A high-frequency lung injury mechanism in blunt thoracic impact

When a mechanical load is applied very rapidly to the thoracic wall, part of the internal damage is suspected to be due to a "high-frequency" injury mechanism, that is, a phenomenon in which waves are involved. This paper addresses a specific high-frequency mechanism for lung injury in which a stress wave is generated through rapid acceleration of the body wall. Displacement-related injuries, which are rather "low-frequency" phenomena, are not considered. The present work was done in the context of assessing behind armor blunt trauma (injury to thoracic organs occurring when a bullet is stopped by a body armor) through mathematical modeling. One aspect of the thorax response to high-speed blunt impact and an associated injury mechanism are investigated based on an idealized model of thorax and a set of computations presented in previous papers. The injury mechanism considered elucidates a possible mathematical relationship between the acceleration at the surface of the thoracic wall and the occurrence of lung injury.     

Inactivation of endotoxin by human plasma gelsolin

Septic shock from bacterial endotoxin, triggered by the release of lipopolysaccharide (LPS) molecules from the outer wall of Gram-negative bacteria, is a major cause of human death for which there is no effective treatment once the complex inflammatory pathways stimulated by these small amphipathic molecules are activated. Here we report that plasma gelsolin, a highly conserved human protein, binds LPS from various bacteria with high affinity. Solid-phase binding assays, fluorescence measurements, and functional assays of actin depolymerizing effects show that gelsolin binds more tightly to LPS than it does to its other known lipid ligands, phosphatidylinositol 4,5-bisphosphate and lysophosphatidic acid. Gelsolin also competes with LPS-binding protein (LBP), a high-affinity carrier for LPS. One result of gelsolin-LPS binding is inhibition of the actin binding activity of gelsolin as well as the actin depolymerizing activity of blood serum. Simultaneously, effects of LPS on cellular functions, including cytoskeletal actin remodeling, and collagen-induced platelet activation by pathways independent of toll-like receptors (TLRs) are neutralized by gelsolin and by a peptide based on gelsolin residues 160-169 (GSN160-169) which comprise part of gelsolin's phosphoinositide binding site. Additionally, TLR-dependent NF-kappaB translocation in astrocytes appears to be blocked by gelsolin. These results show a strong effect of LPS on plasma gelsolin function and suggest that some effects of endotoxin in vivo may be mediated or inhibited by plasma gelsolin.     

N-terminally extended surfactant protein (SP) C isolated from SP-B-deficient children has reduced surface activity and inhibited lipopolysaccharide binding

In both humans and mice, a deficiency of surfactant protein B (SP-B) is associated with a decreased concentration of mature SP-C and accumulation of a larger SP-C peptide, denoted SP-C(i), which is not observed under normal conditions. Isolation of hydrophobic polypeptides from the lungs of children who died with two different SP-B mutations yielded pure SP-C(i) and showed only trace amounts of mature SP-C. Determination of the SP-C(i) covalent structure revealed a 12-residue N-terminal peptide segment, followed by a 35-residue segment that is identical to mature SP-C. The SP-C(i) structure determined herein is similar to that of a proposed late intermediate in the processing of proSP-C, suggesting that SP-C(i) is the immediate precursor of SP-C. In bronchoalveolar lavage fluid from transgenic mice with a focal deficiency of SP-B, SP-C(i) was detected in the biophysically active, large aggregate fraction and was associated with membrane structures that are typical for a large aggregate surfactant. However, unlike SP-C, SP-C(i) exhibited a very poor ability to promote phospholipid adsorption, gave high surface tension during cyclic film compression, and did not bind lipopolysaccharide in vitro. SP-C(i) is thus capable of associating with surfactant lipids, but its N-terminal dodecapeptide segment must be proteolytically removed to generate a biologically functional peptide. The results of this study indicate that the early postnatal fatal respiratory distress seen in SP-B-deficient children is combined with the near absence of active variants of SP-C.     

Anti-inflammatory effects of tocopherol metabolites

Our objective was to assess the anti-inflammatory effects of alpha-tocopherol, gamma-tocopherol, and their metabolites 2,5,7,8-tetramethyl-2-(beta-carboxyethyl)-6-hydroxychroman (alpha-CEHC) and 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman (gamma-CEHC) in defined cell culture systems. Rat aortic endothelial cells and mouse microglial cultures were treated with tumor necrosis factor TNFalpha or bacterial lipopolysaccharide (LPS) and nitrite and prostaglandin E(2) (PGE(2)) were measured. alpha-CEHC suppressed TNFalpha-stimulated nitrite production in both cell types, whereas both CEHC derivatives inhibited LPS-stimulated microglial nitrite efflux. Both alpha-CEHC and gamma-CEHC inhibited microglial PGE(2) production, but neither alpha- nor gamma-tocopherol was effective at inhibiting cytokine-stimulated inflammatory processes. These results show that the anti-inflammatory effects of tocopherols are highly cell type-, stimulus-, and endpoint-dependent.     

