TLR4 deficiency promotes autophagy during cigarette smoke-induced pulmonary emphysema. Academic Article uri icon

Overview

MeSH

  • Aged
  • Aged, 80 and over
  • Animals
  • Apoptosis
  • Case-Control Studies
  • Caspase 3
  • Cells, Cultured
  • Female
  • Gene Expression
  • Humans
  • Lung
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins
  • Middle Aged
  • Oxidative Stress
  • Primary Cell Culture

MeSH Major

  • Autophagy
  • Pulmonary Disease, Chronic Obstructive
  • Pulmonary Emphysema
  • Smoking
  • Toll-Like Receptor 4

abstract

  • Toll-like receptors (TLRs) exert important nonimmune functions in lung homeostasis. TLR4 deficiency promotes pulmonary emphysema. We examined the role of TLR4 in regulating cigarette smoke (CS)-induced autophagy, apoptosis, and emphysema. Lung tissue was obtained from chronic obstructive lung disease (COPD) patients. C3H/HeJ (Tlr4-mutated) mice and C57BL/10ScNJ (Tlr4-deficient) mice and their respective control strains were exposed to chronic CS or air. Human or mouse epithelial cells (wild-type, Tlr4-knockdown, and Tlr4-deficient) were exposed to CS-extract (CSE). Samples were analyzed for TLR4 expression, and for autophagic or apoptotic proteins by Western blot analysis or confocal imaging. Chronic obstructive lung disease lung tissues and human pulmonary epithelial cells exposed to CSE displayed increased TLR4 expression, and increased autophagic [microtubule-associated protein-1 light-chain-3B (LC3B)] and apoptotic (cleaved caspase-3) markers. Beas-2B cells transfected with TLR4 siRNA displayed increased expression of LC3B relative to control cells, basally and after exposure to CSE. The basal and CSE-inducible expression of LC3B and cleaved caspase-3 were elevated in pulmonary alveolar type II cells from Tlr4-deficient mice. Wild-type mice subjected to chronic CS-exposure displayed airspace enlargement;, however, the Tlr4-mutated or Tlr4-deficient mice exhibited a marked increase in airspace relative to wild-type mice after CS-exposure. The Tlr4-mutated or Tlr4-deficient mice showed higher levels of LC3B under basal conditions and after CS exposure. The expression of cleaved caspase-3 was markedly increased in Tlr4-deficient mice exposed to CS. We describe a protective regulatory function of TLR4 against emphysematous changes of the lung in response to CS.

publication date

  • November 1, 2012

has subject area

  • Aged
  • Aged, 80 and over
  • Animals
  • Apoptosis
  • Autophagy
  • Case-Control Studies
  • Caspase 3
  • Cells, Cultured
  • Female
  • Gene Expression
  • Humans
  • Lung
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins
  • Middle Aged
  • Oxidative Stress
  • Primary Cell Culture
  • Pulmonary Disease, Chronic Obstructive
  • Pulmonary Emphysema
  • Smoking
  • Toll-Like Receptor 4

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3517684

Digital Object Identifier (DOI)

  • 10.1152/ajplung.00102.2012

PubMed ID

  • 22983353

Additional Document Info

start page

  • L748

end page

  • L757

volume

  • 303

number

  • 9