Table 4.
Studies of post-treatment with selective PDE inhibitors in animal models of ARDS or sepsis.
| Author (Year) | Type of Injury | Species of Animals | Treatment/Dose | Treatment Duration | Outcomes in Treated Groups |
|---|---|---|---|---|---|
| Kuniyoshi et al. (2005) | LPS-induced endotoxemia (LPS infusion, 1.7 mg/kg/h) | Male pigs | Olprinone (PDE3-I) (0.3 mg/kg/min i.v.), given 150 to 240 min from LPS infusion | 1.5 h | Increased hepatic oxygen delivery and consumption, prevented a decrease in cytochrome aa3 and an increase in lactate |
| Mazzon et al. (2011) | Zymosan-induced septic shock (zymosan 500 mg/kg i.p.) | Male CD mice | Olprinone (PDE3-I) (0.2 mg/kg i.p.) at 1 and 6 h after zymosan) |
17 h/ 7 days | Decreased peritoneal exudation and migration of PMNs, reduced lung, liver, renal and pancreatic injury, diminished pro-inflammatory markers in tissues, prevented systemic toxicity, loss in body weight, and mortality |
| Oishi et al. (2012) | Cecal ligation and puncture (CLP) model of sepsis | Male BALB/c mice | Olprinone (PDE3-I) (2 μg/kg i.p.), given immediately after CLP | 24 h | Enhanced oxygenation, reduced pulmonary vascular permeability, lung damage, and lung cell apoptosis, improved survival |
| Mokra et al. (2012) | Meconium-induced ALI | Adult rabbits | Olprinone (PDE3-I) (0.2 mg/kg i.v. bolus, given 30 min. after meconium) | 5 h | Decreased PMNs in BALF, lung edema formation, and oxidation markers, prevented a decrease in lung TAS, decreased TBARS and increased TAS in the plasma |
| Kosutova et al. (2020) | Saline lung lavage-induced ALI | Adult rabbits | Olprinone (PDE3-I) (1 mg/kg i.v. bolus, given 15 min. after the last lung lavage) | 4 h | Reduced lung PMNs and edema formation, improved oxygenation, reduced right-to-left pulmonary shunts, decreased markers of lung inflammation and oxidative stress, and apoptosis of epithelial cells |
| Shao et al. (2019) | Meconium-induced ALI | Newborn piglets | Milrinone (PDE3-I) (50 μg/kg i.v., followed by infusion of 0.75 μg/kg/h) Rolipram (PDE4-I) (0.8 mg/kg i.v.) |
4 h | Improved oxygenation, tended to decrease markers of inflammation (milrinone: IL-1β and IL-6 in BALF; rolipram: IL-1β in serum, IL-1β, IL-6 in BALF, CRP in lung). |
| Özer et al. (2020) | CLP-induced model of sepsis | Wistar rats | Milrinone (PDE3-I) (1/mg/kg/day i.p.) for 72 h after CLP Sildenafil (PDE5-I) (10/mg/kg/day i.p.) for 72 hours after CLP |
7 days | Increased antioxidant enzymes in lung and kidney, lowered pathological score in lung and kidney |
| Holthoff et al. (2013) | Cecal ligation and puncture (CLP) model of sepsis | Male C57BL/6 mice | Rolipram (PDE4-I) (doses of 0.3-10 mg/kg i.p., given 6 h after CLP) |
6 or 18 h | Increased renal blood flow and glomerular filtration rate, reduced renal microvascular permeability, blood urea nitrogen, and serum creatinine. |
| Flemming et al. (2014) | Colon ascendens stent peritonitis (CASP) model of sepsis | Male Sprague-Dawley rats | Rolipram (PDE4-I) (low-dose 1 mg/kg/h vs high-dose 3 mg/kg/h i.v., given 12 h after operation) | 14 h | Reduced albumin extravasation and improved mesenteric microcirculatory flow at low-dose, but adverse effects at high-dose. Prevented sepsis-induced acute kidney injury, decreased lung edema and neutrophil infiltration, enhanced oxygenation, decreased IL-1α, IL-1β, IL-12, and TNFα |
| Wollborn et al. (2015) | LPS-induced acute endotoxemia(LPS 2.5 mg/kg i.v.) | Male Sprague-Dawley rats | Rolipram (PDE4-I) (300 μg/100 g i.v., given 1 h after LPS) |
4 h | Improved hepatic volumetric flow and cell death; no influence on inflammatory impact |
| Sims et al. (2017) | Cecal ligation and puncture (CLP) model of sepsis | Rat pups (17-18-days old) | Rolipram (PDE4-I) (0.1 mg/kg i.p., single dose at 6 h post-CLP) |
6 or 18 h/4 days | Restored cardiac function and renal microcirculation, reduced microvascular leakage, improved 4-day survival |
