title: Annexin V decreases PS-mediated macrophage efferocytosis and deteriorates elastase-induced pulmonary emphysema in mice.
abstract: Efferocytosis is believed to be a key regulator for lung inflammation in chronic obstructive pulmonary disease. In this study we pharmacologically inhibited efferocytosis with annexin V and attempted to determine its impact on the progression of pulmonary emphysema in mouse. We first demonstrated in vitro and in vivo efferocytosis experiments using annexin V, an inhibitor for phosphatidylserine-mediated efferocytosis. We then inhibited efferocytosis in porcine pancreatic elastase (PPE)-treated mice. PPE-treated mice were instilled annexin V intranasally starting from day 8 until day 20. Mean linear intercept (Lm) was measured, and cell apoptosis was assessed in lung specimen obtained on day 21. Cell profile, apoptosis, and mRNA expression of matrix metalloproteinases (MMPs) and growth factors were evaluated in bronchoalveolar lavage (BAL) cells on day 15. Annexin V attenuated macrophage efferocytosis both in vitro and in vivo. PPE-treated mice had a significant higher Lm, and annexin V further increased that by 32%. More number of macrophages was found in BAL fluid in this group. Interestingly, cell apoptosis was not increased by annexin V treatment both in lung specimens and BAL fluid, but macrophages from mice treated with both PPE and annexin V expressed higher MMP-2 mRNA levels and had a trend for higher MMP-12 mRNA expression. mRNA expression of keratinocyte growth factor tended to be downregulated. We showed that inhibited efferocytosis with annexin V worsened elastase-induced pulmonary emphysema in mice, which was, at least partly, attributed to a lack of phenotypic change in macrophages toward anti-inflammatory one.
authors.affiliation: Dept. of Pulmonary Medicine, Keio Univ. School of Medicine, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Yoshida
authors.forename: N
authors.initials: N
authors.lastname: Minematsu
authors.forename: S
authors.initials: S
authors.lastname: Chubachi
authors.forename: H
authors.initials: H
authors.lastname: Nakamura
authors.forename: M
authors.initials: M
authors.lastname: Miyazaki
authors.forename: K
authors.initials: K
authors.lastname: Tsuduki
authors.forename: S
authors.initials: S
authors.lastname: Takahashi
authors.forename: T
authors.initials: T
authors.lastname: Miyasho
authors.forename: T
authors.initials: T
authors.lastname: Iwabuchi
authors.forename: R
authors.initials: R
authors.lastname: Takamiya
authors.forename: H
authors.initials: H
authors.lastname: Tateno
authors.forename: M
authors.initials: M
authors.lastname: Mouded
authors.forename: S D
authors.initials: SD
authors.lastname: Shapiro
authors.forename: K
authors.initials: K
authors.lastname: Asano
authors.forename: T
authors.initials: T
authors.lastname: Betsuyaku
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018893:Bronchoalveolar Lavage; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D016676:Macrophages, Alveolar / Q000201:enzymology* / Q000473:pathology; D053508:Matrix Metalloproteinase 12 / Q000096:biosynthesis; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D051379:Mice; D010196:Pancreatic Elastase / Q000009:adverse effects* / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D013552:Swine
chemical_list: D017304:Annexin A5; D012333:RNA, Messenger; D010196:Pancreatic Elastase; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12