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

IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse 3, A-1030 Vienna, Austria.
Cell (Impact Factor: 32.24). 05/2008; 133(2):235-49. DOI: 10.1016/j.cell.2008.02.043
Source: PubMed


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.

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    • "An alteration of the intracellular redox balance, which occurs during several viral infections, is associated with the progression of virus-induced diseases (Beck et al., 2000; reviewed in Nencioni et al., 2011). This redox imbalance can be determined by several factors, including an overproduction of reactive oxygen species (ROS) (Petherans et al., 1987; Elbim et al., 2001; Machida et al., 2006; Imai et al., 2008; Hu et al., 2011) and/or a decrease of reduced glutathione (GSH), the main intracellular non-enzymatic antioxidant (Cai et al., 2003; Nencioni et al., 2003). We previously reported that, during viral infections, the decrease of intracellular GSH varies in intensity, duration and mechanism of induction depending on the type of virus and the infected host cell (Garaci et al., 1992; 1997; Palamara et al., 1995; 1996; Ciriolo et al., 1997). "
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    ABSTRACT: An overproduction of reactive oxygen species (ROS) mediated by NADPH oxidase 2 (NOX2) has been related to airway inflammation typical of influenza infection. Virus-induced oxidative stress may also control viral replication, but the mechanisms underlying ROS production, as well as their role in activating intracellular pathways and specific steps of viral life cycle under redox control have to be fully elucidated. In this study, we demonstrate that influenza A virus infection of lung epithelial cells causes a significant ROS increase that depends mainly on NOX4, which is up-regulated at both mRNA and protein levels, while the expression of NOX2, the primary source of ROS in inflammatory cells, is down-regulated. Inhibition of NOX4 activity through chemical inhibitors or RNA silencing blocks the ROS increase, prevents MAPK phosphorylation, and inhibits viral ribonucleoprotein (vRNP) nuclear export and viral release. Overall these data, obtained in cell lines and primary culture, describe a so far unrecognized role for NOX4-derived ROS in activating redox-regulated intracellular pathways during influenza virus infection and highlight their relevance in controlling specific steps of viral replication in epithelial cells. Pharmacological modulation of NOX4-mediated ROS production may open the way for new therapeutic approaches to fighting influenza by targeting cell and not the virus.
    Full-text · Article · Aug 2014 · Cellular Microbiology
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    • "On the other hand, toll-like receptor 4 (TLR4) signaling was believed to be another pathway of acid and LPS-induced ALI other than RAGE expression. In mice treated with adenovirus-mediated siRNA targeting the TLR4 gene, a protective effect was shown against LPS challenge [41]. Thus, whether TLR4 signaling was involved in the beneficial effects of GLN remains to be explored in future studies. "
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    ABSTRACT: Background Glutamine (GLN) has been reported to improve clinical and experimental sepsis outcomes. However, the mechanisms underlying the actions of GLN remain unclear, and may depend upon the route of GLN administration and the model of acute lung injury (ALI) used. The aim of this study was to investigate whether short-term GLN supplementation had an ameliorative effect on the inflammation induced by direct acid and lipopolysaccharide (LPS) challenge in mice. Methods Female BALB/c mice were divided into two groups, a control group and a GLN group (4.17% GLN supplementation). After a 10-day feeding period, ALI was induced by intratracheal administration of hydrochloric acid (pH 1.0; 2 mL/kg of body weight [BW]) and LPS (5 mg/kg BW). Mice were sacrificed 3 h after ALI challenge. In this early phase of ALI, serum, lungs, and bronchoalveolar lavage fluid (BALF) from the mice were collected for further analysis. Results The results of this study showed that ALI-challenged mice had a significant increase in myeloperoxidase activity and expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in the lung compared with unchallenged mice. Compared with the control group, GLN pretreatment in ALI-challenged mice reduced the levels of receptor for advanced glycation end-products (RAGE) and IL-1β production in BALF, with a corresponding decrease in their mRNA expression. The GLN group also had markedly lower in mRNA expression of cyclooxygenase-2 and NADPH oxidase-1. Conclusions These results suggest that the benefit of dietary GLN may be partly contributed to an inhibitory effect on RAGE expression and pro-inflammatory cytokines production at an early stage in direct acid and LPS-induced ALI in mice.
    Full-text · Article · Jul 2014 · BMC Pulmonary Medicine
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    • "In this respect, and in contrast to our findings, several studies have indicated a role for Mal in mediating oxidative stress in inflammatory disease conditions [40]–[42], including sepsis-associated acute lung injury [43]. Similarly, a detrimental role for MyD88 by activating oxidative stress has been implicated in acute lung injury [44]–[46]. As per our earlier discussion, we speculate that such differences in the role of Mal in emphysema versus inflammatory disorders are most likely attributed to differences in the disease-associated cell type(s), as well as the nature of the upstream TLR stimuli leading to Mal activation. "
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    ABSTRACT: Myeloid differentiation factor 88 (MyD88) and MyD88-adaptor like (Mal)/Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) play a critical role in transducing signals downstream of the Toll-like receptor (TLR) family. While genetic ablation of the TLR4/MyD88 signaling axis in mice leads to pulmonary cell death and oxidative stress culminating in emphysema, the involvement of Mal, as well as TLR2 which like TLR4 also signals via MyD88 and Mal, in the pathogenesis of emphysema has not been studied. By employing an in vivo genetic approach, we reveal here that unlike the spontaneous pulmonary emphysema which developed in Tlr4(-/-) mice by 6 months of age, the lungs of Tlr2(-/-) mice showed no physiological or morphological signs of emphysema. A more detailed comparative analysis of the lungs from these mice confirmed that elevated oxidative protein carbonylation levels and increased numbers of alveolar cell apoptosis were only detected in Tlr4(-/-) mice, along with up-regulation of NADPH oxidase 3 (Nox3) mRNA expression. With respect to Mal, the architecture of the lungs of Mal(-/-) mice was normal. However, despite normal oxidative protein carbonylation levels in the lungs of emphysema-free Mal(-/-) mice, these mice displayed increased levels of apoptosis comparable to those observed in emphysematous Tlr4(-/-) mice. In conclusion, our data provide in vivo evidence for the non-essential role for TLR2, unlike the related TLR4, in maintaining the normal architecture of the lung. In addition, we reveal that Mal differentially facilitates the anti-apoptotic, but not oxidant suppressive, activities of TLR4 in the lung, both of which appear to be essential for TLR4 to prevent the onset of emphysema.
    Full-text · Article · Oct 2013 · PLoS ONE
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