Table 2.
Studies of post-treatment with nonselective PDE inhibitors in animal models of acute respiratory distress syndrome (ARDS) or sepsis.
| Author (Year) | Type of Injury | Species of Animals | Treatment/Dose | Duration of Treatment | Outcomes in Treated Groups |
|---|---|---|---|---|---|
| Sciuto et al. (1997) | Phosgene-induced ALI (nebulized LPS 100 μg/mL for 60 min.) | Wistar rats | Aminophylline (lung perfusion with 30 mg/kg) | 2.5 h | Decreased pulmonary artery pressure, tracheal pressure, and lung weight gain, reduced TBARS and perfusate LTC4/D4/E4, prevented decrease in lung cAMP |
| Fakioglu et al. (2004) | LPS-induced acute endotoxemia (LPS 4 mg/kg i.v.) |
Sprague–Dawley rats | Aminophylline (1 mg/kg i.v. bolus 30 min, then 0.5 mg/kg/h infusion), concomitant injection with LPS) |
6 h | No decrease in tissue (lung, kidney, heart) water content |
| Mokra et al. (2007) | Meconium-induced ALI | Rabbits | Aminophylline (2 mg/kg i.v. bolus 0.5 and 2.5 h after i.t. meconium) | 5 h | Improved gas exchange, decreased right-to-left shunts and ventilatory pressures, reduced edema formation, neutrophils in BALF, markers of oxidative stress, airway reactivity to histamine |
| Mokra et al. (2008) | Meconium-induced ALI | Rabbits | Aminophylline (2 mg/kg or 1 mg/kg i.v. bolus 0.5 and 2.5 h after i.t. meconium) | 5 h | With 2 mg/kg A: superior effect on gas exchange, lung edema, lipid peroxidation, neutrophil counts in BALF and tracheal reactivity to histamine; 1 mg/kg A: reduced protein oxidation in the lung and lung tissue reactivity to histamine |
| Shao et al. (2019) | Meconium-induced ALI | Newborn piglets | Aminophylline (6 mg/kg followed by continuous infusion of 0.5 mg/kg/h) | 4 h | Improved oxygenation, trend to decrease markers of inflammation (IL-8 and CRP in BALF, IL-8 and PLA2 in lung) |
| Hoffmann et al. (1991) | E.coli-induced sepsis (2 × 109 Escherichia coli bacteria i.v.) | Guinea pigs | Pentoxifylline (20 mg/kg i.v. followed by infusion of 20 mg/kg/h) or Dibutyryl (db)-cAMP (2 mg/kg i.v. + 2 mg/kg/h infusion) 30 min. after E. coli | 7.5 h | Both treatments prevented edema formation; reduced in vitro endotoxin-induced PMNs chemiluminescence, no change in leukocyte counts in BALF or peripheral leukocytes |
| Riddings et al. (1994) | Pseudomonas aeruginosa-induced Gram-negative sepsis by i.v. infusion | Yorkshire swine | Pentoxifylline (20 mg/kg followed by 6 mg/kg/h) prior to the onset of sepsis, or at 1 h or 2 h after the onset of bacteria infusion | 5 h | Both pre- and post-treatments improved PaO2 and lung injury, pre- and early post-treatment improved cardiac index, but late treatment in established septic shock caused fatal systemic hypotension in a half of animals |
| Nelson et al. (1999) | Peritoneal sepsis | Lewis rats | Pentoxifylline (low dose of 5 mg/kg/day vs. high dose of 20 mg/kg/day) | 7 d | Low-dose P: improved survival, down-regulated IL-6 mRNA in liver and LPS-binding protein mRNA in liver and intestine |
| Ji et al. (2004) | LPS-induced sepsis (LPS 5 mg/kg i.p.) | Rats | Pentoxifylline (doses of 6.25, 12.5, 25, 50, or 100 mg/kg at 1 min after LPS challenge) | 1, 4 and 6 h | Pentoxifylline at all dosages reduced activation of NF-κB and production of TNFα and IL-6, and enhanced a release of IL-10 |
| Coimbra et al. (2005) | LPS-induced acute endotoxemia (LPS 5 mg/kg i.v.) |
