Inflammation induced by inhaled lipopolysaccharide depends on particle size in healthy volunteers
Aims In drug development, the anti‐inflammatory properties of new molecules in the lung are currently tested using the inhaled lipopolysaccharide (LPS) model. The total and regional lung bioavailability of inhaled particles depends significantly on their size. The objective of the present study was...
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| Veröffentlicht in: | British journal of clinical pharmacology 2016-11, Vol.82 (5), p.1371-1381 |
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| container_title | British journal of clinical pharmacology |
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| creator | Doyen, Virginie Pilcer, Gabrielle Dinh, Phong Huy Duc Corazza, Francis Bernard, Alfred Bergmann, Pierre Lefevre, Nicolas Amighi, Karim Michel, Olivier |
| description | Aims
In drug development, the anti‐inflammatory properties of new molecules in the lung are currently tested using the inhaled lipopolysaccharide (LPS) model. The total and regional lung bioavailability of inhaled particles depends significantly on their size. The objective of the present study was to compare inflammatory responses in healthy volunteers after the inhalation of LPS of varying droplet size.
Methods
Three nebulizers were characterized by different droplet size distributions [mean mass median aerodynamic diameters: Microcirrus (2.0 μm), MB2 (3.2 μm) and Pari (7.9 μm)]. Participants inhaled three boluses of a 20 μg (technetium 99 m‐labelled) solution of LPS, randomly delivered by each nebulizer. We measured the lung deposition of the nebulized LPS by gamma‐scintigraphy, while blood and sputum biomarkers were evaluated before and after challenges.
Results
MB2 and Pari achieved greater lung deposition than Microcirrus [171.5 (±72.9) and 217.6 (±97.8) counts pixel–1, respectively, vs. 67.9 (±20.6) counts pixel–1; P < 0.01]. MB2 and Pari caused higher levels of blood C‐reactive protein and more total cells and neutrophils in sputum compared with Microcirrus (P < 0.05). C‐reactive protein levels correlated positively with lung deposition (P < 0.01).
Conclusions
Inhalation of large droplets of LPS gave rise to greater lung deposition and induced a more pronounced systemic and bronchial inflammatory response than small droplets. The systemic inflammatory response correlated with lung deposition. NCT01081392. |
| doi_str_mv | 10.1111/bcp.13052 |
| format | Article |
| fullrecord | <record><control><sourceid>wiley_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5061781</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>BCP13052</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5552-d9e2b19687255a0d2cf86aa20f28c5ca20a9eb4ad481d1e992a777ac58ad4683</originalsourceid><addsrcrecordid>eNp1kEtPwzAQhC0EoqVw4A-gXDmktZ06jwsSVDwqVYJD79bG3hAj56E4BYVfjyFQwYG97Mie-VYaQs4ZnTM_i1y1cxZRwQ_IlEWxCDnj4pBMaUTjUHDBJuTEuRdKWcRicUwmPIkib0ymBNZ1YaGqoDdNHZha7xTqIB-8LMF6aU3btI0dHChVQmc0BhpbrLULfKCFrjfKYuDMO_pMUCLYvhyC18bu6h6xc6fkqADr8Ox7z8j27na7egg3j_fr1fUmVEIIHuoMec6yOE24EEA1V0UaA3Ba8FQJ5QVkmC9BL1OmGWYZhyRJQInUP8VpNCNXI7bd5RVqhXXfgZVtZyroBtmAkX9_alPK5-ZVChqzJGUecDkCVNc412GxzzIqP2uWvmb5VbP3Xvw-tnf-9OoNi9HwZiwO_5PkzeppRH4AAUeKXA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Inflammation induced by inhaled lipopolysaccharide depends on particle size in healthy volunteers</title><source>MEDLINE</source><source>Access via Wiley Online Library</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Wiley Online Library (Open Access Collection)</source><creator>Doyen, Virginie ; Pilcer, Gabrielle ; Dinh, Phong Huy Duc ; Corazza, Francis ; Bernard, Alfred ; Bergmann, Pierre ; Lefevre, Nicolas ; Amighi, Karim ; Michel, Olivier</creator><creatorcontrib>Doyen, Virginie ; Pilcer, Gabrielle ; Dinh, Phong Huy Duc ; Corazza, Francis ; Bernard, Alfred ; Bergmann, Pierre ; Lefevre, Nicolas ; Amighi, Karim ; Michel, Olivier</creatorcontrib><description>Aims
In drug development, the anti‐inflammatory properties of new molecules in the lung are currently tested using the inhaled lipopolysaccharide (LPS) model. The total and regional lung bioavailability of inhaled particles depends significantly on their size. The objective of the present study was to compare inflammatory responses in healthy volunteers after the inhalation of LPS of varying droplet size.
