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Autophagy Activation in Asthma Airways Remodeling.

Identifieur interne : 000480 ( Ncbi/Merge ); précédent : 000479; suivant : 000481

Autophagy Activation in Asthma Airways Remodeling.

Auteurs : Kielan D. Mcalinden ; Deepak A. Deshpande [États-Unis] ; Saeid Ghavami [Canada] ; Dia Xenaki [Australie] ; Sukhwinder Singh Sohal [Australie] ; Brian G. Oliver [Australie] ; Mehra Haghi ; Pawan Sharma [Australie]

Source :

RBID : pubmed:30383396

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English descriptors

Abstract

Current asthma therapies fail to target airway remodeling that correlates with asthma severity driving disease progression that ultimately leads to loss of lung function. Macroautophagy (hereinafter "autophagy") is a fundamental cell-recycling mechanism in all eukaryotic cells; emerging evidence suggests that it is dysregulated in asthma. We investigated the interrelationship between autophagy and airway remodeling and assessed preclinical efficacy of a known autophagy inhibitor in murine models of asthma. Human asthmatic and nonasthmatic lung tissues were histologically evaluated and were immunostained for key autophagy markers. The percentage area of positive staining was quantified in the epithelium and airway smooth muscle bundles using ImageJ software. Furthermore, the autophagy inhibitor chloroquine was tested intranasally in prophylactic (3 wk) and treatment (5 wk) models of allergic asthma in mice. Human asthmatic tissues showed greater tissue inflammation and demonstrated hallmark features of airway remodeling, displaying thickened epithelium (P < 0.001) and reticular basement membrane (P < 0.0001), greater lamina propria depth (P < 0.005), and increased airway smooth muscle bundles (P < 0.001) with higher expression of Beclin-1 (P < 0.01) and ATG5 (autophagy-related gene 5) (P < 0.05) together with reduced p62 (P < 0.05) compared with nonasthmatic control tissues. Beclin-1 expression was significantly higher in asthmatic epithelium and ciliated cells (P < 0.05), suggesting a potential role of ciliophagy in asthma. Murine asthma models demonstrated effective preclinical efficacy (reduced key features of allergic asthma: airway inflammation, airway hyperresponsiveness, and airway remodeling) of the autophagy inhibitor chloroquine. Our data demonstrate cell context-dependent and selective activation of autophagy in structural cells in asthma. Furthermore, this pathway can be effectively targeted to ameliorate airway remodeling in asthma.

