Time course of the inflammatory and oxidative stress response to pulmonary infection in mice

Abstract

The pathophysiological response to pulmonary infection includes a surge of proinflammatory cytokines and excessive production of nitric oxide (NO), but the time changes are not sufficiently defined. The current study was designed to assess the time course of proinflammatory cytokines and NO production in a murine model of pulmonary infection. The injury was induced by intranasal administration of live Pseudomonas aeruginosa (3.2 × 10(7) colony-forming units) in C57BL/6 wild-type mice. The animals were euthanized at 3, 6, 9, 12, and 15 hours postinjury. Additional mice received sham injury (0 hours; control). Lung tissue and plasma samples were harvested at the respective time points. The injury induced an early increase in interleukin (IL)-1 β protein in lung tissue that persisted during the entire study period with a peak at the 9-hour time point. The increases in TNF-α and IL-6 proteins in lung tissue were less intense, but showed a peak about 9 hours postinjury. The plasma levels of IL-1 β and tumor necrosis factor (TNF)-α protein were not elevated during the experimental period, but only an increase in plasma levels of IL-6 plasma protein was detected. These findings compensate for the limitations of previous experiments with similar infection models and improve the understanding of pathophysiologic alterations in response to pulmonary infection. In addition, the identification of the time changes of the described pathogenetic factors may enhance the timing of innovate therapeutic approaches in future experiments.

Dimethylarginine Dimethylaminohydrolase II Overexpression Attenuates LPS-Mediated Lung Leak in Acute Lung Injury

“…Our data suggest that attenuating ADMA levels or increasing DDAH activity prevents NOS uncoupling, reduces superoxide generation, and inhibits oxidative/nitrative damage. Although the NOS isoform responsible for the increase in superoxide in our study has not yet been determined, ADMA is known to induce the uncoupling of all the NOS isoforms (15,24), and is an effective inhibitor of NO production from eNOS (8), but only a weak inhibitor of NO production by inducible NOS (iNOS) (25). As LPS induces iNOS protein levels in the mouse lung (5), it is possible that the increased NOS-derived superoxide and peroxynitrite formation that we observed could be generated from both iNOS and eNOS.…”

“…For instance, in a small clinical trial, N-acetylcysteine caused the repletion of glutathione in patients with ALI, but only moderately improved lung function (42). In addition, the use of NOS inhibitors has failed to reduce oxidative stress, and have even tended to increase mortality in mice (24) and in patients with severe sepsis (25). Although the administration of an iNOS inhibitor improved survival when given 12 hours after peritonitis-induced sepsis in rats, the same intervention increased mortality when given 6 hours earlier (26).…”

Adipose-derived stem cells attenuate pulmonary microvascular hyperpermeability after smoke inhalation

“…Another limitation of our present study is that we were not able to measure inflammatory or permeability markers in the lung tissue at different time points after the injury. It is possible that the peak time of the expression of ANG2 and LXA4 occurred much earlier; as we have reported in our previous studies that inflammatory mediators (lung IL-1β, TNF-α, IL-6) in mice lung tissue peaked around 9 hours after the injury [ 36 ]. We have also reported on the time course of cytokines in sheep sepsis study, in which IL-6 and PARP activation in lung tissue peaked at 8 hours and 12 hours after injury [ 37 ].…”