Methods
Three nebulizers were characterized by different droplet size distributions [mean mass median aerodynamic diameters: Microcirrus (2.0 μm), MB2 (3.2 μm) and Pari (7.9 μm)]. Participants inhaled three boluses of a 20 μg (technetium 99 m‐labelled) solution of LPS, randomly delivered by each nebulizer. We measured the lung deposition of the nebulized LPS by gamma‐scintigraphy, while blood and sputum biomarkers were evaluated before and after challenges.
Results
MB2 and Pari achieved greater lung deposition than Microcirrus [171.5 (±72.9) and 217.6 (±97.8) counts pixel–1, respectively, vs. 67.9 (±20.6) counts pixel–1; P < 0.01]. MB2 and Pari caused higher levels of blood C‐reactive protein and more total cells and neutrophils in sputum compared with Microcirrus (P < 0.05). C‐reactive protein levels correlated positively with lung deposition (P < 0.01).
Conclusions
Inhalation of large droplets of LPS gave rise to greater lung deposition and induced a more pronounced systemic and bronchial inflammatory response than small droplets. The systemic inflammatory response correlated with lung deposition. NCT01081392.</description><identifier>ISSN: 0306-5251</identifier><identifier>EISSN: 1365-2125</identifier><identifier>DOI: 10.1111/bcp.13052</identifier><identifier>PMID: 27331367</identifier><language>eng</language><publisher>England: John Wiley and Sons Inc</publisher><subject>Administration, Inhalation ; Adolescent ; Adult ; asthma ; C-Reactive Protein - metabolism ; Cell Count ; endotoxin ; Female ; Healthy Volunteers ; Humans ; inflammation ; Inflammation - chemically induced ; Inflammation - metabolism ; Lipopolysaccharides - administration & dosage ; Lipopolysaccharides - pharmacokinetics ; Lung - metabolism ; lung deposition ; Male ; Methods in Clinical Pharmacology ; Middle Aged ; Nebulizers and Vaporizers ; Neutrophils - drug effects ; Particle Size ; Radionuclide Imaging ; Sputum - cytology ; Technetium - administration & dosage ; Technetium - pharmacokinetics ; Young Adult</subject><ispartof>British journal of clinical pharmacology, 2016-11, Vol.82 (5), p.1371-1381</ispartof><rights>2016 The 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-c5552-d9e2b19687255a0d2cf86aa20f28c5ca20a9eb4ad481d1e992a777ac58ad4683</citedby><cites>FETCH-LOGICAL-c5552-d9e2b19687255a0d2cf86aa20f28c5ca20a9eb4ad481d1e992a777ac58ad4683</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%2Fbcp.13052$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fbcp.13052$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1417,1433,27924,27925,45574,45575,46409,46833</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27331367$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Doyen, Virginie</creatorcontrib><creatorcontrib>Pilcer, Gabrielle</creatorcontrib><creatorcontrib>Dinh, Phong Huy Duc</creatorcontrib><creatorcontrib>Corazza, Francis</creatorcontrib><creatorcontrib>Bernard, Alfred</creatorcontrib><creatorcontrib>Bergmann, Pierre</creatorcontrib><creatorcontrib>Lefevre, Nicolas</creatorcontrib><creatorcontrib>Amighi, Karim</creatorcontrib><creatorcontrib>Michel, Olivier</creatorcontrib><title>Inflammation induced by inhaled lipopolysaccharide depends on particle size in healthy volunteers</title><title>British journal of clinical pharmacology</title><addtitle>Br J Clin Pharmacol</addtitle><description>Aims
In drug development, the anti‐inflammatory properties of new molecules in the lung are currently tested using the inhaled lipopolysaccharide (LPS) model. The total and regional lung bioavailability of inhaled particles depends significantly on their size. The objective of the present study was to compare inflammatory responses in healthy volunteers after the inhalation of LPS of varying droplet size.
Methods
Three nebulizers were characterized by different droplet size distributions [mean mass median aerodynamic diameters: Microcirrus (2.0 μm), MB2 (3.2 μm) and Pari (7.9 μm)]. Participants inhaled three boluses of a 20 μg (technetium 99 m‐labelled) solution of LPS, randomly delivered by each nebulizer. We measured the lung deposition of the nebulized LPS by gamma‐scintigraphy, while blood and sputum biomarkers were evaluated before and after challenges.
