NET formation is involved in de-escalation therapy in sepsis.
To elucidate the relationship between NET formation and organ injury in the late stage of sepsis, we performed histological and immunohistochemical staining of samples from the lung, intestine, and liver. The damage in the sepsis groups was significantly worse than that in the sham group, and compared with escalation therapy, de-escalation therapy reduced intra-alveolar hemorrhage, interstitial edema, and acute inflammatory cell infiltration. The lung injury score in the de-escalation group was lower than that in the escalation group. In the liver and intestine samples, we compared the results of the histological and immunohistochemical analyses of citH3 and apoptosis (Fig 6A-C). The injury, injury scores, and apoptosis levels were closely associated with citH3 in the liver and intestine samples of those groups. The de-escalation group had milder liver and intestine injuries and lower NETs than the escalation group. Finally, the survival rates were calculated in the four groups. Compared with the control, antibiotic administration was more effective, but de-escalation therapy in the CLP mice did not lead to significantly higher survival than escalation therapy (p=0.051, Fig 6D).
All the data suggested that de-escalation antibiotic therapy positively regulates immune function by increasing NET formation to maximize the capacity to kill bacteria during the early stage of sepsis and negatively regulates immune function by decreasing NET formation to minimize the associated overwhelming and excessive tissue injury during the late stage of sepsis.