The influence of genetic variation in surfactant protein B on severe lung injury in African American children*

Dahmer, Mary K.; O'Cain, Peggy; Patwari, Pallavi P.; Simpson, Pippa; Li, Shun Hwa; Halligan, Nadine; Quasney, Michael W.

doi:10.1097/ccm.0b013e31820a9416

Cited by 32 publications

(23 citation statements)

References 46 publications

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“…However, similar to adult studies, SP-B polymorphisms were associated with worse lung injury in AfricanAmerican children with community-acquired pneumonia (83). In contrast to adults, exogenous surfactant therapy has improved oxygenation and reduced mortality in children with ARDS (84,85).…”

Section: Surfactant Systemmentioning

confidence: 92%

Mechanisms of Acute Respiratory Distress Syndrome in Children and Adults

Smith

Zimmerman

Martin

2013

Pediatric Critical Care Medicine

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There are significant obstacles to performing research on children with acute respiratory distress syndrome. However, epidemiologic, clinical, and animal studies suggest age-dependent differences in the pathophysiology of acute respiratory distress syndrome. In order to reduce the prevalence and improve the outcome of patients with acute respiratory distress syndrome, translational studies of inflammatory, apoptotic, alveolar fluid clearance, and repair mechanisms are needed. Understanding the differences in pathophysiologic mechanisms in acute respiratory distress syndrome between children and adults should facilitate identification of novel therapeutic interventions to prevent or modulate lung injury and improve lung repair.

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Section: Surfactant Systemmentioning

confidence: 92%

Mechanisms of Acute Respiratory Distress Syndrome in Children and Adults

Smith

Zimmerman

Martin

2013

Pediatric Critical Care Medicine

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“…SP-BC/T1580 is functionally one of the most important (26,27). This SP-BC/T1580 polymorphism is not only associated with pneumonia and pneumonia-induced ARDS (21,28,29), but also with neonatal respiratory distress syndrome (RDS) (30), and interstitial lung disease (ILD) (31). The detailed mechanisms for the increased susceptibility of SP-B C allele to these pulmonary diseases are unknown (6,27,32).…”

Section: Resultsmentioning

confidence: 99%

Differential Susceptibility of Human Sp-B Genetic Variants on Lung Injury Caused by Bacterial Pneumonia and the Effect of a Chemically Modified Curcumin

Abdel-Razek

et al. 2016

Shock

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Staphylococcus aureus is a common cause of nosocomial pneumonia frequently resulting in acute respiratory distress syndrome (ARDS). Surfactant protein B (SP-B) gene expresses two proteins involved in lowering surface tension and host defense. Genotyping studies demonstrate a significant association between human SP-B genetic variants and ARDS. Curcumins have been shown to attenuate host inflammation in many sepsis models. Our hypothesis is that functional differences of SP-B variants and treatment with curcumin (CMC2.24) modulate lung injury in bacterial pneumonia. Humanized transgenic mice, expressing either SP-B T or C allele without mouse SP-B gene, were used. Bioluminescent labeled S. aureus Xen36 (50 μl) was injected intratracheally to cause pneumonia. Infected mice received daily CMC2.24 (40 mg/kg) or vehicle alone by oral gavage. Dynamic changes of bacteria were monitored using in vivo imaging system. Histological, cellular and molecular indices of lung injury were studied in infected mice 48h after infection. In vivo imaging analysis revealed total flux (bacterial number) was higher in the lung of infected SP-B-C mice compared to infected SP-B-T mice (p<0.05). Infected SP-B-C mice demonstrated increased mortality, lung injury, apoptosis and NF-κB expression compared to infected SP-B-T mice. Compared to controls, CMC2.24 treatment significantly reduced the following: mortality, total bacterial flux and lung tissue apoptosis, inflammatory cells, NF-κB expression (p<0.05), and MMPs-2, -9, -12 activities (p<0.05). We conclude that mice with SP-B-C allele are more susceptible to S. aureus pneumonia than mice with SP-B-T allele; and that CMC2.24 attenuates lung injury thus reducing mortality.

