Protective role of metallothionein in acute lung injury induced by bacterial endotoxin

National Institute for Environmental Studies, Tsukuba, Japan.
Thorax (Impact Factor: 8.29). 01/2005; 59(12):1057-62. DOI: 10.1136/thx.2004.024232
Source: PubMed
Metallothionein (MT) is a protein that can be induced by inflammatory mediators and participate in cytoprotection. However, its role in inflammation remains to be established. A study was undertaken to determine whether intrinsic MT protects against acute inflammatory lung injury induced by bacterial endotoxin in MT-I/II knock out (-/-) and wild type (WT) mice.
MT (-/-) and WT mice were given vehicle or lipopolysaccharide (LPS, 125 microg/kg) intratracheally and the cellular profile of the bronchoalveolar lavage (BAL) fluid, pulmonary oedema, lung histology, expression of proinflammatory molecules, and nuclear localisation of nuclear factor-kappaB (NF-kappaB) in the lung were evaluated.
MT (-/-) mice were more susceptible than WT mice to lung inflammation, especially to lung oedema induced by intratracheal challenge with LPS. After LPS challenge, MT deficiency enhanced vacuolar degeneration of pulmonary endothelial cells and type I alveolar epithelial cells and caused focal loss of the basement membrane. LPS treatment caused no significant differences in the enhanced expression of proinflammatory cytokines and chemokines nor in the activation of the NF-kappaB pathway in the lung between the two genotypes. Lipid peroxide levels in the lungs were significantly higher in LPS treated MT (-/-) mice than in LPS treated WT mice.
Endogenous MT protects against acute lung injury related to LPS. The effects are possibly mediated by the enhancement of pulmonary endothelial and epithelial integrity, not by the inhibition of the NF-kappaB pathway.

