TLR signaling prevents hyperoxia-induced lung injury by protecting the alveolar epithelium from oxidant-mediated death.
Mechanical ventilation using high oxygen tensions is often necessary to treat patients with respiratory failure. Recently, TLRs were identified as regulators of noninfectious oxidative lung injury. IRAK-M is an inhibitor of MyD88-dependent TLR signaling. Exposure of mice deficient in IRAK-M (IRAK-M(-/-)) to 95% oxygen resulted in reduced mortality compared with wild-type mice and occurred in association with decreased alveolar permeability and cell death. Using a bone marrow chimera model, we determined that IRAK-M's effects were mediated by structural cells rather than bone marrow-derived cells. We confirmed the expression of IRAK-M in alveolar epithelial cells (AECs) and showed that hyperoxia can induce the expression of this protein. In addition, IRAK-M(-/-) AECs exposed to hyperoxia experienced a decrease in cell death. IRAK-M may potentiate hyperoxic injury by suppression of key antioxidant pathways, because lungs and AECs isolated from IRAK-M(-/-) mice have increased expression/activity of heme oxygenase-1, a phase II antioxidant, and NF (erythroid-derived)-related factor-2, a transcription factor that initiates antioxidant generation. Treatment of IRAK-M(-/-) mice in vivo and IRAK-M(-/-) AECs in vitro with the heme oxygenase-1 inhibitor, tin protoporphyrin, substantially decreased survival and significantly reduced the number of live cells after hyperoxia exposure. Collectively, our data suggest that IRAK-M inhibits the induction of antioxidants essential for protecting the lungs against cell death, resulting in enhanced susceptibility to hyperoxic lung injury.
Division of Pulmonary and Critical Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Megan N
MN
Ballinger
Michael W
MW
Newstead
Xianying
X
Zeng
Urvashi
U
Bhan
Jeffrey C
JC
Horowitz
Bethany B
BB
Moore
David J
DJ
Pinsky
Richard A
RA
Flavell
Theodore J
TJ
Standiford
D055371:Acute Lung Injury / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D018496:Hyperoxia / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors / Q000502:physiology; D016877:Oxidants / Q000502:physiology*; D011650:Pulmonary Alveoli / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*
C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016877:Oxidants; D051193:Toll-Like Receptors; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse