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Inhibition of PI3K promotes dilation of human small airways in a rho kinase‐dependent manner
Background and Purpose Asthma manifests as a heterogeneous syndrome characterized by airway obstruction, inflammation and hyperresponsiveness (AHR). Although the molecular mechanisms remain unclear, activation of specific PI3K isoforms mediate inflammation and AHR. We aimed to determine whether inhi...
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| Published in: | British journal of pharmacology 2016-09, Vol.173 (18), p.2726-2738 |
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| container_end_page | 2738 |
| container_issue | 18 |
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| container_title | British journal of pharmacology |
| container_volume | 173 |
| creator | Koziol‐White, Cynthia J Yoo, Edwin J Cao, Gaoyuan Zhang, Jie Papanikolaou, Eleni Pushkarsky, Ivan Andrews, Adam Himes, Blanca E Damoiseaux, Robert D Liggett, Stephen B Di Carlo, Dino Kurten, Richard C Panettieri, Reynold A |
| description | Background and Purpose
Asthma manifests as a heterogeneous syndrome characterized by airway obstruction, inflammation and hyperresponsiveness (AHR). Although the molecular mechanisms remain unclear, activation of specific PI3K isoforms mediate inflammation and AHR. We aimed to determine whether inhibition of PI3Kδ evokes dilation of airways and to elucidate potential mechanisms.
Experimental Approach
Human precision cut lung slices from non‐asthma donors and primary human airway smooth muscle (HASM) cells from both non‐asthma and asthma donors were utilized. Phosphorylation of Akt, myosin phosphatase target subunit 1 (MYPT1) and myosin light chain (MLC) were assessed in HASM cells following either PI3K inhibitor or siRNA treatment. HASM relaxation was assessed by micro‐pattern deformation. Reversal of constriction of airways was assessed following stimulation with PI3K or ROCK inhibitors.
Key Results
Soluble inhibitors or PI3Kδ knockdown reversed carbachol‐induced constriction of human airways, relaxed agonist‐contracted HASM and inhibited pAkt, pMYPT1 and pMLC in HASM. Similarly, inhibition of Rho kinase also dilated human PCLS airways and suppressed pMYPT1 and pMLC. Baseline pMYPT1 was significantly elevated in HASM cells derived from asthma donors in comparison with non‐asthma donors. After desensitization of the β2‐adrenoceptors, a PI3Kδ inhibitor remained an effective dilator. In the presence of IL‐13, dilation by a β agonist, but not PI3K inhibitor, was attenuated.
Conclusion and Implications
PI3Kδ inhibitors act as dilators of human small airways. Taken together, these findings provide alternative approaches to the clinical management of airway obstruction in asthma. |
| doi_str_mv | 10.1111/bph.13542 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4995285</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1977789604</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5132-a1dc526f746a51976081a49622b31f6ae27447f551b3a5a7281b90da271b051f3</originalsourceid><addsrcrecordid>eNp1kc1O3DAUhS3UihkoC14AWeqqi4CvE8fJBqkgfkZF6izoFutm4hAPiZ3aM0Wz4xF4Rp4Ew8CILvDGi_Pp85EPIfvADiGeo2poDyEVGd8iY8hknoi0gC9kzBiTCUBRjMhOCHPGYijFNhlxmQrO83JMbia2NZVZGGepa-h0kv6ig3e9W-hAa9Phe9Iue7Q09Nh1FI2_x1WgxlKkvnX0zlgM-unhsdaDtrW2Cxppq_038rXBLui9t3uX_Dk_uz69TK5-X0xOf14lMwEpTxDqmeB5I7McBZQyZwVgVuacVyk0OWous0w2QkCVokDJC6hKViOXUDEBTbpLjtfeYVn1up7FBh47NXjTo18ph0b9n1jTqlv3T2VlKXghouD7m8C7v0sdFmrult7Gzir2kbIoc5ZF6seamnkXgtfN5gVg6mUKFadQr1NE9uBjpQ35_vcROFoD96bTq89N6mR6uVY-Ayn0k78</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1977789604</pqid></control><display><type>article</type><title>Inhibition of PI3K promotes