Toll-like receptor 4 deficiency causes pulmonary emphysema
Xuchen Zhang, … , Lauren Cohn, Patty J. Lee
Xuchen Zhang, … , Lauren Cohn, Patty J. Lee
Published November 1, 2006
Citation Information: J Clin Invest. 2006;116(11):3050-3059. https://doi.org/10.1172/JCI28139.
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Research Article Pulmonology

Toll-like receptor 4 deficiency causes pulmonary emphysema

Abstract

TLRs have been studied extensively in the context of pathogen challenges, yet their role in the unchallenged lung is unknown. Given their direct interface with the external environment, TLRs in the lungs are prime candidates to respond to air constituents, namely particulates and oxygen. The mechanism whereby the lung maintains structural integrity in the face of constant ambient exposures is essential to our understanding of lung disease. Emphysema is characterized by gradual loss of lung elasticity and irreversible airspace enlargement, usually in the later decades of life and after years of insult, most commonly cigarette smoke. Here we show Tlr4–/– mice exhibited emphysema as they aged. Adoptive transfer experiments revealed that TLR4 expression in lung structural cells was required for maintaining normal lung architecture. TLR4 deficiency led to the upregulation of what we believe to be a novel NADPH oxidase (Nox), Nox3, in lungs and endothelial cells, resulting in increased oxidant generation and elastolytic activity. Treatment of Tlr4–/– mice or endothelial cells with chemical NADPH inhibitors or Nox3 siRNA reversed the observed phenotype. Our data identify a role for TLR4 in maintaining constitutive lung integrity by modulating oxidant generation and provide insights into the development of emphysema.

Authors

Xuchen Zhang, Peiying Shan, Ge Jiang, Lauren Cohn, Patty J. Lee

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Figure 7

TLR4 deficiency leads to increased Nox3 expression in lung and lung endothelial cells.

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TLR4 deficiency leads to increased Nox3 expression in lung and lung end...
(A) Nox3 mRNA expression in 3-month-old WT and Tlr4–/– mouse lungs as detected by real-time RT-PCR (n = 3). (B) Nox3 protein expression in 3-month-old WT and Tlr4–/– mouse lungs (n = 3). (C) Nox3 mRNA expression in MLECs isolated from WT and Tlr4–/– mice as detected by real-time RT-PCR (n = 3). (D) Nox3 mRNA expression in WT MLECs transfected with nonspecific siRNA or TLR4 siRNA (80 nM) as detected by real-time RT-PCR compared with untransfected controls (n = 3). (E) Nox3 mRNA expression in WT MLECs transfected with nonspecific siRNA or Nox3 siRNA (80 nM) as detected by real time RT-PCR compared with untransfected controls (n = 3). (F) Elastolytic activity was detected in Tlr4–/– MLECs transfected with Nox3 siRNA or nonspecific siRNA and WT MLECs transfected with TLR4 siRNA or nonspecific siRNA (n = 3). Data are shown as mean ± SEM. *P < 0.05 versus WT (A and C), untransfected controls (D and E), and Tlr4–/– (F).