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“…The Institutional Review Board from each institution approved the study. Some members of this cohort have been used in studies reported in previous publications (35–37). As the frequency of genetic polymorphisms and the linkage disequilibrium (LD) patterns differ between ethnicities and races (38, 39), such groups should be analyzed separately (40).…”

Section: Methodsmentioning

confidence: 99%

“…Inclusion and exclusion criteria as well as data collection for children with CAP have been described in detail in previous publications (35–37). In brief, CAP was defined by 1) an acute illness (<14 days of symptoms); 2) the presence of a new chest radiographic infiltrate or consolidation confirmed by a radiologist; and 3) clinical features compatible with pneumonia, including one of the following: fever >37.8°C, hypothermia <36°C, peripheral white blood count >10,000/μL or <4500/μL, or >15% immature neutrophils; and two of the following: tachypnea (respiratory rate >2 standard deviations from the mean for age), dyspnea, or hypoxemia (pulse oximetry ≤94% on room air on initial evaluation without a known mixing heart lesion).…”

Section: Methodsmentioning

confidence: 99%

Association of cystic fibrosis transmembrane conductance regulator gene variants with acute lung injury in African American children with pneumonia*

Baughn

Quasney

Simpson

et al. 2012

Critical Care Medicine

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Objectives The cystic fibrosis transmembrane conductance regulator regulates fluid balance in alveolar epithelial cells and appears to modulate the inflammatory response. To determine whether more severe lung injury in children who develop community-acquired pneumonia is associated with variations known to affect function in the gene coding for cystic fibrosis transmembrane conductance regulator. Design A prospective cohort genetic association study of lung injury in children with community-acquired pneumonia. Setting Three major tertiary care children’s hospitals. Subjects Caucasian and African American children with community-acquired pneumonia either evaluated in the emergency department or admitted to the hospital. Interventions None. Measurements and Main Results Caucasian and African American children with pneumonia were genotyped for the most common variants reported to affect cystic fibrosis transmembrane conductance regulator function, the p.508del mutation, the (TG)mTn variable repeat region, and the M470V polymorphism in the cystic fibrosis transmembrane conductance regulator gene. Genotypes and haplotypes were determined, and the association of high-risk alleles or high-risk haplotypes (defined as the presence of at least one variant known to decrease the level of functional cystic fibrosis transmembrane conductance regulator) with the need for mechanical ventilation or the development of acute lung injury was evaluated. Forty-two children in the Caucasian cohort (n = 304) required mechanical ventilation; 32 developed acute lung injury. Forty-three children in the African American cohort (n = 474) required mechanical ventilation; 29 developed acute lung injury. In African American children, high-risk (TG)mTn alleles known to result in decreased levels of functional cystic fibrosis transmembrane conductance regulator were associated with the need for mechanical ventilation (p = .0013) and the development of acute lung injury (p = .0061). Multivariable analysis demonstrated that high-risk (TG)mTn alleles were independently associated with mechanical ventilation (odds ratios = 3.19; 95% confidence interval, 1.63–6.26) and acute lung injury (odds ratios = 3.36; 95% confidence interval, 1.50–7.53) in African American children. Conclusion Genetic variation in cystic fibrosis transmembrane conductance regulator is associated with acute lung injury in African American children with community-acquired pneumonia.

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The influence of genetic variation in surfactant protein B on severe lung injury in African American children*

Cited by 32 publications

References 46 publications

Mechanisms of Acute Respiratory Distress Syndrome in Children and Adults

Mechanisms of Acute Respiratory Distress Syndrome in Children and Adults

Differential Susceptibility of Human Sp-B Genetic Variants on Lung Injury Caused by Bacterial Pneumonia and the Effect of a Chemically Modified Curcumin

Association of cystic fibrosis transmembrane conductance regulator gene variants with acute lung injury in African American children with pneumonia*

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