scholarly journals A genetic mouse model to investigate hyperoxic acute lung injury survival

2007 ◽  
Vol 30 (3) ◽  
pp. 262-270 ◽  
Author(s):  
Daniel R. Prows ◽  
Amanda P. Hafertepen ◽  
William J. Gibbons ◽  
Abby V. Winterberg ◽  
Todd G. Nick
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Mouse Model ◽  
Survival Time ◽  
Therapeutic Potential ◽  
Inbred Mouse ◽  
Mouse Strains ◽  
Genetic Mouse Model ◽  
Genetic Components ◽  
Survival Difference

Acute lung injury (ALI) is a devastating disease that maintains a high mortality rate, despite decades of research. Hyperoxia, a universal treatment for ALI and other critically ill patients, can itself cause pulmonary damage, which drastically restricts its therapeutic potential. We stipulate that having the ability to use higher levels of supplemental O2 for longer periods would improve recovery rates. Toward this goal, a mouse model was sought to identify genes contributing to hyperoxic ALI (HALI) mortality. Eighteen inbred mouse strains were screened in continuous >95% O2. A significant survival difference was identified between sensitive C57BL/6J and resistant 129X1/SvJ strains. Although resistant, only one-fourth of 129X1/SvJ mice survived longer than any C57BL/6J mouse, demonstrating decreased penetrance of resistance. A survival time difference between reciprocal F1 mice implicated a parent-of-origin (imprinting) effect. To further evaluate imprinting and begin to delineate the genetic components of HALI survival, we generated and phenotyped offspring from all four possible intercrosses. Segregation analysis supported maternal inheritance of one or more genes but paternal inheritance of one or more contributor genes. A significant sex effect was demonstrated, with males more resistant than females for all F2 crosses. Survival time ranges and sensitive-to-resistant ratios of the different F2 crosses also supported imprinting and predicted that increased survival is due to dominant resistance alleles contributed by both the resistant and sensitive parental strains. HALI survival is multigenic with a complex mode of inheritance, which should be amenable to genetic dissection with this mouse model.

Ozone-induced acute lung injury: genetic analysis of F2 mice generated from A/J and C57BL/6J strains

1999 ◽  
Vol 277 (2) ◽  
pp. L372-L380 ◽  
Author(s):  
Daniel R. Prows ◽  
Mark J. Daly ◽  
Howard G. Shertzer ◽  
George D. Leikauf
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Genetic Analysis ◽  
Survival Time ◽  
Complex Disease ◽  
Major Gene ◽  
Inbred Mouse ◽  
Mouse Strains ◽  
Survival Times ◽  
Chromosome 11

Acute lung injury (or acute respiratory distress syndrome) is a devastating and often lethal condition. This complex disease (trait) may be associated with numerous candidate genes. To discern the major gene(s) controlling mortality from acute lung injury, two inbred mouse strains displaying contrasting survival times to 10 parts/million ozone were identified. A/J (A) mice were sensitive [6.6 ± 1 (SE) h] and C57BL/6J (B) were resistant (20.6 ± 1 h). The designation for these phenotypes was 13 h, a point that clearly separated their survival time distributions. Our prior segregation studies suggested that survival time to ozone-induced acute lung injury was a quantitative trait, and genetic analysis identified three linked loci [acute lung injury-1, -2, and -3 ( Ali1–3, respectively)]. In this report, acute lung injury in A or B mice was characterized histologically and by measuring lung wet-to-dry weight ratios at death. Ozone produced comparable effects in both strains. To further delineate genetic loci associated with reduced survival, a genomewide scan was performed with F2 mice generated from the A and B strains. The results strengthen and extend our initial findings and firmly establish that Ali1 on mouse chromosome 11 has significant linkage to this phenotype. Ali3 was suggestive of linkage, supporting previous recombinant inbred analysis, whereas Ali2 showed no linkage. Together, our findings support the fact that several genes, including Ali1 and Ali3, control susceptibility to death after acute lung injury. Identification of these loci should allow a more focused effort to determine the key events leading to mortality after oxidant-induced acute lung injury.

