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- 166 results found
- Rodent Models
- Swine Models
Natural Killer Cells Activated Through NKG2D Mediate Lung Ischemia-Reperfusion Injury
Calabrese et al., Journal of Clinical Investigation. 2021.
https://www.jci.org/articles/view/137047
Pulmonary ischemia-reperfusion injury (IRI) causes early mortality and has no effective therapies. While natural killer (NK) cells are innate lymphocytes capable of recognizing injured cells, their roles in acute lung injury are incompletely understood. Here, investigators demonstrated that NK cells were increased in frequency and cytotoxicity in 2 different IRI mouse models. They showed that NK cells trafficked to the lung tissue from peripheral reservoirs and were more mature within lung tissue. Acute lung ischemia-reperfusion injury was blunted in a NK cell–deficient mouse strain but restored with adoptive transfer of NK cells. In human lung tissue, NK cells were increased at sites of ischemia-reperfusion injury and activated NK cells were increased in prospectively-collected human bronchoalveolar lavage in subjects with severe IRI. These data support a causal role for recipient peripheral NK cells in pulmonary IRI via NK cell NKG2D receptor ligation. Therapies targeting NK cells may hold promise in acute lung injury. Supported by ORIP (S10OD026940), NHLBI, and NIDDK.
Lung Expression of Human Angiotensin-Converting Enzyme 2 Sensitizes the Mouse to SARS-CoV-2 Infection
Han et al., American Journal of Respiratory Cell and Molecular Biology. 2021.
https://doi.org/10.1165/rcmb.2020-0354OC
A rapidly deployable mouse model that recapitulates a disease caused by a novel pathogen would be a valuable research tool during a pandemic. Researchers were able to produce C57BL/6J mice with lung expression of human angiotensin-converting enzyme 2 (hACE2), the receptor for SARS-CoV-2. They did so by oropharyngeal delivery of a recombinant human adenovirus type 5 expressing hACE2. The transduced mice were then infected with SARS-CoV-2. Thereafter, the mice developed interstitial pneumonia with perivascular inflammation, exhibited higher viral load in lungs compared to controls, and displayed a gene expression phenotype resembling the clinical response in lungs of humans with COVID-19. Supported by ORIP (P51OD011104, R21OD024931), NHLBI, and NIGMS.
Biological Activities of a New Crotamine-like Peptide from Crotalus oreganus helleri on C2C12 and CHO Cell Lines, and Ultrastructural Changes on Motor Endplate and Striated Muscle
Salazar et al., Toxicon. 2020.
https://pubmed.ncbi.nlm.nih.gov/33065200/
Crotamine and crotamine-like peptides are non-enzymatic polypeptides found in high concentration in the Crotalus genus venom. Helleramine was isolated and purified from the venom of the rattlesnake, Crotalus oreganus helleri. Purified helleramine increased intracellular Ca2+ in Chinese Hamster Ovary (CHO) cell line, inhibited cell viability of C2C12 (immortalized skeletal myoblast) and promoted early apoptosis and cell death. Skeletal muscle harvested from mice 24 hours after helleramine injection showed contracted myofibrils and profound vacuolization, with loss of plasmatic and basal membrane integrity. The effects of helleramine provide evidence of myotoxic activities of crotamine-like peptides and their possible role in crotalid envenoming. Supported by ORIP (P40OD010960).
Lipocalin-2 Is an Anorexigenic Signal in Primates
Petropoulou et al., eLife. 2020.
https://doi.org/10.7554/eLife.58949
The hormone lipocalin-2 (LCN2) suppresses food intake in mice. Researchers demonstrated that LCN2 increases after a meal and reduces hunger in people with normal weight or overweight, but not in obese individuals. The researchers also showed that LCN2 crosses the blood-brain barrier and binds to the hypothalamus in vervet monkeys. LCN2 was found to bind to the hypothalamus in human, baboon, and rhesus macaque brain sections. When injected into vervets, LCN2 suppressed food intake and lowered body weight without toxic effects in short-term experiments. These findings lay the groundwork to investigate whether LCN2 might be a useful treatment for obesity. Supported by ORIP (P40OD010965), NCATS, NIDDK, NIA, and NHLBI.
Fructose Stimulated De Novo Lipogenesis Is Promoted by Inflammation
Jelena et al., Nature Metabolism. 2020.
https://pubmed.ncbi.nlm.nih.gov/32839596
Non-alcoholic fatty liver disease (NAFD) affects 30% of adult Americans. While NAFD starts as simple steatosis with little liver damage, its severe manifestation as non-alcoholic steatohepatitis (NASH) is a leading cause of liver failure, cirrhosis, and cancer. Fructose consumption is proposed to increase the risk of hepatosteatosis and NASH. Excessive intake of fructose causes barrier deterioration and low-grade endotoxemia. Using a mouse model, the study examined the mechanism of how fructose triggers these alterations and their roles in hepatosteatosis and NASH pathogenesis. The results demonstrated that microbiota-derived Toll-like receptor (TLR) agonists promote hepatosteatosis without affecting fructose-1-phosphate (F1P) and cytosolic acetyl-CoA. Activation of mucosal-regenerative gp130 signaling, administration of the YAP-induced matricellular protein CCN1 or expression of the antimicrobial peptide Reg3b (beta) counteract fructose-induced barrier deterioration, which depends on endoplasmic-reticulum stress and subsequent endotoxemia. Endotoxin engages TLR4 to trigger TNF production by liver macrophages, thereby inducing lipogenic enzymes that convert F1P and acetyl-CoA to fatty acid in both mouse and human hepatocytes. The finding may be of relevance to several common liver diseases and metabolic disorders. Supported by ORIP (S10OD020025), NCI, NIEHS, NIDDK, NIAID, and NIAAA.
Induction and Characterization of Pancreatic Cancer in a Transgenic Pig Model
Boas et al., PLOS One. 2020.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239391
Preclinical testing of new therapies for pancreatic cancer has been challenging due to lack of a suitable large animal model. Pigs, however, have similar physiology and immune response to humans. Boas et al report the development of a porcine model for pancreatic cancer. H&E and immunohistochemical stains revealed undifferentiated carcinomas, like those of human pancreatobiliary systems. In several pigs, angiographies revealed that the artery supplying the pancreatic tumor could be catheterized using a 2.4 F microcatheter. In summary, pancreatic cancer can be induced in a transgenic pig, and intra-arterial procedures using catheters designed for human interventions were feasible in this model. Supported by ORIP (U42OD011140) and NCI.