Table 2.
Summary of the Effects of Inhibition of Poly (ADP-Ribose) Polymerase (PARP) in Experimental Models of Sepsis
| No | Species | Sex | Age | Sepsis Model | PARP Inhibition | Characteristics of the Group with PARP Inhibition Compared with the Control Group | Ref |
|---|---|---|---|---|---|---|---|
| 1 | Mice (C57BL/6) | Male and female | 6–8 weeks | LPS from E. coli 0111:B4 40 mg/kg i.p. |
PARP-1-KO | Resistance to LPS-induced endotoxic shock Lack of rapid activation of NF-κB in macrophages ↓↓ NF-κB-dependent accumulation of TNF-α in the serum ↓ iNOS. |
[111] |
| 2 | Mice (129/Sv × C57BL/6) | Male | 8 weeks | CLP | PARP-1-KO | ↑ survival ↓ plasma levels of TNF-α, IL-6, and IL-10 ↓ degree of organ inflammation (gut, lungs) |
[112] |
| 3 | Mice (129/Sv × C57BL/6) | ND | 3 months | LPS from E. coli 0111:B4 40 mg/kg i.p. |
PARP-1-KO | ↓ plasma levels of TNF-α (1088 ± 84 pg/mL) ↓ plasma levels of IL-6 (586 ± 47 ng/mL) ↓ inflammatory infiltrates in organs (liver, lungs) |
[113] |
| Mice (129/Sv × C57BL/6) | ND | 3 months | LPS from E. coli 0111:B4 40 mg/kg i.p. |
PJ34 10 mg/kg 1 h before LPS treatment |
↓ plasma levels of TNF-α (862 ± 155 pg/mL) ↓ plasma levels of IL-6 (381 ± 53 ng) ↓ inflammatory infiltrates in organs (liver, lungs) |
[113] | |
| Mice (129/Sv × C57BL/6) | ND | 3 months | CLP | PARP-1-KO | ↓ plasma levels of IL-6 ↓ inflammatory infiltrates in organs (liver, lungs) |
[113] | |
| Mice (129/Sv × C57BL/6) | ND | 3 months | CLP | PJ34 10 mg/kga |
↓ plasma levels of IL-6 ↓ inflammatory infiltrates in organs (liver, lungs) |
[113] | |
| 4 | LACA mice | Female | ND | LPS from E. coli O111: B4 50 μg per mouse i.t. |
Olaparib 5 mg/kg i.p. 0.5 h after LPS administration |
↓ inflammatory infiltrates in lungs ↑ kidney function ↓ uric acid level ↓ level of MDA in lungs and kidneys ↑ level of GSH in lungs and kidneys ↓ activation of p65-NF-κB (but not expression of total p65-NF-κB) ↓ tissue expression of TNF-α, IL-1β, and VCAM-1 (NF-κB-dependent genes) |
[103] |
| 5 | Wild-type mice | ND | 4–6 weeks | CLP | PJ34 10 mg/kg i.p. 3 h before CLP |
↓ serum HMGB1 levels | [66] |
| 6 | C57BL6 mice | Male | 8 weeks | CLP | Olaparib 1 mg/kg, 3 mg/kg or 10 mg/kg i.p. 24-hour protocol 1st dose 0.5 h after CLP 2nd dose 8 h after CLP experiment was terminated at 24 h Survival protocol 1st dose 0.5 h after CLP 2nd dose 8 h after CLP subsequent doses every 8 h experiment was terminated at 48 h |
↑ survival (at 10 mg/kg but not at the two lower doses) ↓ degree of mitochondrial DNA damage in the liver ↓ number of bacteria in the plasma and spleen ↓ plasma levels of TNFα, IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-12p40 ↑ CD4+ and CD8+ lymphocytes in the spleen (reduced in response to CLP) ↓ CLP-induced alterations in miR15, miR17, miR181 and miR365 levels in the spleen ↓ CLP-induced downregulation of miR146 in the spleen ↑ CLP-induced upregulation of miR146 in circulating leukocytes |
[104] |
| C57BL6 mice | Female | 8 weeksa | CLP | Olaparib 10 mg/kg i.p. |
No beneficial effects | [104] | |
