G. Kasotakis1, M. Galvan1, P. Osathanugrah1, N. Dharia1, L. Bufe1, Z. Breed1, D. Mabarak1, N. Singh1, E. Kintsurashvili1, D. Remick1 1Boston University,Dept Of Trauma, Acute Care Surgery & Surgical Critical Care,Boston, MA, USA
Introduction: Acute Respiratory Distress Syndrome (ARDS) is a clinical syndrome characterized by uncontrolled inflammation of the lungs, after application of a severe inflammatory stimulus. We have previously demonstrated an ameliorated syndrome and improved survival in mice with the early administration (30 min) of valproic acid (VPA), a broad-spectrum Histone Deacetylase Inhibitor (HDACI), while studies in humans have shown no benefit when anti-inflammatories are administered late in the course of disease. With the current project we aim to identify the window of time within which, if an HDACI is administered, clinical and laboratory improvement can be seen.
Methods: Mice (C57BL/6, n=12/group) had 50×106 E. coli (strain 19138) instilled endotracheally and VPA (250mg/kg) administered intraperitoneally 3, 4, 6, and 9 hours later. These were compared with controls without VPA. Six hours after VPA administration, the animals were sacrificed, and bronchoalveolar lavage fluid (BAL) IL-6, TNF, neutrophils and macrophages, as well as the E.coli Colony Forming Units (CFU) were quantified. Plasma IL-6 was also measured. A separate groups of mice (n=12/group) were followed prospectively for 14 days to assess survival. Continuous variables were compared with a t-test and survival with the log-rank test. Statistical significance was declared at p<0.05.
Results: BAL IL-6 and TNF were significantly lower in the animals administered VPA within 3h (p<0.05), but not when administered later (4, 6, 9h). There was no difference in the BAL E. coli CFU, macrophage or neutrophil numbers with any timing of administration studied in this project (3, 4, 6 or 9h). Survival improved only when VPA was administered up to 3h.
Conclusion: A narrow therapeutic window of opportunity exists in this clinically relevant murine model of gram negative pneumonia-induced ARDS, and likely explains the lack of response in studies with late administration of anti-inflammatory therapies in humans. Future directions include use of murine models with kinetics similar to those of ARDS development in humans, and study of narrow spectrum HDACI.
