Milk Fat Globule Epidermal Growth Factor 8 Attenuates Acute Lung Injury in Mice after Intestinal Ischemia and Reperfusion

Abstract

Rationale: Milk fat globule epidermal growth factor 8 (MFG-E8) is a potent opsonin for the clearance of apoptotic cells and is produced by mononuclear cells of immune competent organs including the spleen and lungs. It attenuates chronic and acute inflammation such as autoimmune glomerulonephritis and bacterial sepsis by enhancing apoptotic cell clearance. Ischemia-reperfusion (I/R) injury of the gut results in severe inflammation, apoptosis, and remote organ damage, including acute lung injury (ALI). Objectives: To determine whether MFG-E8 attenuates intestinal and pulmonary inflammation after gut I/R. Methods: Wild-type (WT) and MFG-E8 2/2 mice underwent superior mesenteric artery occlusion for 90 minutes, followed by reperfusion for 4 hours. A group of WT mice was treated with 0.4 mg/20 g recombinant murine MFG-E8 (rmMFG-E8) at the beginning of reperfusion. Four hours after reperfusion, MFG-E8, cytokines, myeloperoxidase activity, apoptosis, and histopathology were assessed. A 24-hour survival study was conducted in rmMFG-E8-and vehicletreated WT mice. Measurements and Main Results: Mesenteric I/R caused severe widespread injury and inflammation of the small intestines and remote organs, including the lungs. MFG-E8 levels decreased in the spleen and lungs by 50 to 60%, suggesting impaired apoptotic cell clearance. Treatment with rmMFG-E8 significantly suppressed inflammation (TNF-a, IL-6, IL-1b, and myeloperoxidase) and injury of the lungs, liver, and kidneys. MFG-E8-deficient mice suffered from greatly increased inflammation and potentiated ALI, whereas treatment with rmMFG-E8 significantly improved the survival in WT mice. Conclusions: MFG-E8 attenuates inflammation and ALI after gut I/R and may represent a novel therapeutic agent.

Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction

“…We have previously found no differences in lung inflammation in bleomycin-treated Mfge8 −/− mice (29). Other studies have shown that Mfge8 −/− mice develop exaggerated lung inflammation after intratracheal LPS instillation or after reperfusion injury secondary to intestinal ischemia (42,43). Given the important role of the immune system in asthma, we were curious to determine whether there would be differences in airway inflammation in Ova-challenged Mfge8 −/− mice.…”

Role of milk fat globule-epidermal growth factor 8 in osteoimmunology

“…In pathophysiological conditions such as sepsis, 34 I/R injury, 35,36 ulcerative colitis 37,38 and atherosclerosis, 39 a significant downregulation of MFG-E8 was reported (Figure 1). For instance, tissue concentrations of MFG-E8 in septic rats have been described to decrease while the number of apoptotic cells increased simultaneously.…”

“…For example, treatment with recombinant MFG-E8 accelerated mucosal healing in various models of I/R injury models as well as in septic mice and mice with radiation-induced intestinal mucosal damage. 36,[44][45][46][47][48] In most cases, the increased clearance of apoptotic cells, the reduced inflammation and an increase in epithelial cell proliferation have been described as underlying mechanisms. Importantly, treatment with recombinant MFG-E8 has been shown to both, prevent colitis when given before disease onset and ameliorate disease burden when given once the full-blown disease was established.…”

Butyric acid attenuates intestinal inflammation in murine DSS-induced colitis model via milk fat globule-EGF factor 8

“…28 Also, Chogle et al 29 demonstrated that MFG-E8KO mice develop more severe crypt-epithelial injury during the onset of DSSinduced acute colitis, 29 whereas a recent study revealed the anti-inflammatory effects of recombinant MFG-E8 protein in a mouse model of ischemia and reperfusion-induced intestinal injuries. 16 Thus, a beneficial effect of MFG-E8 on downregulation of inflammation has been shown. In this study, we demonstrated its anti-inflammatory function via modulation of butyric acid during acute colitis.…”

“…12,13 Several studies have revealed that MFG-E8 has important roles in the pathogenesis of inflammatory and autoimmune diseases, as well as sepsis, atherosclerosis, and neurodegenerative disorders, [14][15][16] whereas recent findings have also revealed that MFG-E8 mRNA and protein levels were lower in inflamed intestinal specimens obtained during biopsies from patients with ulcerative colitis (UC) as compared with control biopsy specimens. 17 Those features have been suggested to be dependent not only on enhanced clearance of apoptotic cells but also on various novel molecular mechanisms.…”