Identification of Oxidative Stress and Toll-like Receptor 4 Signaling as a Key Pathway of Acute Lung Injury

نویسندگان

  • Yumiko Imai
  • Keiji Kuba
  • G. Greg Neely
  • Rubina Yaghubian-Malhami
  • Thomas Perkmann
  • Geert van Loo
  • Maria Ermolaeva
  • Ruud Veldhuizen
  • Y. H. Connie Leung
  • Hongliang Wang
  • Haolin Liu
  • Yang Sun
  • Manolis Pasparakis
  • Manfred Kopf
  • Christin Mech
  • Sina Bavari
  • J. S. Malik Peiris
  • Arthur S. Slutsky
  • Shizuo Akira
  • Malin Hultqvist
  • Rikard Holmdahl
  • John Nicholls
  • Chengyu Jiang
  • Christoph J. Binder
  • Josef M. Penninger
چکیده

Multiple lung pathogens such as chemical agents, H5N1 avian flu, or SARS cause high lethality due to acute respiratory distress syndrome. Here we report that Toll-like receptor 4 (TLR4) mutant mice display natural resistance to acid-induced acute lung injury (ALI). We show that TLR4-TRIF-TRAF6 signaling is a key disease pathway that controls the severity of ALI. The oxidized phospholipid (OxPL) OxPAPC was identified to induce lung injury and cytokine production by lung macrophages via TLR4-TRIF. We observed OxPL production in the lungs of humans and animals infected with SARS, Anthrax, or H5N1. Pulmonary challenge with an inactivated H5N1 avian influenza virus rapidly induces ALI and OxPL formation in mice. Loss of TLR4 or TRIF expression protects mice from H5N1-induced ALI. Moreover, deletion of ncf1, which controls ROS production, improves the severity of H5N1-mediated ALI. Our data identify oxidative stress and innate immunity as key lung injury pathways that control the severity of ALI.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Time course changes of oxidative stress and inflammation in hyperoxia-induced acute lung injury in rats

Objective(s):Therapies with high levels of oxygen are commonly used in the management of critical care. However, prolonged exposure to hyperoxia can cause acute lung injury. Although oxidative stress and inflammation are purported to play an important role in the pathogenesis of acute lung injury, the exact mechanisms are still less known in the hyperoxic acute lung injury (HALI).   Materials ...

متن کامل

Ameliorative effects of silymarin on HCl-induced acute lung injury in rats; role of the Nrf-2/HO-1 pathway

Objective(s): Aspiration is a common cause of acute lung injury (ALI), which lacks an effective treatment. Inflammation and oxidative stress play key roles in ALI development. Silymarin is an active extract of Silybum marianum plant seeds (milk thistle). Silymarin has potent anti-inflammatory and antioxidant effects; however its role in aspiration induced ALI has not b...

متن کامل

I-33: Oxidative Stress Responses in EarlyPregnancy

Background: Survival of the conceptus is dependent on continuous progesterone signaling in the maternal decidua but how this is achieved under conditions of oxidative stress that characterize early pregnancy is unknown. Materials and Methods: Laboratory-based analysis of endometrial biopsies and primary endometrial cultures. Results: Using primary cultures, we show that modest levels of reactiv...

متن کامل

Endoplasmic reticulum stress regulates inflammation in adipocyte of obese rats via toll-like receptors 4 signaling

Objective(s): To explore whether endoplasmic reticulum (ER) stress regulates inflammation in adipose tissue of obese rats via TLR4 signaling. Materials and Methods: Sprague Dawley rats were randomly divided into four groups, and body weight, food intake, and free fatty acids (FFA) were measured. Real-time PCR and Western blot were used to determine mRNA or protein expression of TLR4, TRAF6, IKK...

متن کامل

Intra-Peritoneal Administration of Mitochondrial DNA Provokes Acute Lung Injury and Systemic Inflammation via Toll-Like Receptor 9

The pathogenesis of sepsis is complex. Mitochondrial dysfunction, which is responsible for energy metabolism, intrinsic apoptotic pathway, oxidative stress, and systemic inflammatory responses, is closely related with severe sepsis induced death. Mitochondria DNA (mtDNA) contain un-methylated cytosine phosphate guanine (CpG) motifs, which exhibit immune stimulatory capacities. The aim of this s...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Cell

دوره 133  شماره 

صفحات  -

تاریخ انتشار 2008