Toxicological sciences : an official journal of the Society of Toxicology
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Cigarette smoke is associated with chronic and enhanced pulmonary inflammation characterized by increased cytokine production and leukocyte recruitment to the lung. Although the aryl hydrocarbon receptor (AhR) is well-known to mediate toxic effects of manmade environmental contaminants, the AhR has emerged as a suppressor of acute cigarette smoke-induced neutrophilia by a mechanism involving the NF-κB protein RelB. Yet individuals who smoke often smoke for many years and vary in their cigarette consumption. ⋯ Inhibition of AhR activity by CH-223191 in endothelial cells potentiated ICAM-1 expression and prevented RelB nuclear translocation but had no effect on neutrophil adhesion. These data support that genetic absence of the AhR contributes to heightened pulmonary neutrophilia in response to ongoing cigarette smoke exposure. Interindividual variations in AhR expression may enhance the susceptibility to cigarette smoke-induced diseases.
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Naphthalene is a nasal carcinogen, inducing respiratory adenomas in male and olfactory neuroblastomas in female rats, respectively. The reasons for the site and sex-specific tumorigenic response are unknown. Naphthalene is bioactivated to electrophilic metabolites; cytotoxicity followed by regenerative cell proliferation is likely involved in the tumorigenic response. ⋯ Sex differences were observed in the induction of antielectrophilic genes in OM: glutamyl cysteine ligase (catalytic subunit) (Gclc), NADPH quinone oxidase 1 (Nqo1), and heme oxygenase 1 (Hmox1) were all induced to a greater extent in the male OM compared with the female. No consistent sex differences were observed in the RTM. Although the mechanism of the sex difference in the RTM adenoma response remains enigmatic, sex differences in the induction of antioxidant/electrophile-responsive genes may contribute to the heightened sensitivity of the female OM to the carcinogenic effects of naphthalene.
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Hard metal lung disease (HMLD) is an occupational lung disease specific to inhalation of cobalt-containing particles whose mechanism is largely unknown. Cobalt is a known hypoxia mimic and stabilizer of the alpha subunits of hypoxia-inducible factors (HIFs). Previous work revealed that though HIF1α contrib utes to cobalt toxicity in vitro, loss of HIF1α in the alveolar epithelial cells does not provide in vivo protection from cobalt-induced lung inflammation. ⋯ Additionally, control mice demonstrated a mild recovery from cobalt-induced lung injury compared with HIF2α(Δ/Δ) mice, suggesting a role for epithelial HIF2α in repair mechanisms. The expression of important cytokines, such as interleukin (IL)-5 and IL-10, displayed significant differences following cobalt exposure when HIF2α(Δ/Δ) and control mice were compared. In summary, our data suggest that although loss of HIF2α does not afford protection from cobalt-induced lung inflammation, epithelial HIF2α signaling does play an important role in modulating the inflammatory and repair response in the lung.
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Randomized Controlled Trial
Reactivation of plasma butyrylcholinesterase by pralidoxime chloride in patients poisoned by WHO class II toxicity organophosphorus insecticides.
Some clinicians assess the efficacy of pralidoxime in organophosphorus (OP) poisoned patients by measuring reactivation of butyrylcholinesterase (BuChE). However, the degree of BuChE inhibition varies by OP insecticide, and it is unclear how well oximes reactivate BuChE in vivo. We aimed to assess the usefulness of BuChE activity to monitor pralidoxime treatment by studying its reactivation after pralidoxime administration to patients with laboratory-proven World Health Organization (WHO) class II OP insecticide poisoning. ⋯ The 1-g dose produced no reactivation. Pralidoxime produced variable reactivation of BuChE in WHO class II OP-poisoned patients according to the pralidoxime dose administered, OP ingested, and individual patient. The use of BuChE assays for monitoring the effect of pralidoxime treatment is unlikely to be clinically useful.
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Nephrogenic systemic fibrosis (NSF) is a scleroderma-like disease associated with prior administration of certain gadolinium chelates (GCs). NSF occurs in patients with severe renal failure. The purpose of this study was to set up a rat model of GC-associated NSF to elucidate the mechanism of this devastating disease. ⋯ Unlike macrocyclic GCs, gadodiamide, gadopentetate, and gadobenate gradually increased the r(1) relaxivity value, consistent with in vivo dissociation and release of soluble Gd (or, in the case of gadobenate, the consequence of protein binding). Gadodiamide-induced cutaneous and systemic toxicity depended on baseline renal function. We demonstrate in vivo dissociation of linear GCs, gadodiamide, and gadopentetate, whereas macrocyclic agents remained stable over the study period.