Genetic Determinants of Oxidant-Induced Nuclear and Mitochondrial DNA Lesions in a Neonatal Inbred Mouse Model of Acute Lung Injury

2014 ◽  
Vol 76 ◽  
pp. S167-S168
Author(s):  
Kirsten C Verhein ◽  
Jennifer L Nichols ◽  
Vijayalakshmi Panduri ◽  
Wesley Gladwell ◽  
Jacqui Marzec ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Mouse Model ◽  
Inbred Mouse ◽  
Dna Lesions ◽  
Genetic Determinants

Genetic susceptibility to irritant-induced acute lung injury in mice

2000 ◽  
Vol 279 (3) ◽  
pp. L575-L582 ◽  
Author(s):  
Scott C. Wesselkamper ◽  
Daniel R. Prows ◽  
Pratim Biswas ◽  
Klaus Willeke ◽  
Eula Bingham ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inbred Mouse ◽  
Nickel Sulfate ◽  
Lavage Fluid ◽  
Mouse Strains ◽  
Common Mechanism ◽  
Recessive Trait ◽  
Strain Sensitivity ◽  
Sensitivity Pattern

Recent studies suggest that genetic variability can influence irritant-induced lung injury and inflammation. To begin identifying genes controlling susceptibility to inhaled irritants, seven inbred mouse strains were continuously exposed to nickel sulfate (NiSO4), polytetrafluoroethylene, or ozone (O3), and survival time was recorded. The A/J (A) mouse strain was sensitive, the C3H/He (C3) strain was intermediate, and the C57BL/6 (B6) strain was resistant to NiSO4-induced acute lung injury. The B6AF1 offspring were also resistant. The strain sensitivity pattern for NiSO4 exposure was similar to that of polytetrafluoroethylene or ozone (O3). Pulmonary pathology was comparable for A and B6 mice. In the A strain, 15 μg/m3 of NiSO4 produced 20% mortality. The strain sensitivity patterns for lavage fluid proteins (B6 > C3 > A) and neutrophils (A ≥ B6 > C3) differed from those for acute lung injury. This phenotype discordance suggests that these traits are not causally linked (i.e., controlled by independent arrays of genes). As in acute lung injury, B6C3F1 offspring exhibited phenotypes (lavage fluid proteins and neutrophils) resembling those of the resistant parental strain. Agreement of acute lung injury strain sensitivity patterns among irritants suggested a common mechanism, possibly oxidative stress, and offspring resistance suggested that sensitivity is inherited as a recessive trait.

scholarly journals miR-34b-5p inhibition attenuates lung inflammation and apoptosis in an LPS-induced acute lung injury mouse model by targeting progranulin

2018 ◽  
Vol 233 (9) ◽  
pp. 6615-6631 ◽  
Author(s):  
Wang Xie ◽  
Qingchun Lu ◽  
Kailing Wang ◽  
Jingjing Lu ◽  
Xia Gu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Mouse Model ◽  
Lung Inflammation

scholarly journals Hydrostatin-SN1, a Sea Snake-Derived Bioactive Peptide, Reduces Inflammation in a Mouse Model of Acute Lung Injury

2017 ◽  
Vol 8 ◽  
Author(s):  
Guosheng Wu ◽  
Junjie Wang ◽  
Pengfei Luo ◽  
An Li ◽  
Song Tian ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Mouse Model ◽  
Bioactive Peptide ◽  
Sea Snake

scholarly journals The nanocomposite fullerol reduces oxidative stress, pulmonary injury, and mortality in a rat model of acute lung injury