Full-text preview

Available from:
  • Source
    • "LPS-induced ARDS has been widely used as a clinically relevant model of sepsis-related ARDS since LPS is an important mediator of sepsis in response to gram-negative bacteria. Studies have shown that lower respiratory tract exposure to LPS by intratracheal (i.t.) instillation is a well-recognized model of acute lung injury, which mimics, in many important pathological aspects, the clinical development of ARDS induced by gram-negative pulmonary infection [18,19]. Therefore, we used endotracheal atomization inhalation of LPS to reproduce ARDS model. "
    [Show abstract] [Hide abstract] ABSTRACT: Resolvin D1 (RvD1), an endogenous lipid mediator derived from docosahexaenoic acid, has been reported to promote a biphasic activity in anti-inflammatory response and regulate inflammatory resolution. The present study aimed to determine the endogenous expression pattern of RvD1 in a rat model of self-resolution of lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS) and inflammation. The ARDS model was induced by administrating LPS (2 mg/kg) via tracheotomy in 138 male Sprague–Dawley rats. At specified time points, lung injury and inflammation were respectively assessed by lung histology and analysis of bronchoalveolar lavage fluid and cytokine levels. The expression of endogenous RvD1 was detected by high performance liquid chromatography and tandem mass spectrometry. The results showed that histological lung injury peaked between 6 h (LPS6h) and day 3, followed by recovery over 4–10 days after LPS administration. Lung tissue polymorph nuclear cell (PMN) was significantly increased at LPS6h, and peaked between 6 h to day 2. The levels of interleukin (IL)-6 and IL-10 were significantly increased at LPS6h and remained higher over day 10 as compared to baseline. Intriguingly, the endogenous RvD1 expression was decreased gradually during the first 3 days, followed by almost completely recovery over days 9–10. The finding indicated that endogenous RvD1 underwent a decrease in expression followed by gradual increase that was basically coincident with the lung injury recovery in a rat model of self-resolution LPS-induced ARDS and inflammation. Our results may help define the optimal therapeutic window for endogenous RvD1 to prevent or treat LPS-induced ARDS and inflammation.
    Full-text · Article · Nov 2014 · International Immunopharmacology
  • Source
    • "Some inverse results are reported that ApoMT (metal-free MT) has the potential to remove zinc from NF-κB and hence inactivate the NF-κB-mediated transcriptional activity consequent to zinc clelation [16]. MT possessed antioxidant properties that prevent H 2 O 2, or lipopolysaccharide (LPS)-stimulated NF-κB signaling in many inflammatory diseases [9,414243. Differential expression of MT isoforms was detected in GC cells and tissues, which indicated that the potential role of MT isoforms in carcinogenesis gained attention and make sure that the exact isoform is analyzed in our study. It is therefore not surprising that members of the MT family may be involved pleiotropically in a number of different biological functions except for ROS scavenger and metal-binding ability. "
    [Show abstract] [Hide abstract] ABSTRACT: Metallothionein 2A (MT2A) as a stress protein, plays a protective role in gastric mucosal barrier. Its role in the development of gastric cancer (GC) is unclear. The mechanism of MT2A will be investigated in gastric tumorigenesis. MT2A expression was detected in 973 gastric specimens. The biological function was determined through ectopic expressing MT2A in vitro and in vivo. The possible downstream effectors of MT2A were investigated in NF-kappaB signaling. The protein levels of MT2A, IkappaB-alpha and p-IkappaB-alpha (ser32/36) expression were analyzed in a subset of 258 patients by IHC staining. The prognostic effects of MT2A, status of IkappaB-alpha and TNM stage were evaluated using the Kaplan-Meier method and compared using the log-rank test. Decreased MT2A expression was detected in cell lines and primary tumors of GC. In clinical data, loss of MT2A (MT2A + in Normal (n =171, 76.0%); Intestinal metaplasia (n = 118, 50.8%); GC (n = 684. 22.4%, P < 0.001)) was associated with poor prognosis (P < 0.001), advanced TNM stage (P = 0.05), and down-regulation of IkappaB-alpha expression (P < 0.001). Furthermore, MT2A was the independent prognostic signature segregated from the status of IkappaB-alpha and pathological features. In addition, MT2A inhibited cell growth through apoptosis and G2/M arrest, which negatively regulated NF-kappaB pathway through up-regulation of IkappaB-alpha and down-regulation of p-IkappaB-alpha and cyclin D1 expression. MT2A might play a tumor suppressive activity through inhibiting NF-kappaB signaling and may be a prognostic biomarker and potential target for individual therapy of GC patients.
    Full-text · Article · Jul 2013 · Journal of Translational Medicine
  • Source
    • "Zinc homoeostasis is maintained through MT, a family of zinc-binding proteins controlling cellular zinc distribution in a redox-dependent manner [78]. LPS rapidly up-regulates MT expression in human macrophages [79]; presumably this may act to sequester the free intracellular zinc that is generated immediately after TLR activation [66], and would be broadly consistent with the anti-inflammatory roles of MT, as identified by gene knock-out studies [80–82]. Zinc homoeostasis is additionally controlled by two distinct families of zinc transporters, the SLC30A family (ZnT; vertebrate cation diffusion facilitator family) and the SLC39A family [Zip (Zrt/Irt-like proteins)]. "
    [Show abstract] [Hide abstract] ABSTRACT: The immunomodulatory and antimicrobial properties of zinc and copper have long been appreciated. In addition, these metal ions are also essential for microbial growth and survival. This presents opportunities for the host to either harness their antimicrobial properties or limit their availability as defence strategies. Recent studies have shed some light on mechanisms by which copper and zinc regulation contribute to host defence, but there remain many unanswered questions at the cellular and molecular levels. Here we review the roles of these two metal ions in providing protection against infectious diseases in vivo, and in regulating innate immune responses. In particular, we focus on studies implicating zinc and copper in macrophage antimicrobial pathways, as well as specific host genes encoding zinc transporters (SLC30A, SLC39A family members) and copper transporters (CTR, ATP7 family members) that may contribute to pathogen control by these cells.
    Full-text · Article · Jun 2013 · Bioscience Reports
Show more