dilation of human small airways in a rho kinase‐dependent manner</title><source>Wiley-Blackwell Journals</source><source>PubMed Central</source><creator>Koziol‐White, Cynthia J ; Yoo, Edwin J ; Cao, Gaoyuan ; Zhang, Jie ; Papanikolaou, Eleni ; Pushkarsky, Ivan ; Andrews, Adam ; Himes, Blanca E ; Damoiseaux, Robert D ; Liggett, Stephen B ; Di Carlo, Dino ; Kurten, Richard C ; Panettieri, Reynold A</creator><creatorcontrib>Koziol‐White, Cynthia J ; Yoo, Edwin J ; Cao, Gaoyuan ; Zhang, Jie ; Papanikolaou, Eleni ; Pushkarsky, Ivan ; Andrews, Adam ; Himes, Blanca E ; Damoiseaux, Robert D ; Liggett, Stephen B ; Di Carlo, Dino ; Kurten, Richard C ; Panettieri, Reynold A</creatorcontrib><description>Background and Purpose
Asthma manifests as a heterogeneous syndrome characterized by airway obstruction, inflammation and hyperresponsiveness (AHR). Although the molecular mechanisms remain unclear, activation of specific PI3K isoforms mediate inflammation and AHR. We aimed to determine whether inhibition of PI3Kδ evokes dilation of airways and to elucidate potential mechanisms.
Experimental Approach
Human precision cut lung slices from non‐asthma donors and primary human airway smooth muscle (HASM) cells from both non‐asthma and asthma donors were utilized. Phosphorylation of Akt, myosin phosphatase target subunit 1 (MYPT1) and myosin light chain (MLC) were assessed in HASM cells following either PI3K inhibitor or siRNA treatment. HASM relaxation was assessed by micro‐pattern deformation. Reversal of constriction of airways was assessed following stimulation with PI3K or ROCK inhibitors.
Key Results
Soluble inhibitors or PI3Kδ knockdown reversed carbachol‐induced constriction of human airways, relaxed agonist‐contracted HASM and inhibited pAkt, pMYPT1 and pMLC in HASM. Similarly, inhibition of Rho kinase also dilated human PCLS airways and suppressed pMYPT1 and pMLC. Baseline pMYPT1 was significantly elevated in HASM cells derived from asthma donors in comparison with non‐asthma donors. After desensitization of the β2‐adrenoceptors, a PI3Kδ inhibitor remained an effective dilator. In the presence of IL‐13, dilation by a β agonist, but not PI3K inhibitor, was attenuated.
Conclusion and Implications
PI3Kδ inhibitors act as dilators of human small airways. Taken together, these findings provide alternative approaches to the clinical management of airway obstruction in asthma.</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1111/bph.13542</identifier><identifier>PMID: 27352269</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject>1-Phosphatidylinositol 3-kinase ; Airway management ; AKT protein ; Asthma ; Carbachol ; Cells, Cultured ; Deformation ; Deformation mechanisms ; Desensitization ; Dilation ; Dose-Response Relationship, Drug ; Humans ; Inhibition ; Inhibitors ; Interleukin 13 ; Isoforms ; Lungs ; Molecular modelling ; Muscles ; Myocytes, Smooth Muscle - drug effects ; Myosin ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Phosphorylation ; Protein Kinase Inhibitors - pharmacology ; Receptors (physiology) ; Research Paper ; Research Papers ; Respiratory tract ; Rho-associated kinase ; RNA, Small Interfering - pharmacology ; siRNA ; Smooth muscle ; Structure-Activity Relationship</subject><ispartof>British journal of pharmacology, 2016-09, Vol.173 (18), p.2726-2738</ispartof><rights>2016 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.