Results
MB2 and Pari achieved greater lung deposition than Microcirrus [171.5 (±72.9) and 217.6 (±97.8) counts pixel–1, respectively, vs. 67.9 (±20.6) counts pixel–1; P < 0.01]. MB2 and Pari caused higher levels of blood C‐reactive protein and more total cells and neutrophils in sputum compared with Microcirrus (P < 0.05). C‐reactive protein levels correlated positively with lung deposition (P < 0.01).
Conclusions
Inhalation of large droplets of LPS gave rise to greater lung deposition and induced a more pronounced systemic and bronchial inflammatory response than small droplets. The systemic inflammatory response correlated with lung deposition. NCT01081392.</description><subject>Administration, Inhalation</subject><subject>Adolescent</subject><subject>Adult</subject><subject>asthma</subject><subject>C-Reactive Protein - metabolism</subject><subject>Cell Count</subject><subject>endotoxin</subject><subject>Female</subject><subject>Healthy Volunteers</subject><subject>Humans</subject><subject>inflammation</subject><subject>Inflammation - chemically induced</subject><subject>Inflammation - metabolism</subject><subject>Lipopolysaccharides - administration & dosage</subject><subject>Lipopolysaccharides - pharmacokinetics</subject><subject>Lung - metabolism</subject><subject>lung deposition</subject><subject>Male</subject><subject>Methods in Clinical Pharmacology</subject><subject>Middle Aged</subject><subject>Nebulizers and Vaporizers</subject><subject>Neutrophils - drug effects</subject><subject>Particle Size</subject><subject>Radionuclide Imaging</subject><subject>Sputum - cytology</subject><subject>Technetium - administration & dosage</subject><subject>Technetium - pharmacokinetics</subject><subject>Young Adult</subject><issn>0306-5251</issn><issn>1365-2125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kEtPwzAQhC0EoqVw4A-gXDmktZ06jwsSVDwqVYJD79bG3hAj56E4BYVfjyFQwYG97Mie-VYaQs4ZnTM_i1y1cxZRwQ_IlEWxCDnj4pBMaUTjUHDBJuTEuRdKWcRicUwmPIkib0ymBNZ1YaGqoDdNHZha7xTqIB-8LMF6aU3btI0dHChVQmc0BhpbrLULfKCFrjfKYuDMO_pMUCLYvhyC18bu6h6xc6fkqADr8Ox7z8j27na7egg3j_fr1fUmVEIIHuoMec6yOE24EEA1V0UaA3Ba8FQJ5QVkmC9BL1OmGWYZhyRJQInUP8VpNCNXI7bd5RVqhXXfgZVtZyroBtmAkX9_alPK5-ZVChqzJGUecDkCVNc412GxzzIqP2uWvmb5VbP3Xvw-tnf-9OoNi9HwZiwO_5PkzeppRH4AAUeKXA</recordid><startdate>201611</startdate><enddate>201611</enddate><creator>Doyen, Virginie</creator><creator>Pilcer, Gabrielle</creator><creator>Dinh, Phong Huy Duc</creator><creator>Corazza, Francis</creator><creator>Bernard, Alfred</creator><creator>Bergmann, Pierre</creator><creator>Lefevre, Nicolas</creator><creator>Amighi, Karim</creator><creator>Michel, Olivier</creator><general>John Wiley and Sons Inc</general><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>5PM</scope></search><sort><creationdate>201611</creationdate><title>Inflammation induced by inhaled lipopolysaccharide depends on particle size in healthy volunteers</title><author>Doyen, Virginie ; Pilcer, Gabrielle ; Dinh, Phong Huy Duc ; Corazza, Francis ; Bernard, Alfred ; Bergmann, Pierre ; Lefevre, Nicolas ; Amighi, Karim ; Michel, Olivier</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5552-d9e2b19687255a0d2cf86aa20f28c5ca20a9eb4ad481d1e992a777ac58ad4683</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Administration, Inhalation</topic><topic>Adolescent</topic><topic>Adult</topic><topic>asthma</topic><topic>C-Reactive Protein - metabolism</topic><topic>Cell Count</topic><topic>endotoxin</topic><topic>Female</topic><topic>Healthy Volunteers</topic><topic>Humans</topic><topic>inflammation</topic><topic>Inflammation - chemically induced</topic><topic>Inflammation - metabolism</topic><topic>Lipopolysaccharides - administration & dosage</topic><topic>Lipopolysaccharides - pharmacokinetics</topic><topic>Lung - metabolism</topic><topic>lung deposition</topic><topic>Male</topic><topic>Methods in Clinical Pharmacology</topic><topic>Middle Aged</topic><topic>Nebulizers and Vaporizers</topic><topic>Neutrophils - drug effects</topic><topic>Particle Size</topic><topic>Radionuclide