A three-phase approach for the early identification of acute lung injury induced by severe sepsis

Tomoharu Miyashita, Ali Karim Ahmed, Shinichi Nakanuma, Koichi Okamoto, Seisho Sakai, Jun Kinoshita, Isamu Makino, Keishi Nakamura, Hironori Hayashi, Katsunobu Oyama, Hidehiro Tajima, Hiroyuki Takamura, Itasu Ninomiya, Sachio Fushida, John W. Harmon, Tetsuo Ohta

Research output: Contribution to journalReview articlepeer-review


A number of studies have reported that acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are independent risk factors for organ dysfunction and mortality in patients with sepsis. Although ALI/ARDS might be an essential therapeutic target during the management of sepsis, severe sepsis should be treated effectively and as soon as identified. We have classified three phases, ranging from sepsis to organ dysfunction, characterizing the interaction between neutrophils and platelets. The first phase is neutrophil extracellular trap (NET) formation and intravasated platelet aggregation. The next phase is extravasated platelet aggregation (EPA), promoted by NET-facilitated detachment of endothelial cells. The final phase is organ dysfunction, caused by pulmonary veno-occlusive disease (VOD), fibrosis, and immunoparalysis induced by EPA. Severe sepsis is characterized by a continuum of coagulopathy, with coagulation abnormalities often developing before the onset of clinical symptoms. The initial medical treatment for ALI/ARDS is inhibition of NET formation and intravasated platelet aggregation to prevent endothelial cell damage (Phase 1). Beraprost and silvestat, phosphodiesterase 3 (PDE3) inhibitors, are often administered in clinical practice. To determine hypercoagulopathy, plasma levels of thrombin-antithrombin complex and plasmin-plasmin inhibitor complex are continuously monitored in patients with suspected sepsis. Furthermore, the implementation of quality indicators for the early management of severe sepsis and septic shock is strongly associated with a reduced mortality. We conclude that pathophysiology of organ dysfunction from severe sepsis is caused by pulmonary VOD, fibrosis, and EPA-facilitated immunoparalysis. In order to prevent ALI/ARDS in patients with sepsis, countermeasures for NET and platelet aggregation should be pre-emptively employed and confirmed by several trials.

Original languageEnglish (US)
Pages (from-to)341-349
Number of pages9
JournalIn Vivo
Issue number4
StatePublished - Jul 1 2016


  • Acute lung injury (ALI)
  • Acute respiratory distress syndrome (ARDS)
  • Extravasated platelet aggregation (EPA)
  • Neutrophil extracellular trap (NET)
  • Review
  • Sepsis
  • Veno-occlusive disease

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology


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