7251
        • Liu G.
        • Friggeri A.
        • Yang Y.
        • et al.
        miR-147, a microRNA that is induced upon Toll-like receptor stimulation, regulates murine macrophage inflammatory responses.
        Proc Natl Acad Sci U S A. 2009; 106: 15819-15824
        • Tili E.
        • Michaille J.J.
        • Cimino A.
        • et al.
        Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock.
        J Immunol. 2007; 179: 5082-5089
        • Wang X.
        • Zhao Q.
        • Matta R.
        • et al.
        Inducible nitric-oxide synthase expression is regulated by mitogen-activated protein kinase phosphatase-1.
        J Biol Chem. 2009; 284: 27123-27134
        • Sheedy F.J.
        • Palsson-McDermott E.
        • Hennessy E.J.
        • et al.
        Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21.
        Nat Immunol. 2010; 11: 141-147
        • Ma F.
        • Liu X.
        • Li D.
        • et al.
        MicroRNA-466l upregulates IL-10 expression in TLR-triggered macrophages by antagonizing RNA-binding protein tristetraprolin-mediated IL-10 mRNA degradation.
        J Immunol. 2010; 184: 6053-6059
        • Gamazon E.
        • Im H.-K.
        • Duan S.
        • et al.
        ExprTarget: an integrative approach to predicting human microRNA targets.
        PLoS ONE. 2010; 5: e13534
        • Vaporidi K.
        • Iliopoulos D.
        • Francis R.C.
        • Bloch K.D.
        • Zapol W.M.
        MicroRNA expression profile in a murine model of ventilator-induced lung injury.
        Am J Respir Crit Care Med. 2010; 181: A2031
        • Zambon M.
        • Vincent J.L.
        Mortality rates for patients with acute lung injury/ARDS have decreased over time.
        Chest. 2008; 133: 1120-1127
        • Spizzo R.
        • Rushworth D.
        • Guerrero M.
        • Calin G.A.
        RNA inhibition, microRNAs, and new therapeutic agents for cancer treatment.
        Clin Lymphoma Myeloma. 2009; 9: S313-S318
        • Alevizos I.
        • Illei G.G.
        MicroRNAs as biomarkers in rheumatic diseases.
        Nature Rev. 2010; 6: 391-398
        • Dimmeler S.
        • Zeiher A.M.
        Circulating microRNAs: novel biomarkers for cardiovascular diseases?.
        Eur Heart J. 2010; 31: 2705-2707
      2. Ferracin M, Veronese A, Negrini M. Micromarkers: miRNAs in  cancer diagnosis and prognosis. Expert Rev Mol Diagn 10:297–308.

        • Wang J.F.
        • Yu M.L.
        • Yu G.
        • et al.
        Serum miR-146a and miR-223 as potential new biomarkers for sepsis.
        Biochem Biophys Res Commun. 2010; 394: 184-188
        • Vasilescu C.
        • Rossi S.
        • Shimizu M.
        • et al.
        MicroRNA fingerprints identify miR-150 as a plasma prognostic marker in patients with sepsis.
        PLoS One. 2009; 4: e7405
        • Lewis B.P.
        • Burge C.B.
        • Bartel D.P.
        Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets.
        Cell. 2005; 120: 15-20
        • Lewis B.P.
        • Shih I.H.
        • Jones-Rhoades M.W.
        • Bartel D.P.
        • Burge C.B.
        Prediction of mammalian microRNA targets.
        Cell. 2003; 115: 787-798
        • Krek A.
        • Grun D.
        • Poy M.N.
        • et al.
        Combinatorial microRNA target predictions.
        Nat Genet. 2005; 37: 495-500
        • Sethupathy P.
        • Megraw M.
        • Hatzigeorgiou A.G.
        A guide through present computational approaches for the identification of mammalian microRNA targets.
        Nat Methods. 2006; 3: 881-886
        • Papadopoulos G.L.
        • Reczko M.
        • Simossis V.A.
        • Sethupathy P.
        • Hatzigeorgiou A.G.
        The database of experimentally supported targets: a functional update of TarBase.
        Nucleic Acids Res. 2009; 37: D155-D158
        • Storey J.D.
        • Madeoy J.
        • Strout J.L.
        • et al.
        Gene-expression variation within and among human populations.
        Am J Hum Genet. 2007; 80: 502-509
        • Zhang W.
        • Huang R.S.
        • Duan S.
        • Dolan M.E.
        Gene set enrichment analyses revealed differences in gene expression patterns between males and females.
        In Silico Biol. 2009; 9: 55-63
        • Zhang W.
        • Bleibel W.K.
        • Roe C.A.
        • Cox N.J.
        • Eileen Dolan M.
        Gender-specific differences in expression in human lymphoblastoid cell lines.
        Pharmacogenet Genomics. 2007; 17: 447-450