Table 1.
Summary of in Vivo Experiments in Various Disease Models
| System/disorder | Animal model (species) | Strain | Inhibitors | Effect seen | References |
|---|---|---|---|---|---|
| Neurologic | |||||
| Stroke | Middle cerebral artery occlusion (mouse) | C57BL/6 | Nec-1s | Reduced infarct volume | 30 |
| Middle cerebral artery occlusion (mouse) | Ripk3−/− | None | No effect | 31 | |
| Alzheimer disease | Amyloid precursor protein/presenilin 1 (mouse) | Tg2576 | Nec-1s | Reduction in Aβ plaques and behavioral deficits | 32 |
| Cardiovascular | |||||
| Myocardial infarction | Left anterior descending coronary artery ligation (mouse) | Ripk3−/− | None | Improved ejection fraction, decreased inflammation | 33 |
| Ischemia/reperfusion injury (mouse) | Ripk3−/− | None | Reduced infarct size, improved ejection fraction | 12 | |
| Left anterior descending coronary artery ligation (mouse) | C57BL/6 | Nec-1 | Reduced inflammation, reduced infarct size | 34,35 | |
| Aortic aneurysm | Elastase model (mouse) | Ripk3−/− | None | AAA formation prevented | 36 |
| Elastase model (mouse) | C57BL/6 | Nec-1, Nec-1s | Decreased aneurysm diameter | 37 | |
| Calcium phosphate (mouse) | C57BL/6 | GSK'074 | Decreased aneurysm diameter | 27 | |
| Pulmonary | |||||
| Respiratory distress syndrome | IV injection oleic acid (rat) | Sprague-Dawley | None | Elevated levels of RIPK1, RIPK3, and MLKL in lung tissue | 38 |
| Intratracheal injection LPS (mouse) | Ripk3−/− | None | RIPK3 deficiency increased survival and decreased inflammation | 39 | |
| IV injection oleic acid (rat) | Sprague-Dawley | Nec-1 | Decreased inflammation within the lung parenchyma | 40 | |
| Chronic pulmonary disease | Cigarette smoking (mouse) | Pink1−/− | Nec-1 | Cigarette smoke-induced cell-death decreased | 41 |
| Cigarette smoking (mouse) | BALB/cByJ | Nec-1 | Reduced levels of DAMPs and neutrophils on BAL fluid | 42 | |
| Gastrointestinal | |||||
| Acute liver injury | Excessive acetaminophen toxicity (mouse) | C57BL/6 | Nec-1 | Decreased reactive oxygen species within the liver | 43 |
| Excessive acetaminophen toxicity (mouse) | C57BL/6, Ripk3−/− | anti-sense morpholinos | Attenuated necrotic cell death within livers | 44 | |
| Excessive acetaminophen toxicity (mouse) | Ripk3−/−, Mlkl−/− | Nec-1 | RIPK1 mediated acetaminophen toxicity independent of necroptosis | 45 | |
| Hepatic IR injury (mouse) | Ripk3−/− | Nec-1 | No effect | 46 | |
| Hepatic IR injury + hepatic steatosis (mouse) | Mlkl−/− | None | Protected from hepatic IR injury | 47 | |
| Chronic liver injury | Chronic ethanol feeding (mouse) | Ripk3−/− | Nec-1s | RIPK3-deficient mice were protected but Nec-1s had no effect | 48 |
| Gao-binge alcohol treatment (mouse) | Ripk3−/−, liver-specific PSMC1 knockout | Nec-1 | Impaired hepatic proteasome function by alcohol exposure led to the accumulation of RIPK3 | 49 | |
| Pancreatitis | Cerulean-induced acute pancreatitis (mouse) | Mlkl−/− | None | Protected from acute pancreatitis and necrosis | 50 |
| Cerulean-induced acute pancreatitis (mouse) | Ripk3−/− | None | Protected from acute pancreatitis and necrosis | 51 | |
| Bile acid- and secretagogue-induced pancreatitis (mouse) | C57BL/6 | Nec-1 | Decreased cell injury and severity of pancreatitis | 52 | |
| Inflammatory bowel disease | DSS-induced colitis | Casp8(ΔIEC) | Nec-1 | Inflammation within the terminal ileum than can be prevented with Nec-1 | 53 |
| DSS-induced colitis | Ripk3−/− | None | RIPK3 important for tissue repair and protected against colitis | 54 | |
| Autoimmune diseases | Collagen-induced arthritis (mouse) | Ifnγ−/− | None | MLKL, RIPK1, and RIPK3 elevated within joints | 55 |
| Renal | |||||
| Acute kidney injury | Bilateral renal pedicle clamping (mouse) | RIPK1-kinase dead, Ripk3−/−, Mlkl−/− | Nec-1 | Mice protected from renal injury except MLKL deficient mice | 31,56,57 |
| Cisplatin-induced kidney injury (mouse) | Ripk3−/−, Mlkl−/− | None | Diminished proximal tubule damage | 58 | |
| Oxalate crystal-induced kidney injury (mouse) | Ripk3−/−, Mlkl−/−, C57BL/6 | Nec-1, Necrosulfonamide | Reduced crystal-induced cell death | 59 | |
| Organ rejection/injury | Kidney transplant (mouse) | Ripk3−/− | None | Improved survival and renal function | 1 |
| Cardiac transplant (mouse) | Ripk3−/− | None | Chronic graft injury reduced | 2 | |
| Infectious disease | Vaccina virus infection | Ripk3−/− | None | Severely impaired control of viral replication | 60 |
| Vaccina virus infection | Tnfr2−/− | None | Reduced inflammation in liver and defective viral clearance | 61 | |
| West-Nile virus infection | Ripk3−/− | None | Enhanced mortality, suppressed inflammatory response | 62 | |
| Influenzae virus infection | Ripk3−/− | None | Increased susceptibility to infection | 63 |
AAA, abdominal aortic aneurysm; BAL, bronchoalveolar lavage; DAMPs, damage-associated molecular pattern molecules; DSS, dextran sodium sulfate; I/R, ischemic reperfusion; LPS, lipopolysaccharide; MLKL, mixed-lineage kinase domain-like protein; PSMC, proteasome 26S subunit, ATPase; RIPK, receptor-interacting protein kinase.