Male Sprague-Dawley rats | Pentoxifylline (25 mg/kg i.v., concomitant injection with LPS) | 2, 4 or 24 h | Decreased plasma TNFα, IL-6, nitrite, AST and ALT, reduced liver injury score and neutrophil infiltration, decreased NF-κB in hepatocytes and Kupffer cells, decreased iNOS in Kupffer cells |
| Coimbra et al. (2006) | LPS-induced acute endotoxemia (LPS 5 mg/kg i.v.) |
Male Sprague-Dawley rats | Pentoxifylline (25 mg/kg i.v., concomitant injection with LPS) | 4 h | Decreased IL-8 and MMP-2 in BALF, and plasma MMP-9 activity, decreased lung MPO, ICAM-1 expression, and NF-κB activation, attenuated lung injury |
| Korhonen et al. (2004) | Meconium-induced ALI | Neonatal piglets | Pentoxifylline (20 mg/kg bolus i.v. followed by infusion of 20 mg/kg/h) since 15 min. after meconium | 12 h | Enhanced regional ventilation, prevented an increase of alveolar macrophages in BALF and lung, concentrations of TNFα and protein, but had no effect on lung neutrophil accumulation |
| Sunil et al. (2014) | Nitrogen mustard- induced ALI | Wistar rats | Pentoxifylline (46.7 mg/kg, i.p.) daily for 3d beginning 15 min after nitrogen mustard | 3 days | Reduced lung injury, protein content, and cells in BALF, decreased COX-2 and MMP-9, oxidative stress proteins lipocalin and heme-oxygenase-1 in lung, stimulated wound repair |
| Özer et al. (2020) | CLP-induced model of sepsis | Wistar rats | Pentoxifylline (50/mg/kg/day i.p.) for 72 h after CLP | 7 days | Increased antioxidant enzymes and lowered pathological score in the lung and kidney |
| Hasegawa et al. (1997) | Pseudomonas aeruginosa-induced sepsis by i.v. infusion | Hanford minipigs | Lisofylline (25 mg/kg followed by 10 mg/kg/h) 30 min prior to, or 1 h or 2 h after bacteria infusion | 6 h | Attenuated sepsis-induced pulmonary hypertension, neutropenia, hypoxemia, increased MPO activity, and lung injury parameters in the Pre- and Post-1 h groups |
| Oka et al. (1999) | Pseudomonas aeruginosa-induced sepsis by i.v. infusion | Hanford minipigs | Lisofylline (25 mg/kg bolus followed by infusion of 10 mg/kg/h) 30 min prior to sepsis, or 1 h or 2 h after bacteria infusion | 6 h | Pretreatment reduced sepsis-enhanced phagocytic activity, attenuated neutrophil attachment to fibronectin, and produced neutrophilia; 1-h post-treatment attenuated neutrophil attachment to fibronectin and caused neutropenia to recover |
| Weichelt et al. (2013) | Hyperoxia-induced ALI | Neonatal rats | Caffeine (10 mg/kg i.p.) at the beginning of hyperoxia | 6, 24, or 48 h | Diminished lung leukocyte infiltration, perturbation of alveolar development, and mRNA expressions of pro-inflammatory chemokines and cytokines |
| Jing et al. (2017) | Hyperoxia-induced ALI | Neonatal rats | Caffeine (20 mg/kg i.p.) from day 2 of life | 9 or 20 days | Increased lung cAMP levels and phosphorylated endothelial NO synthase, improved alveolar structure and angiogenesis, reduced mortality |
| Teng et al. (2017 | Hyperoxia-induced ALI | Neonatal rats | Caffeine (20 mg/kg i.p.) from day 2 of life | 9 or 20 days | Attenuated alveolar injury and endoplasmic reticulum stress, suppressed activation of COX-2 and markers of apoptosis |
| Li et al. (2011) | Oleic acid-induced ALI | Wild type and A2A receptor knockout C57BL/6 mice | Caffeine: chronic (0.1 g/l, 0.25 g/l and 5.0 g/l p.o.) for 2 weeks before ALI, or acute (5 mg/kg, 15 mg/kg and 50 mg/kg i.p.) 30 min. before ALI | 2 weeks or 24 h | Chronic (0.1 g/l or 0.25 g/l) and acute caffeine (50 mg/kg i.p.) attenuated the lung edema, hemorrhage, neutrophil recruitment, TNFα and IL-1 expressions, increased lung cAMP and upregulation of A2B receptor mRNAs |