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 3

Decreased antioxidant capacity and increased oxidant burden in Tlr4–/– mice.

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Decreased antioxidant capacity and increased oxidant burden in Tlr4–/– m...
(A) Total antioxidant activity was measured in the BAL of 3-month-old WT and Tlr4–/– mice (n = 5–6). (B) The ratio of reduced GSH to oxidized GSH was detected in BAL of 3-month-old WT and Tlr4–/– mice (n = 6). (C) Quantitation of flow cytometric results from dihydroethidine staining in total lung cells isolated from 3-month-old WT and Tlr4–/– mice (n = 3). MFI, mean fluorescence intensity. (D) Detection of O2– production by cytochrome C reduction assays in total lung cells isolated from 3-month-old WT and Tlr4–/– mice (n = 3). (E) Representative DNA oxidation detection by 8-OH-dG immunohistochemical staining in the lungs of 3-month-old WT and Tlr4–/– mice. Arrow indicates positive red staining for 8-OH-dG. Original magnification, ×400. (F) Graphical quantitation of 8-OH-dG–positive cells expressed as % of total cells in lung sections (n = 3). (G) Representative merged images of lung sections stained with TUNEL (green) and DAPI stain (blue) from 3-month-old WT and Tlr4–/– mice. Arrows indicate representative TUNEL-positive cells (blue-green). Original magnification, ×200 (top panels); ×400 (bottom panels). (H) Graphical quantitation of TUNEL-positive cells expressed as percent of total cells in lung sections (n = 3). Data are mean ± SEM. *P < 0.05 versus WT.