| C57BL6 mice | Male | 72 weeks | CLP | Olaparib 10 mg/kg i.p. |
No significant beneficial effects on most organ injury markers ↓ plasma levels of IL-4, IL-12p70 |
[104] | |
| C57BL6 mice | Female | 72 weeks | CLP | Olaparib 10 mg/kg i.p. |
↓ CLP-induced liver injury markers ALP and ALT ↓ plasma levels of TNFα, IL-1α, MIP1α, M-CSF and MIG |
[104] | |
| 7 | Sprague–Dawley rats | Male | ND | LPS from E. coli O111: B4 16 mg/kg i.t. |
3-AB 20 mg/kg |
↓ plasma levels of lactate, creatinine, and potassium ↑ arterial blood gas pH ↑ PaO2 ↓ mRNA expressions of TNF-α, IL-1β and IL-6 in the lung and kidney ↓ expressions of PARP and NF-κB in the lung and kidney ↓ lung W/D ratio No perivascular edema in the lungs or kidneys Attenuation of LPS-induced hypotension |
[117] |
| 8 | Sprague-Dawley rats | Male | 8 weeks | CLP | 3-AB 10 mg/kg i.v. Pretreatment group 2 h before CLP Treatment group 2 h after CLP |
↓ serum levels of troponin I and CK-MB ↓ activity of caspase-3 and level of cytochrome C in the myocardial tissues ↑ ATP and NAD+ concentrations in the myocardium tissues ↓ activity of PARP1 in the myocardium tissues ↓ PARP-1 and Bax expressions in the myocardium tissues ↑ Bcl-2 expression in the myocardium tissues ↓ degree of cardiocyte injury |
[119] |
| 9 | New-Zealand rabbits | ND | ND |
P. aeruginosa (ATCC 27,853) 2 mL of a solution i.t. |
PJ34 10 mg/kg bolus + 3 mg/kg/h infusion i.v. |
↓ gut W/D ratio No significant differences in lung W/D ratios |
[118] |
| 10 | Sheep | Female | ND | Cotton smoke exposure (4 x 12 breaths) + Pseudomonas aeruginosa i.b. 5 × 109/kg |
INO-1001 3 mg/kg bolus 1 h after injury + 0.3 mg/kg/h infusion i.v. |
↓ histological injury in the lung (congestion, inflammation, hemorrhage) ↓ PAR accumulation in the lung ↓ lipid peroxidation (MDA formation) in the lung ↓ deposition of nitrotyrosine in the lung ↓ pulmonary vascular permeability ↓ lung W/D ratio ↑ SaO2 ↑ PaO2/FiO2 ratio |
[116] |
Note: aPresumably.
Abbreviations: 3-AB, 3-aminobenzamide; ALP, alkaline phosphatase; ALT, alanine aminotransferase; ATP, adenosine triphosphate; CK-MB, creatine kinase muscle brain; CLP, cecal ligation and puncture; DNA, deoxyribonucleic acid; FiO2, fraction of inspired oxygen; GSH, reduced glutathione; HMGB1, high-mobility group box 1; i.b., intrabronchial; i.p., intraperitoneal; i.t., intratracheal; i.v., intravenous; IL, interleukin; iNOS, inducible nitric oxide synthase; KO, knockout; LPS, lipopolysaccharide; M-CSF, macrophage colony-stimulating factor; MDA, malondialdehyde; MIG, monokine induced by interferon γ; MIP, macrophage inflammatory protein; mRNA, messenger ribonucleic acid; NAD+, nicotinamide adenine dinucleotide; ND, not determined; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PaO2, arterial partial pressure of oxygen; PAR, poly (ADP-ribose); PARP, poly (ADP-ribose) polymerase; PJ34, N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; SaO2, arterial oxygen saturation; TNF-α, tumor necrosis factor α; VCAM-1, vascular cell adhesion molecule-1; W/D, wet/dry.