</rights><rights>2016 The British Pharmacological Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5132-a1dc526f746a51976081a49622b31f6ae27447f551b3a5a7281b90da271b051f3</citedby><cites>FETCH-LOGICAL-c5132-a1dc526f746a51976081a49622b31f6ae27447f551b3a5a7281b90da271b051f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fbph.13542$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fbph.13542$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,1424,27957,27958,45609,45610,50923,51032,53827,53829</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27352269$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Koziol‐White, Cynthia J</creatorcontrib><creatorcontrib>Yoo, Edwin J</creatorcontrib><creatorcontrib>Cao, Gaoyuan</creatorcontrib><creatorcontrib>Zhang, Jie</creatorcontrib><creatorcontrib>Papanikolaou, Eleni</creatorcontrib><creatorcontrib>Pushkarsky, Ivan</creatorcontrib><creatorcontrib>Andrews, Adam</creatorcontrib><creatorcontrib>Himes, Blanca E</creatorcontrib><creatorcontrib>Damoiseaux, Robert D</creatorcontrib><creatorcontrib>Liggett, Stephen B</creatorcontrib><creatorcontrib>Di Carlo, Dino</creatorcontrib><creatorcontrib>Kurten, Richard C</creatorcontrib><creatorcontrib>Panettieri, Reynold A</creatorcontrib><title>Inhibition of PI3K promotes dilation of human small airways in a rho kinase‐dependent manner</title><title>British journal of pharmacology</title><addtitle>Br J Pharmacol</addtitle><description>Background and Purpose
Asthma manifests as a heterogeneous syndrome characterized by airway obstruction, inflammation and hyperresponsiveness (AHR). Although the molecular mechanisms remain unclear, activation of specific PI3K isoforms mediate inflammation and AHR. We aimed to determine whether inhibition of PI3Kδ evokes dilation of airways and to elucidate potential mechanisms.
Experimental Approach
Human precision cut lung slices from non‐asthma donors and primary human airway smooth muscle (HASM) cells from both non‐asthma and asthma donors were utilized. Phosphorylation of Akt, myosin phosphatase target subunit 1 (MYPT1) and myosin light chain (MLC) were assessed in HASM cells following either PI3K inhibitor or siRNA treatment. HASM relaxation was assessed by micro‐pattern deformation. Reversal of constriction of airways was assessed following stimulation with PI3K or ROCK inhibitors.
Key Results
Soluble inhibitors or PI3Kδ knockdown reversed carbachol‐induced constriction of human airways, relaxed agonist‐contracted HASM and inhibited pAkt, pMYPT1 and pMLC in HASM. Similarly, inhibition of Rho kinase also dilated human PCLS airways and suppressed pMYPT1 and pMLC. Baseline pMYPT1 was significantly elevated in HASM cells derived from asthma donors in comparison with non‐asthma donors. After desensitization of the β2‐adrenoceptors, a PI3Kδ inhibitor remained an effective dilator. In the presence of IL‐13, dilation by a β agonist, but not PI3K inhibitor, was attenuated.
Conclusion and Implications
PI3Kδ inhibitors act as dilators of human small airways. Taken together, these findings provide alternative approaches to the clinical management of airway obstruction in asthma.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>Airway management</subject><subject>AKT protein</subject><subject>Asthma</subject><subject>Carbachol</subject><subject>Cells, Cultured</subject><subject>Deformation</subject><subject>Deformation mechanisms</subject><subject>Desensitization</subject><subject>Dilation</subject><subject>Dose-Response Relationship, Drug</subject><subject>Humans</subject><subject>Inhibition</subject><subject>Inhibitors</subject><subject>Interleukin 13</subject><subject>Isoforms</subject><subject>Lungs</subject><subject>Molecular modelling</subject><subject>Muscles</subject><subject>Myocytes, Smooth Muscle - drug effects</subject><subject>Myosin</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphoinositide-3 Kinase Inhibitors</subject><subject>Phosphorylation</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Receptors (physiology)</subject><subject>Research