An amyloidogenic hexapeptide derived from amylin attenuates inflammation and acute lung injury in murine sepsis.
Although the accumulation of amyloidogenic proteins in neuroinflammatory conditions is generally considered pathologic, in a murine model of multiple sclerosis, amyloid-forming fibrils, comprised of hexapeptides, are anti-inflammatory. Whether these molecules modulate systemic inflammatory condition...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2018-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC6039005?pdf=render |
| _version_ | 1811270161003446272 |
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| author | Sidharth Mahapatra Lihua Ying Peggy Pui-Kay Ho Michael Kurnellas Jonathan Rothbard Lawrence Steinman David N Cornfield |
| author_facet | Sidharth Mahapatra Lihua Ying Peggy Pui-Kay Ho Michael Kurnellas Jonathan Rothbard Lawrence Steinman David N Cornfield |
| author_sort | Sidharth Mahapatra |
| collection | DOAJ |
| description | Although the accumulation of amyloidogenic proteins in neuroinflammatory conditions is generally considered pathologic, in a murine model of multiple sclerosis, amyloid-forming fibrils, comprised of hexapeptides, are anti-inflammatory. Whether these molecules modulate systemic inflammatory conditions remains unknown. We hypothesized that an amylin hexapeptide that forms fibrils can attenuate the systemic inflammatory response in a murine model of sepsis. To test this hypothesis, mice were pre-treated with either vehicle or amylin hexapeptide (20 μg) at 12 hours and 6 hours prior to intraperitoneal (i.p.) lipopolysaccharide (LPS, 20 mg/kg) administration. Illness severity and survival were monitored every 6 hours for 3 days. Levels of pro- (IL-6, TNF-α, IFN-γ) and anti-inflammatory (IL-10) cytokines were measured via ELISA at 1, 3, 6, 12, and 24 hours after LPS (i.p.). As a metric of lung injury, pulmonary artery endothelial cell (PAEC) barrier function was tested 24 hours after LPS administration by comparing lung wet-to-dry ratios, Evan's blue dye (EBD) extravasation, lung histology and caspase-3 activity. Compared to controls, pretreatment with amylin hexapeptide significantly reduced mortality (p<0.05 at 72 h), illness severity (p<0.05), and pro-inflammatory cytokine levels, while IL-10 levels were elevated (p<0.05). Amylin pretreatment attenuated LPS-induced lung injury, as demonstrated by decreased lung water and caspase-3 activity (p<0.05, versus PBS). Hence, in a murine model of systemic inflammation, pretreatment with amylin hexapeptide reduced mortality, disease severity, and preserved lung barrier function. Amylin hexapeptide may represent a novel therapeutic tool to mitigate sepsis severity and lung injury. |
| first_indexed | 2024-04-12T21:55:56Z |
| format | Article |
| id | doaj.art-218fbf9028644e6b88bd1cb3009cac2b |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T21:55:56Z |
| publishDate | 2018-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-218fbf9028644e6b88bd1cb3009cac2b2022-12-22T03:15:18ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01137e019920610.1371/journal.pone.0199206An amyloidogenic hexapeptide derived from amylin attenuates inflammation and acute lung injury in murine sepsis.Sidharth MahapatraLihua YingPeggy Pui-Kay HoMichael KurnellasJonathan RothbardLawrence SteinmanDavid N CornfieldAlthough the accumulation of amyloidogenic proteins in neuroinflammatory conditions is generally considered pathologic, in a murine model of multiple sclerosis, amyloid-forming fibrils, comprised of hexapeptides, are anti-inflammatory. Whether these molecules modulate systemic inflammatory conditions remains unknown. We hypothesized that an amylin hexapeptide that forms fibrils can attenuate the systemic inflammatory response in a murine model of sepsis. To test this hypothesis, mice were pre-treated with either vehicle or amylin hexapeptide (20 μg) at 12 hours and 6 hours prior to intraperitoneal (i.p.) lipopolysaccharide (LPS, 20 mg/kg) administration. Illness severity and survival were monitored every 6 hours for 3 days. Levels of pro- (IL-6, TNF-α, IFN-γ) and anti-inflammatory (IL-10) cytokines were measured via ELISA at 1, 3, 6, 12, and 24 hours after LPS (i.p.). As a metric of lung injury, pulmonary artery endothelial cell (PAEC) barrier function was tested 24 hours after LPS administration by comparing lung wet-to-dry ratios, Evan's blue dye (EBD) extravasation, lung histology and caspase-3 activity. Compared to controls, pretreatment with amylin hexapeptide significantly reduced mortality (p<0.05 at 72 h), illness severity (p<0.05), and pro-inflammatory cytokine levels, while IL-10 levels were elevated (p<0.05). Amylin pretreatment attenuated LPS-induced lung injury, as demonstrated by decreased lung water and caspase-3 activity (p<0.05, versus PBS). Hence, in a murine model of systemic inflammation, pretreatment with amylin hexapeptide reduced mortality, disease severity, and preserved lung barrier function. Amylin hexapeptide may represent a novel therapeutic tool to mitigate sepsis severity and lung injury.http://europepmc.org/articles/PMC6039005?pdf=render |
| spellingShingle | Sidharth Mahapatra Lihua Ying Peggy Pui-Kay Ho Michael Kurnellas Jonathan Rothbard Lawrence Steinman David N Cornfield An amyloidogenic hexapeptide derived from amylin attenuates inflammation and acute lung injury in murine sepsis. PLoS ONE |
| title | An amyloidogenic hexapeptide derived from amylin attenuates inflammation and acute lung injury in murine sepsis. |
| title_full | An amyloidogenic hexapeptide derived from amylin attenuates inflammation and acute lung injury in murine sepsis. |
| title_fullStr | An amyloidogenic hexapeptide derived from amylin attenuates inflammation and acute lung injury in murine sepsis. |
| title_full_unstemmed | An amyloidogenic hexapeptide derived from amylin attenuates inflammation and acute lung injury in murine sepsis. |
| title_short | An amyloidogenic hexapeptide derived from amylin attenuates inflammation and acute lung injury in murine sepsis. |
| title_sort | amyloidogenic hexapeptide derived from amylin attenuates inflammation and acute lung injury in murine sepsis |
| url | http://europepmc.org/articles/PMC6039005?pdf=render |
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