RESUMO
Lipopolysaccharide (LPS) binding protein (LBP) is an acute-phase protein that initiates an immune response after recognition of bacterial LPS. Here, we report the crystal structure of murine LBP at 2.9 Å resolution. Several structural differences were observed between LBP and the related bactericidal/permeability-increasing protein (BPI), and the LBP C-terminal domain contained a negatively charged groove and a hydrophobic "phenylalanine core." A frequent human LBP SNP (allelic frequency 0.08) affected this region, potentially generating a proteinase cleavage site. The mutant protein had a reduced binding capacity for LPS and lipopeptides. SNP carriers displayed a reduced cytokine response after in vivo LPS exposure and lower cytokine concentrations in pneumonia. In a retrospective trial, the LBP SNP was associated with increased mortality rates during sepsis and pneumonia. Thus, the structural integrity of LBP may be crucial for fighting infections efficiently, and future patient stratification might help to develop better therapeutic strategies.
Assuntos
Proteínas de Fase Aguda/química , Peptídeos Catiônicos Antimicrobianos/química , Proteínas Sanguíneas/química , Proteínas de Transporte/química , Imunidade Inata/genética , Lipopolissacarídeos/química , Glicoproteínas de Membrana/química , Modelos Moleculares , Mutação , Polimorfismo de Nucleotídeo Único , Proteínas de Fase Aguda/genética , Proteínas de Fase Aguda/imunologia , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/imunologia , Sítios de Ligação , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/imunologia , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Cristalografia por Raios X , Genótipo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lipopolissacarídeos/imunologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Ligação Proteica , Estrutura Terciária de Proteína , Eletricidade Estática , Homologia Estrutural de ProteínaRESUMO
PURPOSE: Our purpose was to assess whether a practice's adaptive reserve and high leadership capability in quality improvement are associated with population blood pressure control. METHODS: We divided practices into quartiles of blood pressure control performance and considered the top quartile as the benchmark for comparison. Using abstracted clinical data from electronic health records, we performed a cross-sectional study to assess the association of top quartile hypertension control and (1) the baseline practice adaptive reserve (PAR) scores and (2) baseline practice leadership scores, using modified Poisson regression models adjusting for practice-level characteristics. RESULTS: Among 181 practices, 46 were in the top quartile, which averaged 68% or better blood pressure control. Practices with higher PAR scores compared with lower PAR scores were not more likely to reside in the top quartile of performance (prevalence ratio [PR] = 1.92 for highest quartile; 95% CI, 0.9-4.1). Similarly, high quality improvement leadership capability compared with lower capability did not predict better blood pressure control performance (PR = 0.94; 95% CI, 0.57-1.56). Practices with higher proportions of commercially insured patients were more likely than practices with lower proportions of commercially insured patients to have top quartile performance (37% vs 26%, P =.002), whereas lower proportions of the uninsured (8% vs 14%, P =.055) were associated with better performance. CONCLUSIONS: Our findings show that adaptive reserve and leadership capability in quality improvement implementation are not statistically associated with achieving top quartile practice-level hypertension control at baseline in the Heart Health NOW project. Our findings, however, may be limited by a lack of patient-related factors and small sample size to preclude strong conclusions.