CFTR Modulates Acute Lung Injury: Evidence from A Genetic Association Study

CFTR Modulates Acute Lung Injury: Evidence from A Genetic Association Stud

Lack of Association of the Caspase-12 Long Allele with Community-Acquired Pneumonia in People of African Descent

<div><p>Community-acquired pneumonia (CAP) is a common cause of sepsis. Active full-length caspase-12 (CASP12L), confined to the people of African descent, has been associated with increased susceptibility to and mortality from severe sepsis. The objective of this study was to determine whether CASP12L was a marker for susceptibility and/or severity of CAP. We examined three CAP cohorts and two control populations: 241 adult Memphis African American CAP patients, 443 pediatric African American CAP patients, 90 adult South African CAP patients, 120 Memphis healthy adult African American controls and 405 adult Chicago African American controls. Clinical outcomes including mortality, acute respiratory distress syndrome (ARDS), septic shock or severe sepsis, need for mechanical ventilation, and <i>S. pneumoniae</i> bacteremia. Neither in the three individual CAP cohorts nor in the combined CAP cohorts, was mortality in CASP12L carriers significantly different from that in non-CASP12L carriers. No statistically significant association between genotype and any measures of CAP severity was found in any cohort. We conclude that the functional CASP12L allele is not a marker for susceptibility and/or severity of CAP.</p></div

Frequency of caspase-12 C125T genotypes in South African community-acquired pneumonia patients related to various clinical outcomes.

<p>MV: mechanical ventilation.</p

BALF protein concentration at Day 1 and Day 3 post MRSA lung infections.

<p>Values are the mean ± SEM (standard error of the mean) of three independent experiments (n = 12 in each group).</p

Interferon-γ, IL17, IL6, IL1β and TNFα levels in BALF samples at Day 1 post MRSA infections.

<p>Values are the mean ± SEM (standard error of the mean) of three independent experiments. There is no statistically significant difference in TNFα levels between the LAC and LAC+LZD groups (p = 0.38).</p

Genome-wide gene expression profiles in lungs at Day 1 and Day 3 post MRSA infection.

<p><b>A</b>) Heat map of eight groups, with four replications per group. Each row represents one sample, and each column represents one gene. Fold change ≥ 1.5 up or down, <i>P</i> < 0.01, FDR < 0.05); <b>B</b>) Functional group concept-gene analysis for the comparison between LAC (Day 1) and PBS (Day 1) and between LAC (Day 3) and PBS (Day 3). The figure shows how many genes are involved in selected relevant biological pathways and which functions are significantly up-regulated or down-regulated between the LAC and PBS groups at Day 1 or Day 3 post MRSA infection. The background color for each cell is proportional to the hypergeometric test p value. The more saturated the color is, the smaller the p-value.</p

Frequency of caspase-12 genotypes in adult, African and pediatric community-acquired pneumonia and healthy control populations.

<p>CAP: community-acquired pneumonia; CC: CASP12L homozygotes; CT: CASP 12L heterozygote; TT: CASP12S homozygotes; * In the South African CAP cohort, 45.6% carried the caspase-12 C allele (CASP12L), significantly higher than in either controls or CAP patients in the US cohorts (<i>p</i><0.001).</p

Demographics of patients.

<p>CAP, community-acquired pneumonia; MV, requirement for mechanical ventilation; ALI, acute lung injury (only for pediatric CAP cohort); ALI/ARDS, acute lung injury/acute respiratory distress syndrome; NA – not assessed; * range of Age: median (minimum, maximum).</p

Frequency of caspase-12 C125T genotypes in pediatric community-acquired pneumonia patients related to various clinical outcomes.

<p>MV: mechanical ventilation; ALI/ARDS, acute lung injury/acute respiratory distress syndrome; BPD: bronchopulmonary dysplasia; CHD: congenital heart disease.</p

Lung hematoxylin and eosin (HE) staining images.

<p>The images in the first row are the representative groups without LZD therapy, and the images in the second row are the representative groups with LZD therapy. Magnification time, x20. Compared to the PBS control group, more inflammation with pulmonary edema, multifocal bacterial aggregates, and lung structure destruction was seen in the lungs at Day 1 post MRSA infection. With LZD treatment, no abscesses were formed, less lung edema and fewer inflammatory cells were observed compared to without LZD treatment. At Day 3 post MRSA infection, no multifocal bacterial aggregates could be found. However, the inflammatory infiltrates were still seen in the lung alveolar space.</p