American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · May 2014
WHOLE EXOME SEQUENCING REVEALS TOPBP1 AS A NOVEL GENE IN IDIOPATHIC PULMONARY ARTERIAL HYPERTENSION.
Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disorder characterized by progressive loss of pulmonary microvessels. Although mutations in the bone morphogenetic receptor 2 (BMPR2) are found in 80% of heritable and ∼15% of patients with IPAH, their low penetrance (∼20%) suggests that other unidentified genetic modifiers are required for manifestation of the disease phenotype. Use of whole-exome sequencing (WES) has recently led to the discovery of novel susceptibility genes in heritable PAH, but whether WES can also accelerate gene discovery in IPAH remains unknown. ⋯ WES led to the discovery of TopBP1, a gene whose deficiency may increase susceptibility to small vessel loss in IPAH. We predict that use of WES will help identify gene modifiers that influence an individual's risk of developing IPAH.
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Am. J. Respir. Crit. Care Med. · May 2014
Impact of Pre-Transplant Anti-HLA Antibodies on Outcomes in Lung Transplant Candidates.
The prevalence of anti-HLA antibodies in lung transplant candidates and their impact on waitlist and transplant outcomes is not known. ⋯ The presence of anti-HLA antibodies at the high MFI threshold (>3,000) was associated with lower transplant rate and higher rates of AMR. Screening for anti-HLA antibodies using the 3,000 MFI threshold may be important in managing transplant candidates and recipients.
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Am. J. Respir. Crit. Care Med. · May 2014
Revealing the pathogenic and aging-related mechanisms of the enigmatic idiopathic pulmonary fibrosis: An integral model.
A growing body of evidence indicates that aberrant activation of alveolar epithelial cells and fibroblasts in an aging lung plays a critical role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, the biopathological processes linking aging with IPF and the mechanisms responsible for the abnormal activation of epithelial cells and fibroblasts have not been elucidated. ⋯ Therefore, an unanswered question is why a current/former smoker of about 60 years of age with shorter telomeres, alveolar epithelial senescence, excessive oxidative stress, and mitochondrial dysfunction develops IPF and not COPD; in other words, what makes old lungs specifically susceptible to develop IPF? In this Perspective, we propose an integral model in which the combination of some gene variants and/or gene expression in the aging lung results in the loss of epithelial integrity and consequently in the failure of the alveoli to correctly respond to injury and to face the stress associated with mechanical stretch. Afterward, a distinctive epigenetic "reprogramming" that affects both epithelial cells and fibroblasts provokes, among others, the recapitulation of developmental pathways and the aberrant activation and miscommunication between both cell types, resulting in the exaggerated production and accumulation of extracellular matrix and the subsequent destruction of the lung architecture.