DOI: 10.1165/rcmb.2018-0169OC
PubMed: 30383396

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Le document en format XML

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<term>Aged, 80 and over</term>
<term>Airway Remodeling (drug effects)</term>
<term>Animals</term>
<term>Anti-Asthmatic Agents (pharmacology)</term>
<term>Asthma (drug therapy)</term>
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<term>Myocytes du muscle lisse (anatomopathologie)</term>
<term>Myocytes du muscle lisse (métabolisme)</term>
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<term>Protéine-5 associée à l'autophagie (antagonistes et inhibiteurs)</term>
<term>Protéine-5 associée à l'autophagie (génétique)</term>
<term>Protéine-5 associée à l'autophagie (métabolisme)</term>
<term>Remodelage des voies aériennes ()</term>
<term>Régulation de l'expression des gènes</term>
<term>Souris</term>
<term>Souris de lignée BALB C</term>
<term>Sujet âgé</term>
<term>Sujet âgé de 80 ans ou plus</term>
<term>Séquestosome-1 (génétique)</term>
<term>Séquestosome-1 (métabolisme)</term>
<term>Transduction du signal</term>
<term>Études cas-témoins</term>
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<term>Sequestosome-1 Protein</term>
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<term>Anti-Asthmatic Agents</term>
<term>Chloroquine</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr">
<term>Asthme</term>
<term>Cils vibratiles</term>
<term>Muqueuse respiratoire</term>
<term>Muscles lisses</term>
<term>Myocytes du muscle lisse</term>
<term>Poumon</term>
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<term>Bécline-1</term>
<term>Protéine-5 associée à l'autophagie</term>
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<keywords scheme="MESH" qualifier="drug effects" xml:lang="en">
<term>Airway Remodeling</term>
<term>Autophagy</term>
<term>Cilia</term>
<term>Lung</term>
<term>Muscle, Smooth</term>
<term>Myocytes, Smooth Muscle</term>
<term>Respiratory Mucosa</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en">
<term>Asthma</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en">
<term>Asthma</term>
<term>Autophagy</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr">
<term>Asthme</term>
<term>Autophagie</term>
<term>Bécline-1</term>
<term>Protéine-5 associée à l'autophagie</term>
<term>Séquestosome-1</term>
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<keywords scheme="MESH" qualifier="metabolism" xml:lang="en">
<term>Asthma</term>
<term>Cilia</term>
<term>Lung</term>
<term>Muscle, Smooth</term>
<term>Myocytes, Smooth Muscle</term>
<term>Respiratory Mucosa</term>
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<term>Asthme</term>
<term>Bécline-1</term>
<term>Cils vibratiles</term>
<term>Muqueuse respiratoire</term>
<term>Muscles lisses</term>
<term>Myocytes du muscle lisse</term>
<term>Poumon</term>
<term>Protéine-5 associée à l'autophagie</term>
<term>Séquestosome-1</term>
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<term>Asthma</term>
<term>Cilia</term>
<term>Lung</term>
<term>Muscle, Smooth</term>
<term>Myocytes, Smooth Muscle</term>
<term>Respiratory Mucosa</term>
</keywords>
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<term>Antiasthmatiques</term>
<term>Chloroquine</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr">
<term>Asthme</term>
</keywords>
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<term>Adolescent</term>
<term>Adult</term>
<term>Aged</term>
<term>Aged, 80 and over</term>
<term>Animals</term>
<term>Case-Control Studies</term>
<term>Disease Models, Animal</term>
<term>Female</term>
<term>Gene Expression Regulation</term>
<term>Humans</term>
<term>Male</term>
<term>Mice</term>
<term>Mice, Inbred BALB C</term>
<term>Middle Aged</term>
<term>Primary Cell Culture</term>
<term>Signal Transduction</term>
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<term>Adolescent</term>
<term>Adulte</term>
<term>Adulte d'âge moyen</term>
<term>Animaux</term>
<term>Autophagie</term>
<term>Cils vibratiles</term>
<term>Culture primaire de cellules</term>
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<term>Humains</term>
<term>Modèles animaux de maladie humaine</term>
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<term>Myocytes du muscle lisse</term>
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<term>Poumon</term>
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<term>Souris de lignée BALB C</term>
<term>Sujet âgé</term>
<term>Sujet âgé de 80 ans ou plus</term>
<term>Transduction du signal</term>
<term>Études cas-témoins</term>
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<front>
