A novel post-exposure medical countermeasure L-97-1 improves survival and acute lung injury following intratracheal infection with Yersinia pestis

Abstract

Yersinia pestis, a Gram-negative bacillus causing plague and Centers for Disease Control and Prevention (CDC) classified Category A pathogen, has high potential as a bioweapon. Lipopolysaccharide, a virulence factor for Y. pestis, binds to and activates A1 adenosine receptor (AR)s and, in animals, A1AR antagonists block induced acute lung injury (ALI) and increase survival following cecal ligation and perforation. In this study, rats were infected intratracheally with viable Y. pestis [CO99 (pCD1+/Δpgm) 1 × 108 CFU/animal] and treated daily for 3 d with ciprofloxacin (cipro), the A1AR antagonist L-97-1, or cipro plus L-97-1 starting at 0, 6, 24, 48, or 72 h post-Y. pestis. At 72 h post-Y. pestis, cipro plus L-97-1 significantly improved 6-d survival to 60–70% vs 28% for cipro plus H2O and 33% for untreated Y. pestis controls (P = 0.02, logrank test). Lung edema, hemorrhage and leukocyte infiltration index (LII) were evaluated histologically to produce ALI scores. Cipro plus L-97-1 significantly reduced lung edema, as well as aggregate lung injury scores vs controls or cipro plus H2O, and LII vs controls (P < 0.05, Student's unpaired t test). These results support efficacy for L-97-1 as a post-exposure medical countermeasure, adjunctive therapy to antibiotics for Y. pestis.

Adenosine at the Interphase of Hypoxia and Inflammation in Lung Injury

“…The same study indicated that pretreatment of A1AR agonist, 2’Me-2-chloro-N6-cyclopentyladenosine, attenuates PMN recruitment and microvascular permeability. On the other hand, post-infection treatment of a combination of A1AR antagonist L-97-1 and ciprofloxacin improves the outcome of Y. pestis infection in rats, indicating a protective effect of A1AR ( 139 ). Furthermore, A1AR knockout mice show significantly increased macrophage and neutrophil infiltration in the airway after influenza A/WSN/33 (H1N1) infection when compared to wild-type counterparts and daily treatment of A1AR antagonist 8-cyclopentyl-1,3-dipropylxanthine results in improved outcome ( 140 ).…”

Adenosine A1 receptor antagonist, L-97-1, improves survival and protects the kidney in a rat model of cecal ligation and puncture induced sepsis

“…Previously it was reported that when administered in combination with antibiotics as a 72 h delayed treatment, L-97-1 improved survival and acute lung injury in a rat model of Y. pestis induced pneumonic plague and sepsis (Wilson, et al, 2011). Moreover, it was reported that adenosine A 1 receptor antagonists block endotoxin induced acute lung injury and the release of thromboxane and IL-6 from human pulmonary artery endothelial cells (Neely et al, 1997; Wilson and Batra, 2002).…”

“…I n vitro studies in humans and in vivo studies in animals suggest that activation of adenosine A 1 receptors may contribute to the pathophysiology of acute lung injury and renal failure of sepsis (Knight, et al., 1993; Neely et al, 1997; Wilson and Batra, 2002; Wilson et al, 2011). In the lung, activation of adenosine A 1 receptors on endothelial cells increases their permeability, while their activation on alveolar type 2 cells decreases lung fluid clearance, actions on both cell types that promote pulmonary edema (Factor et al, 2007; Neely and Keith, 1995; Neely et al., 1997; Satoh et al, 2000).…”

“…In the current study L-97-1 is administered as a continuous i.v. infusion, a route for which pharmacokinetic data for L-97-1 in normal rats has been documented, and for which correlative in vitro pharmacological data for the rat adenosine A 1 receptor, have been previously reported (Wilson et al, 2011). Although plasma levels of L-97-1 were not measured in the current study, the highly significant dose-dependent effects for L-97-1 on 72 h and 7 d survival vs .…”

“…Previously it was reported that L-97-1, an adenosine A 1 receptor antagonist, significantly improves six day (d) survival, blocks acute lung injury, and prevents the decline in mean arterial pressure in a rat model of pneumonic plague and Yersinia pestis ( Y. pestis ) induced sepsis when administered 72 hours (h) post intratracheal administration of Y. pestis CO 99 (Wilson, et al, 2011). Moreover, previously it was reported in proof of concept studies in a rat model of cecal ligation and puncture (CLP) induced polymicrobial intraabdominal sepsis, when administered alone or in combination with antibiotics, that a single intravenous (i.v.)…”