RESUMEN
BACKGROUND: Coagulation and fibrinolysis are important in infections and systemic inflammatory response syndrome. Polymorphisms in plasminogen activator inhibitor-1 (PAI-1, SERPINE1) and tissue plasminogen activator (tPA, PLAT), such as PAI-1 (-675 4G/5G deletion/insertion) and tPA (Alu insertion/deletion [I/D]), are associated with strokes, myocardial infarctions, bacterial infections and septic shock severity, and trauma. Osteomyelitis is a mostly posttraumatic, Staphylococcal bone infection. PATIENTS AND METHODS: tPA Alu (I/D) (rs4646972) and PAI-1 (4G/5G) (rs1799889) polymorphisms were studied by DNA amplification with polymerase chain reaction in 261 patients with osteomyelitis and in 299 matched blood donors. Plasma PAI-1/tPA complex was assessed by enzyme-linked immuosorbent assay. RESULTS: II homozygotes (37.9% vs 19.1%) and I allele carriers (56.3% vs 46.3%) for the tPA Alu (I/D) polymorphism were significantly more frequent in osteomyelitis patients compared to controls (P < .001). II genotype carrier osteomyelitis patients had lower PAI-1/tPA complex levels compared to those with the D allele (P ≤ .04). There was no association between these genotypes and chronicity of osteomyelitis, post-traumatic etiology, or with a specific bacterial etiology. PAI-1 (4G/4G) homozygotes were not significantly different between osteomyelitis patients and controls (P = .1). CONCLUSIONS: We report for the first time to our knowledge an association between the tPA Alu (I/D) polymorphism and susceptibility to bacterial osteomyelitis, perhaps by fibrinolysis dysfunction.
Asunto(s)
Osteomielitis/genética , Activador de Tejido Plasminógeno/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Femenino , Fibrinólisis/genética , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Osteomielitis/sangre , Osteomielitis/microbiología , Polimorfismo Genético , Adulto JovenRESUMEN
Neutrophils (PMN), potent phagocytes, are the first line of the host immune defence against microorganisms, especially bacteria. Their half-life is very short and they are eliminated through apoptosis. Delayed neutrophil apoptosis is a characteristic feature of human osteomyelitis arising from Gram-negative or Gram-positive bacterial infection. The aim of this study was to investigate the modulation of apoptosis during infection of the human neutrophils by Staphylococcus aureus or Escherichia coli, the most common isolate in osteomyelitis. Analysis of host cells by flow cytometry using propidium iodide or annexin V labelling revealed an apoptosis inhibition after bacterial infection or treatment with LPS or LTA. We detected the secretion of cytokines such as IL-6, TNF-alpha and IL-1 beta by infected neutrophils. The addition of monoclonal antibodies to each cytokine abolished the protection against apoptosis. The anti-apoptotic Bcl-x(L) protein expression was increased and the pro-apoptotic Bax-alpha protein expression was decreased. These results identify a novel apoptotic effect in bacteria-infected cells that is mainly dependent on auto-production of cytokines and is correlated with Bax-alpha/Bcl-x(L) ratio. This may be a mechanism through which to resolve bacterial osteomyelitis infection.
Asunto(s)
Apoptosis , Infecciones Bacterianas/inmunología , Neutrófilos/citología , Neutrófilos/microbiología , Anticuerpos Monoclonales/farmacología , Apoptosis/efectos de los fármacos , Citocinas/biosíntesis , Fragmentación del ADN/efectos de los fármacos , Citometría de Flujo , Humanos , Interleucina-6/inmunología , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Propidio/metabolismo , Proteínas Recombinantes/farmacología , Factor de Necrosis Tumoral alfa/inmunología , Proteína X Asociada a bcl-2/metabolismo , Proteína bcl-X/metabolismoRESUMEN
OBJECTIVE: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in extracellular matrix remodelling and adipocyte differentiation and are inhibited by antiretrovirals. MMPs and TIMPs and their single nucleotide polymorphisms (SNPs) might contribute to the HAART-related lipodystrophic syndrome pathogenesis. DESIGN AND SETTING: Cross-sectional study in a university-based outpatient clinic. PATIENTS AND METHODS: Two hundred and sixteen HIV-infected patients on extended HAART were studied. Serum MMPs (1, 2, 3, 8, 9, 10, 13) and TIMPs (1, 2, 4) were measured by ELISA microarrays. MMP1 (-16071G/2G) SNP was also genotyped. Lipodystrophic syndrome was diagnosed by a clinical scale validated by fat dual energy X-ray absorptiometry. RESULTS: Eighty-two patients (38.0%) showed lipodystrophic syndrome, mostly lipoatrophy. The 2G/2G MMP1 SNP genotype was more frequent among lipodystrophic syndrome patients (41.3 vs. 20.5%, odds ratio, 2.73; 95% confidence interval, 1.41-5.29; χ² = 9.62, P = 0.002 for HIV-infected patients with and without lipodystrophic syndrome respectively). Carriers of this genotype had higher serum levels of MMP1 compared with those with the 1G/1G (P = 0.02). Higher MMP1 (P = 0.022) and lower TIMP4 (P = 0.038) serum levels were observed while comparing HIV patients with and without lipodystrophic syndrome. MMP1 2G carriage (P = 0.0008), TIMP4 lower serum levels (P = 0.02), treatment with stavudine (P < 0.0001), treatment with zidovudine (P = 0.006) and absence of hepatitis C virus coinfection (P = 0.002) were associated with lipodystrophic syndrome by logistic regression. CONCLUSION: MMP1 SNP, which induced increased serum levels of this protein, was associated with lipodystrophic syndrome.