<div type="abstract" xml:lang="en">Current asthma therapies fail to target airway remodeling that correlates with asthma severity driving disease progression that ultimately leads to loss of lung function. Macroautophagy (hereinafter "autophagy") is a fundamental cell-recycling mechanism in all eukaryotic cells; emerging evidence suggests that it is dysregulated in asthma. We investigated the interrelationship between autophagy and airway remodeling and assessed preclinical efficacy of a known autophagy inhibitor in murine models of asthma. Human asthmatic and nonasthmatic lung tissues were histologically evaluated and were immunostained for key autophagy markers. The percentage area of positive staining was quantified in the epithelium and airway smooth muscle bundles using ImageJ software. Furthermore, the autophagy inhibitor chloroquine was tested intranasally in prophylactic (3 wk) and treatment (5 wk) models of allergic asthma in mice. Human asthmatic tissues showed greater tissue inflammation and demonstrated hallmark features of airway remodeling, displaying thickened epithelium (
<i>P</i>
 < 0.001) and reticular basement membrane (
<i>P</i>
 < 0.0001), greater lamina propria depth (
<i>P</i>
 < 0.005), and increased airway smooth muscle bundles (
<i>P</i>
 < 0.001) with higher expression of Beclin-1 (
<i>P</i>
 < 0.01) and ATG5 (autophagy-related gene 5) (
<i>P</i>
 < 0.05) together with reduced p62 (
<i>P</i>
 < 0.05) compared with nonasthmatic control tissues. Beclin-1 expression was significantly higher in asthmatic epithelium and ciliated cells (
<i>P</i>
 < 0.05), suggesting a potential role of ciliophagy in asthma. Murine asthma models demonstrated effective preclinical efficacy (reduced key features of allergic asthma: airway inflammation, airway hyperresponsiveness, and airway remodeling) of the autophagy inhibitor chloroquine. Our data demonstrate cell context-dependent and selective activation of autophagy in structural cells in asthma. Furthermore, this pathway can be effectively targeted to ameliorate airway remodeling in asthma.</div>
</front>
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<Abstract>
<AbstractText>Current asthma therapies fail to target airway remodeling that correlates with asthma severity driving disease progression that ultimately leads to loss of lung function. Macroautophagy (hereinafter "autophagy") is a fundamental cell-recycling mechanism in all eukaryotic cells; emerging evidence suggests that it is dysregulated in asthma. We investigated the interrelationship between autophagy and airway remodeling and assessed preclinical efficacy of a known autophagy inhibitor in murine models of asthma. Human asthmatic and nonasthmatic lung tissues were histologically evaluated and were immunostained for key autophagy markers. The percentage area of positive staining was quantified in the epithelium and airway smooth muscle bundles using ImageJ software. Furthermore, the autophagy inhibitor chloroquine was tested intranasally in prophylactic (3 wk) and treatment (5 wk) models of allergic asthma in mice. Human asthmatic tissues showed greater tissue inflammation and demonstrated hallmark features of airway remodeling, displaying thickened epithelium (
<i>P</i>
 < 0.001) and reticular basement membrane (
<i>P</i>
 < 0.0001), greater lamina propria depth (
<i>P</i>
 < 0.005), and increased airway smooth muscle bundles (
<i>P</i>
 < 0.001) with higher expression of Beclin-1 (
<i>P</i>
 < 0.01) and ATG5 (autophagy-related gene 5) (
<i>P</i>
 < 0.05) together with reduced p62 (
<i>P</i>
 < 0.05) compared with nonasthmatic control tissues. Beclin-1 expression was significantly higher in asthmatic epithelium and ciliated cells (
<i>P</i>
 < 0.05), suggesting a potential role of ciliophagy in asthma. Murine asthma models demonstrated effective preclinical efficacy (reduced key features of allergic asthma: airway inflammation, airway hyperresponsiveness, and airway remodeling) of the autophagy inhibitor chloroquine. Our data demonstrate cell context-dependent and selective activation of autophagy in structural cells in asthma. Furthermore, this pathway can be effectively targeted to ameliorate airway remodeling in asthma.</AbstractText>
</Abstract>
<AuthorList CompleteYN="Y">
<Author ValidYN="Y">
<LastName>McAlinden</LastName>
<ForeName>Kielan D</ForeName>
<Initials>KD</Initials>
<AffiliationInfo>
<Affiliation>1 Graduate School of Health and.</Affiliation>
</AffiliationInfo>
<AffiliationInfo>
<Affiliation>3 School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo>
<Affiliation>2 Woolcock Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Deshpande</LastName>
<ForeName>Deepak A</ForeName>
<Initials>DA</Initials>
<AffiliationInfo>
<Affiliation>4 Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Ghavami</LastName>
<ForeName>Saeid</ForeName>
<Initials>S</Initials>
<AffiliationInfo>
<Affiliation>5 Department of Anatomy & Cell Science, University of Manitoba, Winnipeg, Manitoba, Canada; and.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Xenaki</LastName>
<ForeName>Dia</ForeName>
<Initials>D</Initials>
<AffiliationInfo>
<Affiliation>2 Woolcock Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Sohal</LastName>
<ForeName>Sukhwinder Singh</ForeName>
<Initials>SS</Initials>
<AffiliationInfo>
<Affiliation>6 Respiratory Translational Research Group, Department of Laboratory Medicine, University of Tasmania, Launceston, Tasmania, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Oliver</LastName>
<ForeName>Brian G</ForeName>
<Initials>BG</Initials>
<AffiliationInfo>
<Affiliation>3 School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo>
<Affiliation>2 Woolcock Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.</Affiliation>
