Dexamethasone fails to improve bleomycin‐induced acute lung injury in mice

Abstract

Acute respiratory distress syndrome (ARDS) features an exudative phase characterized by alveolar damage, lung edema and exacerbated inflammatory response. Given their anti‐inflammatory properties, the potential therapeutic effect of corticosteroids has been evaluated in ARDS clinical trials and experimental models of ALI. These studies produced contradictory results. Therefore, our aim was to investigate the effects of dexamethasone in an animal model of bleomycin‐induced acute lung injury and then to determine if the lack of response could be related to an impairment in repair ability of alveolar epithelial cells after injury. NMRI mice were challenged with bleomycin and then treated daily with dexamethasone or saline. Bronchoalveolar lavages (BAL) and lungs were collected for assessment of the inflammatory response and wet/dry ratio (lung edema) and for histological analyses. The effect of bleomycin and dexamethasone on wound repair was also evaluated in vitro on primary alveolar epithelial cell (ATII) cultures. Our data first showed that dexamethasone treatment did not reduce the weight loss or mortality rates induced by bleomycin. Although the TNF‐α level in BAL of bleomycin‐treated mice was reduced by dexamethasone, the neutrophil infiltration remained unchanged. Dexamethasone also failed to reduce lung edema and damage scores. Finally, bleomycin elicited a time‐ and dose‐dependent reduction in repair rates of ATII cell cultures. This inhibitory effect was further enhanced by dexamethasone, which also affected the expression of β3‐ and β6‐integrins, key proteins of alveolar repair. Altogether, our data indicate that the inability of dexamethasone to improve the resolution of ALI might be due to his deleterious effect on the alveolar epithelium repair.

Impact of ENaC downregulation in transgenic mice on the outcomes of acute lung injury induced by bleomycin

“…The first one was to evaluate the impact of a treatment with a corticosteroid (dexamethasone) on the resolution of bleomycin‐induced ALI (comparison between the control groups and mice treated with dexamethasone after the bleomycin challenge). These results have already been published (Aubin Vega et al., 2019). The second question was to explore the impact of αENaC down‐regulation (in αENaC(−/−)Tg+ mice) in the bleomycin‐induced ALI model (data presented here comparing the control and αENaC(−/−)Tg+ groups).…”

“…The second question was to explore the impact of αENaC down‐regulation (in αENaC(−/−)Tg+ mice) in the bleomycin‐induced ALI model (data presented here comparing the control and αENaC(−/−)Tg+ groups). Thus, in order to decrease the number of animals used as per the 3Rs principles, the same group of animals was used as control within the two studies performed at the same time and the values reported here (Ctl group) are similar to the ones recently published in (Aubin Vega et al., 2019).…”

“…Primary alveolar epithelial cells were isolated from adult Sprague–Dawley rats (Aubin Vega et al., 2019; Dagenais et al., 2004, 2006). Animals were anaesthetized by i.p.…”

Revisiting Cell Death Responses in Fibrotic Lung Disease: Crosstalk between Structured and Non-Structured Cells

“…However, depletion of the main inflammatory cells such as neutrophils and inflammatory monocytes with an anti-Gr1 antibody does not affect fibrosis development [37,38]. Furthermore, administration of anti-inflammatory drugs like dexamethasone does not inhibit fibrosis development [23,39]. Therefore, inflammation itself may not be an essential component of fibrosis development, and studies on fibrosis-specific cascades are recognized as important for understanding the pathogenesis of fibrosis onset.…”

Dexamethasone and lactoferrin induced PMN-MDSCs relieved inflammatory adverse events of anti-cancer therapy without tumor promotion

“…Glucocorticoids are considered as fundamental choice of drugs for the prevention and treatment for such inflammatory adverse events 1 , 5 , 6 . However, the adverse side effects of glucocorticoids, including opportunistic infections 7 , osteonecrosis of femoral head 8 , and secondary diabetes 9 , makes their continued use in these cases more complicated 8 , 10 .…”