MFG-E8, a clearance glycoprotein of apoptotic cells, as a new marker of disease severity in chronic obstructive pulmonary disease

Abstract

Milk fat globule epidermal growth factor 8 (MFG-E8) is an opsonin involved in the phagocytosis of apoptotic cells. In patients with chronic obstructive pulmonary disease (COPD), apoptotic cell clearance is defective. However, whether aberrant MFG-E8 expression is involved in this defect is unknown. In this study, we examined the expression of MFG-E8 in COPD patients. MFG-E8, interleukin (IL)-1β and transforming growth factor (TGF)-β levels were measured in the plasma of 96 COPD patients (93 males, 3 females; age range: 62.12±10.39) and 87 age-matched healthy controls (85 males, 2 females; age range: 64.81±10.11 years) using an enzyme-linked immunosorbent assay. Compared with controls, COPD patients had a significantly lower plasma MFG-E8 levels (P<0.01) and significantly higher plasma TGF-β levels (P=0.002), whereas there was no difference in plasma IL-1β levels between the two groups. Moreover, plasma MFG-E8 levels decreased progressively between Global Initiative for Chronic Obstructive Lung Disease (GOLD) I and GOLD IV stage COPD. Multiple regression analysis showed that the forced expiratory volume in 1 s (FEV1 % predicted) and smoking habit were powerful predictors of MFG-E8 in COPD (P<0.01 and P=0.026, respectively). MFG-E8 was positively associated with the FEV1 % predicted and negatively associated with smoking habit. The area under the receiver operating characteristic curve was 0.874 (95% confidence interval: 0.798-0.95; P<0.01). Our findings demonstrated the utility of MFG-E8 as a marker of disease severity in COPD and that cigarette smoke impaired MFG-E8 expression in these patients.

Elevated serum milk fat globule‐epidermal growth factor 8 levels in type 2 diabetic patients are suppressed by overweight or obese status

“…Moreover, there was a significant negative and independent correlation between circulating MFG‐E8 and BMI in all subjects. These results are consistent with the result of decreased MFG‐E8 levels in many human and animal diseases, including CHD, COPD, RA, sepsis, acute colitis and intestinal and spleen ischemia/perfusion injury , in which MFG‐E8 plays an anti‐inflammatory role. The mechanisms underlying the decrease in MFG‐E8 levels in overweight or obese subjects remain elusive.…”

“…In addition to its key role in phagocytosis, MFG‐E8 plays many pleiotropic roles in processes like aging, angiogenesis, tissue remodeling and tumor progression . Recently, its anti‐inflammatory properties have been implicated in a number of human diseases such as coronary atherosclerotic heart disease (CHD), chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA) and ulcerative colitis . There has been a growing clinical interest in treatment strategies using exogenous recombinant MFG‐E8 for relieving inflammation by reducing proinflammatory cytokines including TNF‐α, IL‐1β and IL‐6, in a number of animal models, showing sepsis, ischemia–reperfusion‐induced cerebral, hepatic and intestinal injuries .…”

Recombinant milk fat globule-EGF factor-8 reduces apoptosis via integrin β3/FAK/PI3K/AKT signaling pathway in rats after traumatic brain injury

“…Furthermore, the administration of recombinant human MFG-E8 (rhMFG-E8) could attenuate cerebral injury through suppression of inflammation and apoptosis in cerebral ischemia 5 , 12 . Both in vitro and in vivo, MFG-E8 promotes the engulfment of apoptosis cells by acting as a conjunctive molecule that combines with phosphatidylserine and α v β3-integrin on apoptotic cells and macrophages, respectively 13 – 15 . Meanwhile, focal adhesion kinase (FAK), as the downstream molecule of the integrin receptor, activates the downstream effector protein kinase B (AKT) to inhibit apoptosis 16 , 17 .…”

Circulating milk fat globule‐epidermal growth factor 8 levels are increased in pregnancy and gestational diabetes mellitus

“…In mice, the long variant shows a limited tissue distribution, and is predominant during the late stages of gestation and during lactation; whereas the short form is expressed in various tissues, and substantially decreases in a lactation‐dependent manner. To date, MFG‐E8 has been implicated in various human inflammatory diseases, and shows an anti‐inflammation property in coronary atherosclerotic heart disease, chronic obstructive pulmonary disease, ulcerative colitis and rheumatoid arthritis, whereas inversely in brain ischemia and atherosclerosis. Although known to be a mediator of inflammation, MFG‐E8 is a multifunctional molecule that is involved in several cell surface‐mediated regulatory events, such as tissue remodeling, tumor promotion, angiogenesis and facilitation of fertilization.…”