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Pediatric Lung Disease
Published in Philip T. Cagle, Timothy C. Allen, Mary Beth Beasley, Diagnostic Pulmonary Pathology, 2008
Despite its relatively recent description in 2004 as a cause of fatal lung disease in infants, mutations in the ABCA3 gene now account for the greatest proportion of infants and children with abnormalities of surfactant metabolism (48). Like SP-C deficiency, ABCA3 mutations have been recognized also as a cause of chronic interstitial lung disease in older children, adolescents, and young adults (49). ABCA3 deficiency often results in a variant PAP pattern in infancy, which is similar histologically to SP-B deficiency (Fig. 6). Other described patterns include DIP in some infants and NSIP pattern in older infants and children. As with SP-C deficiency, cholesterol clefts (endogenous lipoid pneumonia pattern) may be a conspicuous feature, particularly in older patients (Fig. 7).
Chronic interstitial lung diseases in children: diagnosis approaches
Published in Expert Review of Respiratory Medicine, 2018
Nadia Nathan, Laura Berdah, Keren Borensztajn, Annick Clement
ABCA3 is a lipidic transporter of the hydrophobic SP-B and SP-C into lamellar bodies. Genetic ABCA3 disorders were first reported in a group of full term babies with severe respiratory diseases occurring shortly after birth and with mostly rapid fatal outcome [77]. It is now known that bi-allelic mutations can also be diagnosed in older children with ILD, and in adult with fibrosing ILD. ABCA3 disorders include mainly hereditary deficiencies in an autosomal recessive inheritance. However, heterozygous ABCA3 mutations have also been associated with an increased risk of neonatal respiratory distress in late preterm newborns. The increasing number of mutations documented in a heterozygous state suggests that ABCA3 defects may be the most common causes of inherited surfactant diseases [78]. To date, more than 200 mutations have been reported in ABCA3, located on chromosome 16, with various heterogeneous clinical expressions, even in siblings [79–81]. One variant, c.875A>T (p.Glu292Val), observed in 0.4% of the general population, is found in 4% of a cohort of infants with respiratory distress [82].
Smoking-associated interstitial lung disease: update and review
Published in Expert Review of Respiratory Medicine, 2020
Yaser T Dawod, Noah E Cook, William B Graham, Farah Madhani-Lovely, Choua Thao
The pathogenesis of CPFE has not been clearly elucidated. In dog models, Hammond and colleagues evaluated the effect of cigarettes and demonstrated evidence of emphysema and fibrosis in lung tissue postmortem [113]. Genetics are suspected to play a role in disease as well. Cottin et al. reported a case of a 32-year-old nonsmoker female with CPFE carrying a genetic mutation of the SFTPC gene, which may have influenced the development of CPFE [114]. Additionally, the ABCA3 mutation was identified in a case report of a nonsmoking 41-year-old male [115], further suggesting a genetic predisposition to the development of CPFE. Other plausible molecular pathways include neutrophil elastase and TNF-α [116,117].
The role of the ATP-Binding Cassette A1 (ABCA1) in neurological disorders: a mechanistic review
Published in Expert Opinion on Therapeutic Targets, 2023
Tahere Paseban, Mohaddeseh Sadat Alavi, Leila Etemad, Ali Roohbakhsh
ABCB1 (P-glycoprotein) is an outwardly directed drug and lipid flippase (phospholipids and glycosphingolipids) that promotes multidrug resistance [199]. ABCB1 has also been implicated in Aβ efflux in BBB endothelial cells [85,200]. A collaboration between ABCB1 and LRP-1 make Aβ efflux across BBB possible (see Figure 2). In addition to ABCA1, ABCA7 is involved in cholesterol efflux and HDL formation [201]. However, previous studies have implicated a secondary role for ABCA7 in lipid transport compared to ABCA1. While ABCA7 makes small cholesterol-poor HDL particles, ABCA1 mostly produces big cholesterol-rich HDL particles [202]. In vitro and in vivo experiments showed that ABCA7 has a role in neuronal Aβ production and/or clearance [203,204]. Microglia and macrophages from ABCA7-KO mice exhibited substantial reductions in Aβ phagocytosis [205]. Also, ABCA7 polymorphisms have been associated with memory impairment in AD [206]. ABCG1 is another ABC superfamily member that transports intracellular cholesterol and sphingolipids to HDL [207]. Similar to ABCA1, cholesterol excess provokes ABCG1 expression [208]. ABCA1 and ABCG1 have a notable role in cholesterol efflux from macrophages and astrocytes. This process is overwhelmed during aging and is restored by LXR agonist administration [37]. Interestingly, ABCG1 and ABCG4 functions change γ-secretase distribution on the plasma membrane and decrease Aβ secretion [209]. Similar to ABCB1, ABCG4 effluxes Aβ from BBB into plasma [210]. Another transporter identified in the luminal plasma membrane of endothelial cells is ABCG2. It may contribute to the brain efflux of Aβ [211]. However, ABCG2’s exact role in Aβ elimination from the brain is debated [200]. Lipid homeostasis is regulated by more ABC members. ABCA3 is a transporter expressed in alveolar type II pneumocytes that excrete lung surfactant. ABCA3 transfers lipids into the lamellar bodies and its mutation causes fatal respiratory distress syndrome in the newborn [212]. ABCA12 is phylogenetically related to ABCA3 and participates in epidermal keratinocyte lamellar granule secretion. As a lipid transporter, this protein helps to form ceramides, but not phospholipids [213]. In patients with ABCA12 dysfunction (mainly due to mutations, harlequin-type ichthyosis), the lipid barrier on the skin is compromised, making them more susceptible to pathogens [214].