| Schick et al. (2012) | LPS-induced acute endotoxemia(LPS 5 and 2.5 mg/kg i.v.) | Male Sprague-Dawley rats | Rolipram (PDE4-I) (3 mg/kg i.v. followed by 0.04 μg/100 g/h) Roflumilast (PDE4-I) (240 μg/kg i.v. followed by 4 μg/100 g/h or by repeated boli 240 μg/kg), with or 1.5 h after LPS) |
6 h | Both PDE4-I reduced albumin extravasation, stabilized endothelial barrier, and increased microcirculatory flow in mesenteric venules, reduced mortality, no serious adverse effects |
| Konrad et al. (2015) | Nebulized LPS-induced model of ALI (total of 7 ml, 500 μg/ml) | C57BL/6 male mice | Rolipram (PDE4-I) (1mg/kg i.p.), Roflumilast (PDE4-I) (500 μg/kg i.p.), given 1h after LPS inhalation | 6 h | Both PDE4-I decreased cell migration and TNFα, IL6, CXCL1 and CXCL2/3, both PDE4-I decreased LPS-induced PDE4B |
| Kosutova et al. (2017) | Saline-lavage induced surfactant depletion | New Zealand rabbits | Roflumilast (PDE4-I) (1 mg/kg i.v.) | 4 h | Reduced leak of neutrophils into the lung and lung edema formation, improved respiratory parameters |
| Kosutova et al. (2018a) | Saline-lavage induced surfactant depletion | New Zealand rabbits | Roflumilast (PDE4-I) (1 mg/kg i.v.) | 4 h | Reduced lung edema generation, apoptosis of lung epithelial cells, and neutrophil count in BALF, decreased TNFα, IL-6, IL-8, MDA in the lung and plasma, and 3-nitrotyrosine in the lung |
| Shekerdemian et al. (2002) | Meconium-induced ALI | Piglets | Sildenafil (PDE5-I) (2 mg/kg i.v. infusion over 2 h) started at 2 h after meconium | 2 h | Reversed an increase in pulmonary vascular resistance, no effect on systemic hemodynamics. Increased cardiac output by 30%, but no influence on oxygenation |
| Ryhammer et al. (2006) | Meconium-induced ALI | Piglets | Sildenafil (PDE5-I) (hourly an increasing dose 0.4, 1, and 3 mg/kg i.v., starting 2 h after meconium) | 3 h | Reduced pulmonary artery pressure and pulmonary vascular resistance by 30%, but increased oxygenation index |
| Cadirci et al. (2011) | Cecal ligation and puncture (CLP) model of sepsis | Male Wistar rats | Sildenafil (PDE5-I) (10 or 20 mg/kg p.o., given immediately after CLP) |
16 h | Increased GSH levels, decreased levels of SOD and activation of MPO and LPO; at higher dose: improved biochemical status of lung and kidneys in the sham-operated rats, improved inflammation scores |
| Gokakin et al. (2013) | Severe scald burn-induced ALI | Female Wistar rats | Sildenafil (PDE5-I) (10 or 20 mg/kg p.o., given immediately after the scald burn |
24 h | Decreased lung inflammation scores and oxidation markers, increased anti-oxidation markers |
| Kovalski et al. (2017) | CLP-induced sepsis | Male Wistar rats | Sildenafil (PDE5-I) (10 mg/kg, gavage, given 8 h after the insult |
16 h | Increased renal blood flow and reduced plasma levels of creatinine, lactate and creatine kinase, and reduced lung MPO |
| Kosutova et al. (2018b) | Saline-lavage induced surfactant depletion | New Zealand rabbits | Sildenafil (PDE5-I) (1 mg/kg i.v.) | 4 h | Reduced neutrophils in BALF, TNFα, IL-6, IL-8, nitrite/nitrate, MDA, and 3-nitrotyrosine in the lung, reduced lung edema and apoptosis of lung epithelial cells |
| Fang et al. (2020) | Severe acute pancreatitis-induced ALI | Male SD rats | Sildenafil (PDE5-I) (100 mg/kg i.p.) given 2 h after the insult | 10 h | Prevented ALI and neutrophil infiltration, decreased IL-1β, IL-6 and TNFα, promoted proliferation and inhibited apoptosis, inhibited NF-kB signal pathway |
| Rocco et al. (2003) | LPS-induced ALI (10 μg i.t.) | BALB/c mice | LASSBio596 (PDE4/5-I) (10 mg/kg i.p., given 1 h before or 6 h after LPS) | 24 h | Enhanced lung mechanics, inhibited neutrophil recruitment and TNFα release, prevented LPS- induced bronchoconstriction, alveolar collapse, and increase of collagen |
| Świerczek et al. (2020) | LPS-induced endotoxemia (1 mg/kg i.v.) | Wistar rats | GRMS-55 (PDE7-I) (20 mg/kg i.v., with LPS) | 3 h | Decreased plasma TNFα |