IL-4 increases surfactant and regulates metabolism in vivo.
Mice that express interleukin (IL)-4 in Clara cells (CCSP-IL-4) develop chronic airway inflammation and an alveolar proteinosis-like syndrome. To identify the role of IL-4 in surfactant homeostasis, we measured lipid and protein metabolism in the lungs of CCSP-IL-4 mice in vivo. Alveolar saturated phosphatidylcholine (Sat PC) pools were increased 6.5-fold and lung tissue Sat PC pools were increased 4. 8-fold in the IL-4 transgenic mice. Whereas surfactant protein (SP) A was increased proportionately to Sat PC, SP-D was increased approximately 90-fold in the IL-4 mice compared with wild-type mice and was associated with 2.8-fold increase in SP-D mRNA. The incorporation of palmitate and choline into Sat PC was increased about twofold in CCSP-IL-4 mice. Although trace doses of radiolabeled Sat PC were cleared from the air spaces and lungs of CCSP-IL-4 mice more slowly than in wild-type mice, net clearance of Sat PC from the lungs of CCSP-IL-4 mice was sixfold higher in the IL-4 mice than in wild-type mice because of the larger Sat PC pool sizes. Expression of IL-4 in Clara cells increased surfactant lipid synthesis and clearance, establishing a new equilibrium with increased surfactant pools and an alveolar proteinosis associated with a selective increase in SP-D protein, demonstrating a previously unexpected effect of IL-4 in pulmonary surfactant homeostasis.
Ikegami
M
M
Division of Pulmonary Biology, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA. machiko.ikegami@chmcc.org
Whitsett
J A
JA
Chroneos
Z C
ZC
Ross
G F
GF
Reed
J A
JA
Bachurski
C J
CJ
Jobe
A H
AH
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000493:pharmacokinetics; D000818:Animals; D015847:Interleukin-4 / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D010713:Phosphatidylcholines / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism; D011510:Proteolipids / Q000493:pharmacokinetics; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants / Q000235:genetics / Q000378:metabolism* / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000378:metabolism
D010713:Phosphatidylcholines; D010743:Phospholipids; D011355:Prodrugs; D011510:Proteolipids; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; D012333:RNA, Messenger; D015847:Interleukin-4; D015060:1,2-Dipalmitoylphosphatidylcholine