Morbidity and mortality associated with acute lung injury (ALI) and acute respiratory distress syndrome remain substantial. Although many candidate genes have been tested, a clear understanding of the pathogenesis is lacking, as is our ability to predict individual outcome. Because ALI is a complex disease, single gene approaches cannot easily identify effectors that must be treated concurrently. We employed a strategy to help identify critical genes and gene combinations involved in ALI mortality. Using hyperoxia to induce ALI, a mouse model for genetic analyses of ALI survival time was identified: C57BL/6J (B) mice are sensitive (i.e., die early), whereas 129X1/SvJ (S) mice are significantly more resistant, but with low penetrance. Segregation analysis of reciprocal F(2) mice generated from B and S strains revealed significant sex, cross, and parent of origin effects. Quantitative trait locus (QTL) analysis identified five chromosomal regions significantly linked to hyperoxic ALI survival time (named Shali1-Shali5). Further analyses demonstrated that both parental strains contribute resistance alleles to their offspring and that the phenotype demonstrated parent of origin effects. To validate earlier findings, we generated and tested mice from all eight possible B-S-derived backcrosses. Results from segregation and QTL analyses of 935 backcrosses, alone and combined with the previous 840 B-S-derived F(2) population, further supported the highly significant QTLs on chromosomes 1 (Shali1) and 4 (Shali2) and confirmed that the sex, cross, and parent of origin all contribute to survival time with hyperoxic ALI.
"Analysis of F2 mice identified 5 QTLs (designated Shali for Survival time with hyperoxic acute lung injury) significantly linked to HALI survival time on Chr 1 (Shali1 and the male-specific QTL, Shali5), Chr 4 (Shali2), Chr 9 (Shali4), and Chr 15 (Shali3) . The large backcross population also identified Shali1, Shali2, and Shali3 and, along with the F2 data, consistently suggested that the Shali1 locus on Chr 1 and the Shali2 locus on Chr 4 had opposing allelic effects on overall HALI survival time within each inbred strain . Specifically, QTL analysis of recombinants derived from the X1 and B progenitor strains determined that Shali1 directly correlated with the overall survival time trait of the parental strains, with resistant X1 strain alleles leading to an increased mean HALI survival time and sensitive B strain alleles yielding increased sensitivity. "
[Show abstract][Hide abstract] ABSTRACT: Increased oxygen (O(2)) levels help manage severely injured patients, but too much for too long can cause acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and even death. In fact, continuous hyperoxia has become a prototype in rodents to mimic salient clinical and pathological characteristics of ALI/ARDS. To identify genes affecting hyperoxia-induced ALI (HALI), we previously established a mouse model of differential susceptibility. Genetic analysis of backcross and F(2) populations derived from sensitive (C57BL/6J; B) and resistant (129X1/SvJ; X1) inbred strains identified five quantitative trait loci (QTLs; Shali1-5) linked to HALI survival time. Interestingly, analysis of these recombinant populations supported opposite within-strain effects on survival for the two major-effect QTLs. Whereas Shali1 alleles imparted the expected survival time effects (i.e., X1 alleles increased HALI resistance and B alleles increased sensitivity), the allelic effects of Shali2 were reversed (i.e., X1 alleles increased HALI sensitivity and B alleles increased resistance). For in vivo validation of these inverse allelic effects, we constructed reciprocal congenic lines to synchronize the sensitivity or resistance alleles of Shali1 and Shali2 within the same strain. Specifically, B-derived Shali1 or Shali2 QTL regions were transferred to X1 mice and X1-derived QTL segments were transferred to B mice. Our previous QTL results predicted that substituting Shali1 B alleles onto the resistant X1 background would add sensitivity. Surprisingly, not only were these mice more sensitive than the resistant X1 strain, they were more sensitive than the sensitive B strain. In stark contrast, substituting the Shali2 interval from the sensitive B strain onto the X1 background markedly increased the survival time. Reciprocal congenic lines confirmed the opposing allelic effects of Shali1 and Shali2 on HALI survival time and provide unique models to identify their respective quantitative trait genes and to critically assess the apparent bidirectional epistatic interactions between these major-effect loci.
PLoS ONE 05/2012; 7(5):e38177. DOI:10.1371/journal.pone.0038177 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The technique that can be applied to the calculation of aperture antenna radiation patterns is the equivalence principle followed by physical optics. The equivalence principle is based on replacing the physical antenna aperture with a virtual antenna aperture consisting of an ensemble of Huygen's sources, each of which is a source of spherical wavelets. The total pattern is taken as a construction of these Huygen's secondary waves. A Fourier transform relation exists between the amplitude distribution of these sources, and the radiation pattern in angle space. For most aperture antenna problems, these classical techniques are adequate and give reasonably accurate results. However, more modern analysis techniques such as method of moments (MOM), finite element method (FRM), and the finite difference time domain (FDTD) method are also discussed. These are more robust and accurate, but the complexity and large amount of computer resources required must be traded off with the accuracy desired.
Antenna Theory and Techniques, 2003. 4th International Conference on; 10/2003
[Show abstract][Hide abstract] ABSTRACT: The mechanisms of ventilator-induced lung injury, an iatrogenic inflammatory condition induced by mechanical ventilation, are not completely understood. Toll-like receptor 4 (TLR4) signaling via the adaptor protein myeloid differentiation factor 88 (MyD88) is proinflammatory and plays a critical role in host immune response to invading pathogen and noninfectious tissue injury. The role of TLR4-MyD88 signaling in ventilator-induced lung injury remains incompletely understood.
Mice were ventilated with low or high tidal volume (HTV), 7 or 20 ml/kg, after tracheotomy for 4 h. Control mice were tracheotomized without ventilation. Lung injury was assessed by: alveolar capillary permeability to Evans blue albumin, wet/dry ratio, bronchoalveolar lavage analysis for cell counts, total proteins and cytokines, results of histopathological examination of the lung, and plasma cytokine levels.
Wild-type mice subjected to HTV had increased pulmonary permeability, inflammatory cell infiltration/lung edema, and interleukin-6/macrophage-inflammatory protein-2 in the lavage compared with control mice. In HTV, levels of inhibitor of kappaB alpha decreased, whereas phosphorylated extracellular signal-regulated kinases increased. TLR4 mutant and MyD88 mice showed markedly attenuated response to HTV, including less lung inflammation, pulmonary edema, cell number, protein content, and the cytokines in the lavage. Furthermore, compared with wild-type mice, both TLR4 mutant and MyD88 mice had significantly higher levels of inhibitor of kappaB alpha and reduced extracellular signal-regulated kinase phosphorylation after HTV.
TLR4-MyD88 signaling plays an important role in the development of ventilator-induced lung injury in mice, possibly through mechanisms involving nuclear factor-kappaB and mitogen-activated protein kinase pathways.
Seul-Ki Kim, Yeonsoo Joe, Yingqing Chen, Jinhyun Ryu, Jeong-Hee Lee, Gyeong Jae Cho, Stefan W Ryter, Hun Taeg Chung
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