Paper</subject><subject>Research Papers</subject><subject>Respiratory tract</subject><subject>Rho-associated kinase</subject><subject>RNA, Small Interfering - pharmacology</subject><subject>siRNA</subject><subject>Smooth muscle</subject><subject>Structure-Activity Relationship</subject><issn>0007-1188</issn><issn>1476-5381</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><recordid>eNp1kc1O3DAUhS3UihkoC14AWeqqi4CvE8fJBqkgfkZF6izoFutm4hAPiZ3aM0Wz4xF4Rp4Ew8CILvDGi_Pp85EPIfvADiGeo2poDyEVGd8iY8hknoi0gC9kzBiTCUBRjMhOCHPGYijFNhlxmQrO83JMbia2NZVZGGepa-h0kv6ig3e9W-hAa9Phe9Iue7Q09Nh1FI2_x1WgxlKkvnX0zlgM-unhsdaDtrW2Cxppq_038rXBLui9t3uX_Dk_uz69TK5-X0xOf14lMwEpTxDqmeB5I7McBZQyZwVgVuacVyk0OWous0w2QkCVokDJC6hKViOXUDEBTbpLjtfeYVn1up7FBh47NXjTo18ph0b9n1jTqlv3T2VlKXghouD7m8C7v0sdFmrult7Gzir2kbIoc5ZF6seamnkXgtfN5gVg6mUKFadQr1NE9uBjpQ35_vcROFoD96bTq89N6mR6uVY-Ayn0k78</recordid><startdate>201609</startdate><enddate>201609</enddate><creator>Koziol‐White, Cynthia J</creator><creator>Yoo, Edwin J</creator><creator>Cao, Gaoyuan</creator><creator>Zhang, Jie</creator><creator>Papanikolaou, Eleni</creator><creator>Pushkarsky, Ivan</creator><creator>Andrews, Adam</creator><creator>Himes, Blanca E</creator><creator>Damoiseaux, Robert D</creator><creator>Liggett, Stephen B</creator><creator>Di Carlo, Dino</creator><creator>Kurten, Richard C</creator><creator>Panettieri, Reynold A</creator><general>Blackwell Publishing Ltd</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TK</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>5PM</scope></search><sort><creationdate>201609</creationdate><title>Inhibition of PI3K promotes dilation of human small airways in a rho kinase‐dependent manner</title><author>Koziol‐White, Cynthia J ; Yoo, Edwin J ; Cao, Gaoyuan ; Zhang, Jie ; Papanikolaou, Eleni ; Pushkarsky, Ivan ; Andrews, Adam ; Himes, Blanca E ; Damoiseaux, Robert D ; Liggett, Stephen B ; Di Carlo, Dino ; Kurten, Richard C ; Panettieri, Reynold A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5132-a1dc526f746a51976081a49622b31f6ae27447f551b3a5a7281b90da271b051f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>Airway management</topic><topic>AKT protein</topic><topic>Asthma</topic><topic>Carbachol</topic><topic>Cells, Cultured</topic><topic>Deformation</topic><topic>Deformation mechanisms</topic><topic>Desensitization</topic><topic>Dilation</topic><topic>Dose-Response Relationship, Drug</topic><topic>Humans</topic><topic>Inhibition</topic><topic>Inhibitors</topic><topic>Interleukin 13</topic><topic>Isoforms</topic><topic>Lungs</topic><topic>Molecular modelling</topic><topic>Muscles</topic><topic>Myocytes, Smooth Muscle - drug effects</topic><topic>Myosin</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphoinositide-3 Kinase Inhibitors</topic><topic>Phosphorylation</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Receptors (physiology)</topic><topic>Research Paper</topic><topic>Research Papers</topic><topic>Respiratory tract</topic><topic>Rho-associated kinase</topic><topic>RNA, Small Interfering - pharmacology</topic><topic>siRNA</topic><topic>Smooth muscle</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Koziol‐White, Cynthia J</creatorcontrib><creatorcontrib>Yoo, Edwin J</creatorcontrib><creatorcontrib>Cao, Gaoyuan</creatorcontrib><creatorcontrib>Zhang, Jie</creatorcontrib><creatorcontrib>Papanikolaou, Eleni</creatorcontrib><creatorcontrib>Pushkarsky, Ivan</creatorcontrib><creatorcontrib>Andrews, Adam</creatorcontrib><creatorcontrib>Himes, Blanca E</creatorcontrib><creatorcontrib>Damoiseaux, Robert D</creatorcontrib><creatorcontrib>Liggett, Stephen B</creatorcontrib><creatorcontrib>Di Carlo, Dino</creatorcontrib><creatorcontrib>Kurten, Richard