The arachidonic acid 5-lipoxygenase inhibitor nordihydroguaiaretic acid inhibits tumor necrosis factor alpha activation of microglia and extends survival of G93A-SOD1 transgenic mice

Familial forms of amyotrophic lateral sclerosis (ALS) can be caused by mutations in copper, zinc-superoxide dismutase (SOD1). Mice expressing SOD1 mutants demonstrate a robust neuroinflammatory reaction characterized, in part, by up-regulation of tumor necrosis factor alpha (TNFalpha) and its primary receptor TNF-RI. In an effort to identify small molecule inhibitors of neuroinflammation useful in treatment of ALS, a microglial culture system was established to identify TNFalpha antagonists. Walker EOC-20 microglia cells were stimulated with recombinant TNFalpha, with or without inhibitors, and the cell response was indexed by NO2- output. Three hundred and fifty-five rationally selected compounds were included in this bioassay. The arachidonic acid 5-lipoxygenase (5LOX) and tyrosine kinase inhibitor nordihydroguaiaretic acid (NDGA), a natural dicatechol, was one of the most potent non-cytotoxic antagonists tested (IC50 8 +/- 3 microm). Investigation of the G93A-SOD1 mouse model for ALS revealed increased message and protein levels of 5LOX at 120 days of age. Oral NDGA (2500 p.p.m.) significantly extended lifespan and slowed motor dysfunction in this mouse, when administration was begun relatively late in life (90 days). NDGA extended median total lifespan of G93A-SOD1 mice by 10%, and life expectancy following start of treatment was extended by 32%. Disease-associated gliosis and cleaved microtubule-associated tau protein, an indicator of axon damage, were likewise reduced by NDGA. Thus, TNFalpha antagonists and especially 5LOX inhibitors might offer new opportunities for treatment of ALS.     

ABCdb: an online resource for ABC transporter repertories from sequenced archaeal and bacterial genomes

The ATP-binding cassette (ABC) transporters are one of the major classes of active transporters. They are widespread in archaea, bacteria, and eukaryota, indicating that they have arisen early in evolution. They are involved in many essential physiological processes, but the majority import or export a wide variety of compounds across cellular membranes. These systems share a common architecture composed of four (exporters) or five (importers) domains. To identify and reconstruct functional ABC transporters encoded by archaeal and bacterial genomes, we have developed a bioinformatic strategy. Cross-reference to the transport classification system is used to predict the type of compound transported. A high quality of annotation is achieved by manual verification of the predictions. However, in order to face the rapid increase in the number of published genomes, we also include analyses of genomes issuing directly from the automated strategy. Querying the database (http://www-abcdb.biotoul.fr) allows to easily retrieve ABC transporter repertories and related data. Additional query tools have been developed for the analysis of the ABC family from both functional and evolutionary perspectives.     

Gastrointestinal nematode infection is associated with variation in innate immune responsiveness

Ex vivo monocyte cytokine responses (IL-1beta, TNF-alpha, IL-12p70, IL-10, TGF-beta) to bacterial TLR2 and TLR4 ligands were quantified in 47 gastrointestinal (GI) nematode-exposed children in Pemba Island, Tanzania. Worminess (estimated by faecal egg counts (FEC)) had a positive relationship with pro-inflammatory TNF-alpha and IL-1beta responsiveness to the TLR ligands. In particular, there was a strong significant relationship with TNF-alpha response to TLR4 ligand (LPS). There were no significant associations between regulatory responses (IL-10, TGF-beta) and worminess. These results are consistent with the possibility that GI nematodes modulate innate responses and may indicate a potential mechanism for interactions between GI nematodiasis and important bystander pathogens.     

Legume comparative genomics: progress in phylogenetics and phylogenomics

The legumes are the focus of numerous rapidly expanding genomic projects, all of which involve members of one part of the Leguminosae, the subfamily Papilionoideae. This subfamily is monophyletic, and recent studies concur on a series of clades within it that are well supported and have received informal names. These include the Cladrastis clade, the genistoids (including Lupinus), the mirbelioids, the dalbergioids (including Arachis), the millettioids (including Glycine and Phaseolus), and the hologalegina (galegoid) legumes, which comprise the robinioids (including Lotus) and the inverted repeat loss (IRL) clade (including Medicago and Pisum). The canavanine-accumulating legumes appear to fall into a single clade, consistent with the idea that the production of this toxic amino acid evolved only once. Recent advances in analytical techniques for dating phylogenies support an 'early explosion hypothesis', suggesting that much of the morphological diversity of the legume family evolved rapidly around 50-60 million years ago. Within the papilionoids, the divergence between Glycine and Medicago is estimated to have taken place around 54 million years ago. There is strong evidence for a palaeoduplication event that affected both Glycine (a millettioid) and Medicago (from the IRL clade). As more genomic data are forthcoming for Arachis, it will be possible to test whether this event extends to the dalbergioids.