E hypothesized that fluoxetine can modulate leukocytes recruitment, with activation of anti-inflammatory pathways, limiting the deleterious role of neutrophils.Anti-inflammatory Effects of Fluoxetine in DCSWe found that fluoxetine reduced circulating levels IL-6. Dual function of cytokines is well established from the literature and proinflammatory and anti-inflammatory effects are described with IL-6, however systematic levels of IL-6 are primarily markers of disease severity, i.e. serum IL-6 often correlate with mortality in patients with septic shock [44]. Ersson et al. [4] found elevated serum levels of IL-6 and TNF-alpha by 6 hours after rapid decompression in rats. Bigley et al. [23] confirmed that rapid decompression induced the release of inflammation mediators and resulted in tissue inflammation cascades. They found that increased levels of inflammatory cytokines especially IL-6, TNF-alpha and IFN-gamma were also detected in the circulation 6 hours after decompression, but only IL-6 was still present at 24 hours.Fluoxetine vs DCSAnimal Model of DCSAnimal experimentation is especially useful in studies that would pose unacceptable risks in human subjects. The use of a murine model is relevant in neurological DCS evaluation [26,27], however Adriamycin site specific problems are encountered. For example, a post-dive administration of treatment was not possible in our mouse model. Indeed the average time, from surfacing to onset of initial DCS symptoms, was very short i.e. 5 min with a high mortality rate. Moreover fluoxetine was delivered before the dive to allow the drug to reach its peak at the time of decompression. Nonetheless, we found that fluoxetine dramatically reduces the incidence of DCS and promotes motor recovery in mice. The results of this pilot study suggest that fluoxetine may reduce inflammation processes resulting from DCS, however further studies, including the assessment of inflammation markers in tissues, are needed to elucidate mechanisms of fluoxetine in DCS. It will also be necessary to determine whether the effect persists atlower doses before conducting a human trial in neurological DCS using fluoxetine as an adjunctive treatment associated with hyperbaric oxygen.AcknowledgmentsWe are very grateful to Emmanuel Gempp for his intellectual input and rewriting the first version of this manuscript and to Myriam DLS 10 Dalous for her excellent technical assistance; we also wish to thank the Fondation des Gueules Cassees for their encouragement. ?Author ContributionsConceived and designed the experiments: JEB NV. Performed the experiments: JEB SB AP OC NV. Analyzed the data: JEB JHA JJR NV. Contributed reagents/materials/analysis tools: JEB SB AP OC NV. Wrote the paper: JEB JHA JJR NV.
Apolipoprotein A1 (ApoA1), the major component of highdensity lipoprotein, plays an important role in reverse cholesterol transport by extracting cholesterol and phospholipids from various cells, including lung cells, and transferring them to the liver. In addition to cholesterol efflux, ApoA1 possesses anti-inflammatory and antioxidative properties, and ApoA1 mimetics are an effective treatment for atherosclerosis and several inflammatory disorders in animal models [1,2,3]. Using the lung disease model, it has been reported that treatment with ApoA1 mimetics attenuated allergeninduced airway inflammation in murine models of asthma by decreasing oxidative stress [4]. Recently, we reported that ApoA1 is expressed in the lung epithelium, that lung ApoA1 le.E hypothesized that fluoxetine can modulate leukocytes recruitment, with activation of anti-inflammatory pathways, limiting the deleterious role of neutrophils.Anti-inflammatory Effects of Fluoxetine in DCSWe found that fluoxetine reduced circulating levels IL-6. Dual function of cytokines is well established from the literature and proinflammatory and anti-inflammatory effects are described with IL-6, however systematic levels of IL-6 are primarily markers of disease severity, i.e. serum IL-6 often correlate with mortality in patients with septic shock [44]. Ersson et al. [4] found elevated serum levels of IL-6 and TNF-alpha by 6 hours after rapid decompression in rats. Bigley et al. [23] confirmed that rapid decompression induced the release of inflammation mediators and resulted in tissue inflammation cascades. They found that increased levels of inflammatory cytokines especially IL-6, TNF-alpha and IFN-gamma were also detected in the circulation 6 hours after decompression, but only IL-6 was still present at 24 hours.Fluoxetine vs DCSAnimal Model of DCSAnimal experimentation is especially useful in studies that would pose unacceptable risks in human subjects. The use of a murine model is relevant in neurological DCS evaluation [26,27], however specific problems are encountered. For example, a post-dive administration of treatment was not possible in our mouse model. Indeed the average time, from surfacing to onset of initial DCS symptoms, was very short i.e. 5 min with a high mortality rate. Moreover fluoxetine was delivered before the dive to allow the drug to reach its peak at the time of decompression. Nonetheless, we found that fluoxetine dramatically reduces the incidence of DCS and promotes motor recovery in mice. The results of this pilot study suggest that fluoxetine may reduce inflammation processes resulting from DCS, however further studies, including the assessment of inflammation markers in tissues, are needed to elucidate mechanisms of fluoxetine in DCS. It will also be necessary to determine whether the effect persists atlower doses before conducting a human trial in neurological DCS using fluoxetine as an adjunctive treatment associated with hyperbaric oxygen.AcknowledgmentsWe are very grateful to Emmanuel Gempp for his intellectual input and rewriting the first version of this manuscript and to Myriam Dalous for her excellent technical assistance; we also wish to thank the Fondation des Gueules Cassees for their encouragement. ?Author ContributionsConceived and designed the experiments: JEB NV. Performed the experiments: JEB SB AP OC NV. Analyzed the data: JEB JHA JJR NV. Contributed reagents/materials/analysis tools: JEB SB AP OC NV. Wrote the paper: JEB JHA JJR NV.
Apolipoprotein A1 (ApoA1), the major component of highdensity lipoprotein, plays an important role in reverse cholesterol transport by extracting cholesterol and phospholipids from various cells, including lung cells, and transferring them to the liver. In addition to cholesterol efflux, ApoA1 possesses anti-inflammatory and antioxidative properties, and ApoA1 mimetics are an effective treatment for atherosclerosis and several inflammatory disorders in animal models [1,2,3]. Using the lung disease model, it has been reported that treatment with ApoA1 mimetics attenuated allergeninduced airway inflammation in murine models of asthma by decreasing oxidative stress [4]. Recently, we reported that ApoA1 is expressed in the lung epithelium, that lung ApoA1 le.