C</creatorcontrib><creatorcontrib>Panettieri, Reynold A</creatorcontrib><collection>Open Access: Wiley-Blackwell Open Access Journals</collection><collection>Wiley Online Library Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Koziol‐White, Cynthia J</au><au>Yoo, Edwin J</au><au>Cao, Gaoyuan</au><au>Zhang, Jie</au><au>Papanikolaou, Eleni</au><au>Pushkarsky, Ivan</au><au>Andrews, Adam</au><au>Himes, Blanca E</au><au>Damoiseaux, Robert D</au><au>Liggett, Stephen B</au><au>Di Carlo, Dino</au><au>Kurten, Richard C</au><au>Panettieri, Reynold A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of PI3K promotes dilation of human small airways in a rho kinase‐dependent manner</atitle><jtitle>British journal of pharmacology</jtitle><addtitle>Br J Pharmacol</addtitle><date>2016-09</date><risdate>2016</risdate><volume>173</volume><issue>18</issue><spage>2726</spage><epage>2738</epage><pages>2726-2738</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><notes>Contributed equally as first author.</notes><abstract>Background and Purpose
Asthma manifests as a heterogeneous syndrome characterized by airway obstruction, inflammation and hyperresponsiveness (AHR). Although the molecular mechanisms remain unclear, activation of specific PI3K isoforms mediate inflammation and AHR. We aimed to determine whether inhibition of PI3Kδ evokes dilation of airways and to elucidate potential mechanisms.
Experimental Approach
Human precision cut lung slices from non‐asthma donors and primary human airway smooth muscle (HASM) cells from both non‐asthma and asthma donors were utilized. Phosphorylation of Akt, myosin phosphatase target subunit 1 (MYPT1) and myosin light chain (MLC) were assessed in HASM cells following either PI3K inhibitor or siRNA treatment. HASM relaxation was assessed by micro‐pattern deformation. Reversal of constriction of airways was assessed following stimulation with PI3K or ROCK inhibitors.
Key Results
Soluble inhibitors or PI3Kδ knockdown reversed carbachol‐induced constriction of human airways, relaxed agonist‐contracted HASM and inhibited pAkt, pMYPT1 and pMLC in HASM. Similarly, inhibition of Rho kinase also dilated human PCLS airways and suppressed pMYPT1 and pMLC. Baseline pMYPT1 was significantly elevated in HASM cells derived from asthma donors in comparison with non‐asthma donors. After desensitization of the β2‐adrenoceptors, a PI3Kδ inhibitor remained an effective dilator. In the presence of IL‐13, dilation by a β agonist, but not PI3K inhibitor, was attenuated.
Conclusion and Implications
PI3Kδ inhibitors act as dilators of human small airways. Taken together, these findings provide alternative approaches to the clinical management of airway obstruction in asthma.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>27352269</pmid><doi>10.1111/bph.13542</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| source | Wiley-Blackwell Journals; PubMed Central |
| subjects | 1-Phosphatidylinositol 3-kinase Airway management AKT protein Asthma Carbachol Cells, Cultured Deformation Deformation mechanisms Desensitization Dilation Dose-Response Relationship, Drug Humans Inhibition Inhibitors Interleukin 13 Isoforms Lungs Molecular modelling Muscles Myocytes, Smooth Muscle - drug effects Myosin Phosphatidylinositol 3-Kinases - metabolism Phosphoinositide-3 Kinase Inhibitors Phosphorylation Protein Kinase Inhibitors - pharmacology Receptors (physiology) Research Paper Research Papers Respiratory tract Rho-associated kinase RNA, Small Interfering - pharmacology siRNA Smooth muscle Structure-Activity Relationship |
| title | Inhibition of PI3K promotes dilation of human small airways in a rho kinase‐dependent manner |
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