Imaging</topic><topic>Sputum - cytology</topic><topic>Technetium - administration & dosage</topic><topic>Technetium - pharmacokinetics</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Doyen, Virginie</creatorcontrib><creatorcontrib>Pilcer, Gabrielle</creatorcontrib><creatorcontrib>Dinh, Phong Huy Duc</creatorcontrib><creatorcontrib>Corazza, Francis</creatorcontrib><creatorcontrib>Bernard, Alfred</creatorcontrib><creatorcontrib>Bergmann, Pierre</creatorcontrib><creatorcontrib>Lefevre, Nicolas</creatorcontrib><creatorcontrib>Amighi, Karim</creatorcontrib><creatorcontrib>Michel, Olivier</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Doyen, Virginie</au><au>Pilcer, Gabrielle</au><au>Dinh, Phong Huy Duc</au><au>Corazza, Francis</au><au>Bernard, Alfred</au><au>Bergmann, Pierre</au><au>Lefevre, Nicolas</au><au>Amighi, Karim</au><au>Michel, Olivier</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inflammation induced by inhaled lipopolysaccharide depends on particle size in healthy volunteers</atitle><jtitle>British journal of clinical pharmacology</jtitle><addtitle>Br J Clin Pharmacol</addtitle><date>2016-11</date><risdate>2016</risdate><volume>82</volume><issue>5</issue><spage>1371</spage><epage>1381</epage><pages>1371-1381</pages><issn>0306-5251</issn><eissn>1365-2125</eissn><abstract>Aims
In drug development, the anti‐inflammatory properties of new molecules in the lung are currently tested using the inhaled lipopolysaccharide (LPS) model. The total and regional lung bioavailability of inhaled particles depends significantly on their size. The objective of the present study was to compare inflammatory responses in healthy volunteers after the inhalation of LPS of varying droplet size.
Methods
Three nebulizers were characterized by different droplet size distributions [mean mass median aerodynamic diameters: Microcirrus (2.0 μm), MB2 (3.2 μm) and Pari (7.9 μm)]. Participants inhaled three boluses of a 20 μg (technetium 99 m‐labelled) solution of LPS, randomly delivered by each nebulizer. We measured the lung deposition of the nebulized LPS by gamma‐scintigraphy, while blood and sputum biomarkers were evaluated before and after challenges.
Results
MB2 and Pari achieved greater lung deposition than Microcirrus [171.5 (±72.9) and 217.6 (±97.8) counts pixel–1, respectively, vs. 67.9 (±20.6) counts pixel–1; P < 0.01]. MB2 and Pari caused higher levels of blood C‐reactive protein and more total cells and neutrophils in sputum compared with Microcirrus (P < 0.05). C‐reactive protein levels correlated positively with lung deposition (P < 0.01).
Conclusions
Inhalation of large droplets of LPS gave rise to greater lung deposition and induced a more pronounced systemic and bronchial inflammatory response than small droplets. The systemic inflammatory response correlated with lung deposition. NCT01081392.</abstract><cop>England</cop><pub>John Wiley and Sons Inc</pub><pmid>27331367</pmid><doi>10.1111/bcp.13052</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | British journal of clinical pharmacology, 2016-11, Vol.82 (5), p.1371-1381 |
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| source | MEDLINE; Access via Wiley Online Library; EZB-FREE-00999 freely available EZB journals; Wiley Online Library (Open Access Collection) |
| subjects | Administration, Inhalation Adolescent Adult asthma C-Reactive Protein - metabolism Cell Count endotoxin Female Healthy Volunteers Humans inflammation Inflammation - chemically induced Inflammation - metabolism Lipopolysaccharides - administration & dosage Lipopolysaccharides - pharmacokinetics Lung - metabolism lung deposition Male Methods in Clinical Pharmacology Middle Aged Nebulizers and Vaporizers Neutrophils - drug effects Particle Size Radionuclide Imaging Sputum - cytology Technetium - administration & dosage Technetium - pharmacokinetics Young Adult |
| title | Inflammation induced by inhaled lipopolysaccharide depends on particle size in healthy volunteers |
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