Milk fat globule epidermal growth factor 8 attenuates acute lung injury in mice after intestinal ischemia and reperfusion

Tianpen Cui, Michael Miksa, Rongqian Wu, Hidefumi Komura, Mian Zhou, Weifeng Dong, Zhimin Wang, Shinya Higuchi, Wayne Chaung, Steven A. Blau, Corrado P. Marini, Thanjavur S. Ravikumar, Ping Wang

Research output: Contribution to journalArticle

84 Citations (Scopus)

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-/- 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 μg/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-α, IL-6, IL-1β, and myeloperoxidase) and injury of the lungs, liver, and kidneys. MFG-E8-deficient mice suffered from greatly increased inflammation and potentiated ALI, whereas treatment withrmMFG-E8significantly improved the survival in WTmice. Conclusions: MFG-E8 attenuates inflammation and ALI after gut I/R and may represent a novel therapeutic agent.

Original languageEnglish (US)
Pages (from-to)238-246
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume181
Issue number3
DOIs
StatePublished - Feb 1 2010
Externally publishedYes

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Acute Lung Injury
Epidermal Growth Factor
Reperfusion
Ischemia
Inflammation
Lung
Peroxidase
Spleen
Opsonin Proteins
Apoptosis
Superior Mesenteric Artery
milk fat globule
Lung Injury
Glomerulonephritis
Reperfusion Injury
Interleukin-1
Small Intestine
Interleukin-6
Sepsis
Pneumonia

Keywords

  • Apoptosis
  • Inflammation
  • Organ failure

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Milk fat globule epidermal growth factor 8 attenuates acute lung injury in mice after intestinal ischemia and reperfusion. / Cui, Tianpen; Miksa, Michael; Wu, Rongqian; Komura, Hidefumi; Zhou, Mian; Dong, Weifeng; Wang, Zhimin; Higuchi, Shinya; Chaung, Wayne; Blau, Steven A.; Marini, Corrado P.; Ravikumar, Thanjavur S.; Wang, Ping.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 181, No. 3, 01.02.2010, p. 238-246.

Research output: Contribution to journalArticle

Cui, T, Miksa, M, Wu, R, Komura, H, Zhou, M, Dong, W, Wang, Z, Higuchi, S, Chaung, W, Blau, SA, Marini, CP, Ravikumar, TS & Wang, P 2010, 'Milk fat globule epidermal growth factor 8 attenuates acute lung injury in mice after intestinal ischemia and reperfusion', American Journal of Respiratory and Critical Care Medicine, vol. 181, no. 3, pp. 238-246. https://doi.org/10.1164/rccm.200804-625OC
Cui, Tianpen ; Miksa, Michael ; Wu, Rongqian ; Komura, Hidefumi ; Zhou, Mian ; Dong, Weifeng ; Wang, Zhimin ; Higuchi, Shinya ; Chaung, Wayne ; Blau, Steven A. ; Marini, Corrado P. ; Ravikumar, Thanjavur S. ; Wang, Ping. / Milk fat globule epidermal growth factor 8 attenuates acute lung injury in mice after intestinal ischemia and reperfusion. In: American Journal of Respiratory and Critical Care Medicine. 2010 ; Vol. 181, No. 3. pp. 238-246.
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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-/- 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 μg/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-α, IL-6, IL-1β, and myeloperoxidase) and injury of the lungs, liver, and kidneys. MFG-E8-deficient mice suffered from greatly increased inflammation and potentiated ALI, whereas treatment withrmMFG-E8significantly improved the survival in WTmice. Conclusions: MFG-E8 attenuates inflammation and ALI after gut I/R and may represent a novel therapeutic agent.",
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AU - Zhou, Mian

AU - Dong, Weifeng

AU - Wang, Zhimin

AU - Higuchi, Shinya

AU - Chaung, Wayne

AU - Blau, Steven A.

AU - Marini, Corrado P.

AU - Ravikumar, Thanjavur S.

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