2021 ◽  
Author(s):  
Rosária Aires ◽  
Ildernandes Vieira-Alves ◽  
Leda Maria Coimbra-Campos ◽  
Marina Ladeira ◽  
Teresa Socarras ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
High Mortality ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Mortality Rates ◽  
Kaplan Meier ◽  
Pulmonary Damage

BACKGROUND AND PURPOSE Acute lung injury (ALI) is a critical disorder that has high mortality rates, and pharmacological therapies are so far ineffective. The pathophysiology of ALI involves pulmonary oxidative stress and inflammatory response. Fullerol is a carbon nanocomposite that possesses antioxidant and anti-inflammatory properties. Here, we evaluated the therapeutic potential of fullerol and its mechanisms in a model of paraquat-induced ALI. EXPERIMENTAL APPROACH Rats were divided into ALI (paraquat alone), fullerol (paraquat plus fullerol), and control groups. Survival curves were estimated using the Kaplan-Meier method. The myeloperoxidase assay, ELISA, and hematoxylin and eosin staining were used to determine neutrophils infiltration, cytokines production, and histopathological parameters in lung samples, respectively. The antioxidant effect of fullerol was evaluated in vitro and ex vivo. KEY RESULTS Fullerol (0.01 to 0.3 mg/kg) markedly reduced the severe lung injury and high mortality rates observed in ALI rats. Moreover, fullerol (0.03 mg/kg) inhibited the reactive oxygen species formation and lipid peroxidation seen in lungs from ALI rats, and exhibited a potent concentration-dependent (10 to 10 mg/ml) in vitro antioxidant activity. Importantly, fullerol (0.03 mg/kg) inhibited neutrophils accumulation in bronchoalveolar lavage and lungs, and the increase in pulmonary levels of TNF-α, IL-1β, IL-6, and CINC-1 in ALI rats. CONCLUSIONS AND IMPLICATIONS Fullerol treatment was effective in reducing pulmonary damage and ALI-induced mortality, highlighting its therapeutic potential in an ALI condition. Searching for new pharmacological therapies to treat ALI may be desirable especially in view of the new coronavirus disease 2019 that currently plagues the world.

scholarly journals Mesenchymal stromal cell-derived extracellular vesicles reduce lung inflammation and damage in nonclinical acute lung injury: Implications for COVID-19

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0259732
Author(s):  
Caryn Cloer ◽  
Laila Roudsari ◽  
Lauren Rochelle ◽  
Timothy Petrie ◽  
Michaela Welch ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Extracellular Vesicles ◽  
Immune Modulation ◽  
Therapeutic Potential ◽  
Dose Range ◽  
Surface Protein ◽  
Respiratory Dysfunction ◽  
Cellular Environment ◽  
Alveolar Capillary

Mesenchymal stem cell derived extracellular vesicles (MSC-EVs) are bioactive particles that evoke beneficial responses in recipient cells. We identified a role for MSC-EV in immune modulation and cellular salvage in a model of SARS-CoV-2 induced acute lung injury (ALI) using pulmonary epithelial cells and exposure to cytokines or the SARS-CoV-2 receptor binding domain (RBD). Whereas RBD or cytokine exposure caused a pro-inflammatory cellular environment and injurious signaling, impairing alveolar-capillary barrier function, and inducing cell death, MSC-EVs reduced inflammation and reestablished target cell health. Importantly, MSC-EV treatment increased active ACE2 surface protein compared to RBD injury, identifying a previously unknown role for MSC-EV treatment in COVID-19 signaling and pathogenesis. The beneficial effect of MSC-EV treatment was confirmed in an LPS-induced rat model of ALI wherein MSC-EVs reduced pro-inflammatory cytokine secretion and respiratory dysfunction associated with disease. MSC-EV administration was dose-responsive, demonstrating a large effective dose range for clinical translation. These data provide direct evidence of an MSC-EV-mediated improvement in ALI and contribute new insights into the therapeutic potential of MSC-EVs in COVID-19 or similar pathologies of respiratory distress.

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