The molecular mechanisms that control stem cell renewal and tissue fibrosis remain incompletely understood.Thisprogramisourcontinuousefforttoelucidatetheroleofextracellularmatrixcomponentsand innate immune receptors in regulating lung injury, inflammation, and fibrosis. Idiopathic pulmonary fibrosis (IPF)isafatallungdiseaseresulting,inpart,frominadequatealveolarepithelialrepairleadingtodetonationof excessive fibroblast activity. Our laboratory has generated a body of work during the last founding period showing that glycosaminoglycan hyaluronan (HA) and innate immune receptor TLR4 expressed on alveolar epithelial cells and macrophages have important roles in regulating lung inflammation and fibrosis in the contextofnoninfectiouslunginjury.HAissynthesizedatthecellmembranebyhyaluronansynthase2(HAS2). WehavediscoveredthatHAexpressedonthecellsurfaceoflungepithelialcellsservesaprotectivefunction againstnoninfectiousinsultsthatisdependentuponTLR4.Thenewfindingsthatleadustoformsthebasisfor this renewal application is that innate immune receptors interact with endogenous extracellular matrix to promotealveolarprogenitorcellrenewal.Duringthepastseveralyears,ourteamhasdevelopedstate-of-the- art tools to target both Type 2 alveolar epithelial cells (AEC2s) in the context of noninfectious lung injury. During the funding period of this award, we discovered that mice deficient in either TLR4 or with a targeted deletion of HAS2 in AEC2s are enormously sensitive to non-infectious lung injury and develop fulminant interstitialfibrosis.AEC2sisolatedfrommicedeficientineitherTLR4orwithatargeteddeletionofHAS2show reducedself-renewalcapacity.Weshowforthefirsttime,thatinnateimmunereceptorsinteractingwithmatrix are necessary for lung stem cell renewal and prevention of severe fibrosis. We have identified IL-6 as a putative cytokine mediator released by AEC2s in a manner dependent on HA-TLR4 interactions promotes stem cell renewal and modulates lung fibrosis. Most importantly, we have found that there is a significant reductionofAEC2sfromthelungofpatientswithIPFcomparedtothelungofhealthydonors.AEC2sfromthe IPF lungs showed reduced cell surface HA and impaired renewal capacity relative to the cells from healthy lungs. These data further support the concept that IPF is a disease of AEC2 failure and our mouse model recapitulates key aspects of the human lung fibrotic disease. Based on our preliminary studies, we have generatedthehypothesisthatinteractionsbetweencellsurfaceHAanditsreceptorsareessentialcomponents ofAEC2progenitorcellrenewalandlungrepair,andlossoftheseinteractionsresultsinseverelungfibrosis.In this proposal, we will define the mechanisms by which TLR4, CD44, NF-k?B, and HAS2 in AEC2s promote progenitorcellrenewalandlungrepairinmouseandhuman.Achievementofthegoalsofthisapplicationwill resultinacompletelynovelapproachtothetreatmentoflungdiseases.

Public Health Relevance

Themolecularmechanismsthatcontroltissuefibrosisremainincompletelyunderstoodandeffectivetherapies forseverepulmonaryfibrosisarelacking.Inthisproposal,wewilltestourhypothesisthatinteractionsbetween innate immune receptors (TLR4 and CD44) and cell surface hyaluronan are essential components of lung alveolar stem cell renewal and lung repair, and loss of this interaction results in severe lung fibrosis. Achievementofthegoalsofthisapplicationwillresultinacompletelynovelapproachtothetreatmentoflung diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Davidson, Wendy F
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Cedars-Sinai Medical Center
Los Angeles
United States
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Liang, Jiurong; Liu, Ningshan; Liu, Xue et al. (2018) MK2 Inhibition Attenuates Fibroblast Invasion and Severe Lung Fibrosis. Am J Respir Cell Mol Biol :
Xie, Ting; Wang, Yizhou; Deng, Nan et al. (2018) Single-Cell Deconvolution of Fibroblast Heterogeneity in Mouse Pulmonary Fibrosis. Cell Rep 22:3625-3640
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Xie, Ting; Liang, Jiurong; Geng, Yan et al. (2017) MicroRNA-29c Prevents Pulmonary Fibrosis by Regulating Epithelial Cell Renewal and Apoptosis. Am J Respir Cell Mol Biol 57:721-732
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Liang, Jiurong; Zhang, Yanli; Xie, Ting et al. (2016) Hyaluronan and TLR4 promote surfactant-protein-C-positive alveolar progenitor cell renewal and prevent severe pulmonary fibrosis in mice. Nat Med 22:1285-1293
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Liang, Jiurong; Jiang, Dianhua; Noble, Paul W (2016) Hyaluronan as a therapeutic target in human diseases. Adv Drug Deliv Rev 97:186-203
Xie, Ting; Liang, Jiurong; Liu, Ningshan et al. (2016) Transcription factor TBX4 regulates myofibroblast accumulation and lung fibrosis. J Clin Invest 126:3063-79
Noble, Paul W; Barkauskas, Christina E; Jiang, Dianhua (2012) Pulmonary fibrosis: patterns and perpetrators. J Clin Invest 122:2756-62

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