</AffiliationInfo>
</Author>
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<LastName>Haghi</LastName>
<ForeName>Mehra</ForeName>
<Initials>M</Initials>
<AffiliationInfo>
<Affiliation>1 Graduate School of Health and.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Sharma</LastName>
<ForeName>Pawan</ForeName>
<Initials>P</Initials>
<Identifier Source="ORCID">0000-0002-2904-2306</Identifier>
<AffiliationInfo>
<Affiliation>3 School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.</Affiliation>
</AffiliationInfo>
<AffiliationInfo>
<Affiliation>2 Woolcock Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<GrantList CompleteYN="Y">
<Grant>
<GrantID>R01 HL137030</GrantID>
<Acronym>HL</Acronym>
<Agency>NHLBI NIH HHS</Agency>
<Country>United States</Country>
</Grant>
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<Chemical>
<RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C502778">ATG5 protein, human</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D018927">Anti-Asthmatic Agents</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000071187">Autophagy-Related Protein 5</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C491997">BECN1 protein, human</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000071186">Beclin-1</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C099718">SQSTM1 protein, human</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000071456">Sequestosome-1 Protein</NameOfSubstance>
</Chemical>
<Chemical>
<RegistryNumber>886U3H6UFF</RegistryNumber>
<NameOfSubstance UI="D002738">Chloroquine</NameOfSubstance>
</Chemical>
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<CitationSubset>IM</CitationSubset>
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<CommentsCorrections RefType="CommentIn">
<RefSource>Am J Respir Cell Mol Biol. 2019 May;60(5):494-496</RefSource>
<PMID Version="1">30423254</PMID>
</CommentsCorrections>
</CommentsCorrectionsList>
<MeshHeadingList>
<MeshHeading>
<DescriptorName UI="D000293" MajorTopicYN="N">Adolescent</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D000328" MajorTopicYN="N">Adult</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D000368" MajorTopicYN="N">Aged</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D000369" MajorTopicYN="N">Aged, 80 and over</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D056151" MajorTopicYN="N">Airway Remodeling</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D018927" MajorTopicYN="N">Anti-Asthmatic Agents</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D001249" MajorTopicYN="N">Asthma</DescriptorName>
<QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
<QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D001343" MajorTopicYN="N">Autophagy</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D000071187" MajorTopicYN="N">Autophagy-Related Protein 5</DescriptorName>
<QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D000071186" MajorTopicYN="N">Beclin-1</DescriptorName>
<QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D016022" MajorTopicYN="N">Case-Control Studies</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D002738" MajorTopicYN="N">Chloroquine</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D002923" MajorTopicYN="N">Cilia</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
<QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D004195" MajorTopicYN="N">Disease Models, Animal</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D005786" MajorTopicYN="N">Gene Expression Regulation</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D008168" MajorTopicYN="N">Lung</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
<QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D008807" MajorTopicYN="N">Mice, Inbred BALB C</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D008875" MajorTopicYN="N">Middle Aged</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D009130" MajorTopicYN="N">Muscle, Smooth</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
<QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D032389" MajorTopicYN="N">Myocytes, Smooth Muscle</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
<QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D061251" MajorTopicYN="N">Primary Cell Culture</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D020545" MajorTopicYN="N">Respiratory Mucosa</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
<QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D000071456" MajorTopicYN="N">Sequestosome-1 Protein</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
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<MeshHeading>
<DescriptorName UI="D015398" MajorTopicYN="N">Signal Transduction</DescriptorName>
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<Keyword MajorTopicYN="Y">Beclin-1</Keyword>
<Keyword MajorTopicYN="Y">asthma</Keyword>
<Keyword MajorTopicYN="Y">autophagy</Keyword>
<Keyword MajorTopicYN="Y">immunohistochemistry</Keyword>
<Keyword MajorTopicYN="Y">remodeling</Keyword>
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<li>Manitoba</li>
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