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2014 ; 320
(ä): 1-5
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One man s poison is another man s meat: using azithromycin-induced
phospholipidosis to promote ocular surface health
#MMPMID24613571
Liu Y
; Kam WR
; Ding J
; Sullivan DA
Toxicology
2014[Jun]; 320
(ä): 1-5
PMID24613571
show ga
Drug-induced phospholipidosis (PLD) is a common adverse effect which has led to
the termination of clinical trials for many candidate pharmaceuticals. However,
this lipid-inducing effect may be beneficial in the treatment of meibomian gland
dysfunction (MGD). MGD is the major cause of dry eye disease (DED), which affects
40 million people in the USA and has no cure. Azithromycin (AZM) is a
PLD-inducing antibiotic that is used off-label to treat MGD, and is presumably
effective because it suppresses the MGD-associated conjunctival inflammation
(i.e. posterior blepharitis) and growth of lid bacteria. We hypothesize that AZM
can act directly to promote the function of human meibomian gland epithelial
cells by inducing PLD in these cells, characterized by the accumulation of lipids
and lysosomes. Immortalized human meibomian gland epithelial cells (HMGEC) were
cultured with or without azithromycin for 5 days. Cells were evaluated for
cholesterol (Filipin) and neutral lipid (LipidTox) staining, as well as the
appearance of lysosomes (LysoTracker) and lamellar bodies (transmission electron
microscopy, TEM). The lipid composition of cellular lysates was analyzed by high
performance thin-layer chromatography. Our findings demonstrate that AZM
stimulates the accumulation of free cholesterol, neutral lipids and lysosomes in
HMGEC. This AZM-induced increase of neutral lipid content occurred predominantly
within lysosomes. Many of these vesicles appeared to be lamellar bodies by TEM,
which is the characteristic of PLD. Our findings also show that AZM promotes an
accumulation of free and esterified cholesterol, as well as phospholipids in
HMGECimmortalized. Our results support our hypothesis and confirm the beneficial
effect of PLD induced by AZM on HMGEC. Our discovery reveals a new potential use
of PLD-inducing drugs, and makes this adverse effect a beneficial effect.