Abstract
Lipopolysaccharide (LPS), a component of the outer membrane of gram-negative bacteria, disrupts the alveolar-capillary barrier, triggering pulmonary vascular leak thus inducing acute lung injury (ALI). Extracellular purines, adenosine and ATP, protected against ALI induced by purified LPS. In this study, we investigated whether these purines can impact vascular injury in more clinically-relevant E.coli (non-sterile LPS) murine ALI model. Mice were inoculated with live E. coli intratracheally (i.t.) with or without adenosine or a non-hydrolyzable ATP analog, adenosine 5′-(γ-thio)-triphosphate (ATPγS) added intravenously (i.v.). After 24 h of E. coli treatment, we found that injections of either adenosine or ATPγS 15 min prior or adenosine 3 h after E.coli insult significantly attenuated the E.coli-mediated increase in inflammatory responses. Furthermore, adenosine prevented weight loss, tachycardia, and compromised lung function in E. coli-exposed mice. Accordingly, treatment with adenosine or ATPγS increased oxygen saturation and reduced histopathological signs of lung injury in mice exposed to E. coli. Lastly, lung-targeting gene delivery of adenosine or ATPγS downstream effector, myosin phosphatase, significantly attenuated the E. coli-induced compromise of lung function. Collectively, our study has demonstrated that adenosine or ATPγS mitigates E. coli-induced ALI in mice and may be useful as an adjuvant therapy in future pre-clinical studies.
Highlights
Acute respiratory distress syndrome (ARDS) and its less severe form, acute lung injury (ALI), are severe inflammatory disorders of the lung which involve massive leukocyte infiltration, increased vascular permeability and hypoxemia[1,2]
Mice were administered intravenous adenosine, ATPγS, or saline which was followed 15 min later by intratracheal inoculation of saline or the E. coli. 24 h after inoculation analysis of the bronchoalveolar lavage fluid (BALF) revealed that pretreatment with adenosine (Fig. 1A) or ATPγS (Fig. 2A) reduced E. coli stimulated protein extravasation into the airspaces
Histological assessment of lung sections stained with H & E and MPO indicated that treatment with either adenosine (Fig. 5A) or ATPγS (Fig. 6A) attenuated the morphological changes induced by E. coli instillation
Summary
Acute respiratory distress syndrome (ARDS) and its less severe form, acute lung injury (ALI), are severe inflammatory disorders of the lung which involve massive leukocyte infiltration, increased vascular permeability and hypoxemia[1,2]. The P2Y1 and P2Y2 receptors have been shown to mediate improved survival and reduced pulmonary capillary protein leak in mice infected with the gram-negative bacteria Pseudomonas aeruginosa[24]. ATP administration has been shown to improve survival and reduce bacterial counts in murine models of gram-negative and gram-positive sepsis induced by E. coli and Staphylococcus aureus[25], respectively. Extracellular adenosine has been shown to improve survival and reduced lung bacterial counts in mice exposed to gram-positive Streptococcus pneumoniae[26]. Along with our published[18,19] results on the protective effects of ATPγS and adenosine in sterile ALI model induced by purified LPS, these data suggested promising pre-clinical potential of these purines for the treatment of ALI/ARDS
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