RESUMO
BACKGROUND: Irritant contact dermatitis (ICD) is a frequent and often underrated problem for which the major efficacious therapy is still local glucocorticoids, although they have known adverse effects due to their wide spectrum of action. A more focused therapeutic strategy would be the inhibition of a key enzyme for biosynthesis of the lipid mediators, cytosolic phospholipase A(2) α (cPLA(2) α), in ICD. We are analysing the pharmacological and biological effects of a selective cPLA(2) α inhibitor. OBJECTIVES: To examine the usefulness of the potent and selective cPLA(2) α inhibitor 3-(5-carboxypentanoyl)-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid (compound 1) for therapy of inflammatory skin disorders. METHODS: We examined clinical and cellular effects of a selective cPLA(2) α inhibitor (compound 1) on ICD in mice. RESULTS: Topical application of the compound significantly reduced ear swelling after induction by the irritant benzalkonium chloride. Concomitantly, compound 1 inhibited the accumulation of granulocytes as well as the expression of inflammatory proteins such as tumour necrosis factor-α, interleukin-1ß and macrophage inflammatory proteins 1α and 1ß in the ear tissue. In primary murine keratinocytes, the benzalkonium chloride-induced expression of these proteins was also downregulated after treatment with compound 1 in vitro. CONCLUSIONS: Compound 1 is a well-aimed agent for the treatment of nonspecific skin inflammation as it selectively inhibits cPLA(2) α and as it acts on an early stage of skin inflammation after its elicitation.
Assuntos
Compostos de Benzalcônio/toxicidade , Dermatite Irritante/prevenção & controle , Inibidores Enzimáticos/farmacologia , Fosfolipases A2 do Grupo IV/antagonistas & inibidores , Irritantes/toxicidade , Otite Externa/prevenção & controle , Administração Cutânea , Amidoidrolases/metabolismo , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Quimiocinas/metabolismo , Clobetasol/administração & dosagem , Clobetasol/farmacologia , Citocinas/metabolismo , Inibidores Enzimáticos/administração & dosagem , Feminino , Indóis/administração & dosagem , Indóis/farmacologia , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Monoacilglicerol Lipases/metabolismo , Proteínas S100/metabolismoRESUMO
Deficiency of the urea cycle enzyme carbamylphosphate synthetase 1 (CPS1) causes hyperammonemia with a vast range of clinical severity from neonatal onset with early lethality to onset after age 40 with rare episodes of hyperammonemic confusion. The cause for this variability is not understood. We report two patients from one family with highly divergent clinical course, one presenting neonatally with a fatal form and the other at age 45 with benign diet-responsive disease. The patients are compound heterozygous for two mutations of the CPS1 gene, c.3558 + 1G > C and c.4101 + 2T > C. The haplotypes containing each mutation are identical between the two patients, as are the sequences of CPS1 exons and flanking introns. Transcriptional experiments show that the abnormal CPS1 transcripts generated by both mutations are identical in these two patients. We characterize promoter and enhancer sequences of the CPS1 gene and find also in these regions no sequence differences between patients. Finally, we perform cloning experiments and find that in the neonatal-onset case, clones of messenger RNA (mRNA) expressed from the allele carrying the c.4101 + 2T > C mutation are threefold more than clones of mRNA from the allele with the c.3558 + 1G > C mutation, whereas in the adult-onset case the two types of clones are equal, indicating skewed expression towards the c.4101 + 2T > C allele in the neonatal case. Although we are yet to understand the mechanism of this differential expression, our work suggests that allelic imbalance may explain clinical variability in CPS1 deficiency in some families.