Jong Min Lee1, Chang Dong Yeo1, Hwa Young Lee1, Chin Kook Rhee1, In Kyoung Kim1, Dong Gun Lee2, Sang Haak Lee1, Jin Woo Kim3. 1. Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Uijeongbu St. Mary's Hospital, 65-1 Geumo-dong, Uijeongbu, Seoul, Gyunggi-do, Republic of Korea. 2. Division of Infectious Diseases, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Seoul, Korea. 3. Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Uijeongbu St. Mary's Hospital, 65-1 Geumo-dong, Uijeongbu, Seoul, Gyunggi-do, Republic of Korea. medkjw@catholic.ac.kr.
Abstract
PURPOSE: Patients in whom neutropenia recovery is complicated by pneumonia have an increased risk of acute lung injury (ALI) and detrimental outcomes. The aim of the present study was to investigate whether inhibition of neutrophil elastase (NE) is effective in lipopolysaccharide (LPS)-induced ALI during neutropenia recovery in a murine model, and whether it upregulates the activation of the MerTK signaling pathway. METHODS: Cyclophosphamide was given to mice to induce neutropenia. Seven days later, they were administered LPS by intratracheal instillation. Sivelestat, a neutrophil elastase inhibitor, was given by intraperitoneal injection once daily starting on day 0 and continuing until mice were sacrificed on day 5 (preventive group). Alternatively, sivelestat was given after, instead of before, LPS administration on day 2 (therapeutic group). RESULTS: Sivelestat attenuated the lung edema and histopathological changes associated with LPS-induced lung injury. The accumulation of neutrophils and the concentrations of TNF-α, IL-6, and MPO in bronchoalveolar lavage (BAL) fluids were inhibited effectively by sivelestat. The expression of ICAM-1 and NF-κB p65 was also reduced after sivelestat administration. The protein and gene expression of MerTK tended to increase with sivelestat treatment. CONCLUSIONS: Sivelestat significantly attenuated LPS-induced ALI during recovery from neutropenia, and this effect was associated with MerTK induction. These findings suggest that NE inhibition could be a promising means of alleviating lung inflammation without increasing susceptibility to infection in ALI/ARDS during neutropenia recovery.
PURPOSE:Patients in whom neutropenia recovery is complicated by pneumonia have an increased risk of acute lung injury (ALI) and detrimental outcomes. The aim of the present study was to investigate whether inhibition of neutrophil elastase (NE) is effective in lipopolysaccharide (LPS)-induced ALI during neutropenia recovery in a murine model, and whether it upregulates the activation of the MerTK signaling pathway. METHODS:Cyclophosphamide was given to mice to induce neutropenia. Seven days later, they were administered LPS by intratracheal instillation. Sivelestat, a neutrophil elastase inhibitor, was given by intraperitoneal injection once daily starting on day 0 and continuing until mice were sacrificed on day 5 (preventive group). Alternatively, sivelestat was given after, instead of before, LPS administration on day 2 (therapeutic group). RESULTS:Sivelestat attenuated the lung edema and histopathological changes associated with LPS-induced lung injury. The accumulation of neutrophils and the concentrations of TNF-α, IL-6, and MPO in bronchoalveolar lavage (BAL) fluids were inhibited effectively by sivelestat. The expression of ICAM-1 and NF-κB p65 was also reduced after sivelestat administration. The protein and gene expression of MerTK tended to increase with sivelestat treatment. CONCLUSIONS:Sivelestat significantly attenuated LPS-induced ALI during recovery from neutropenia, and this effect was associated with MerTK induction. These findings suggest that NE inhibition could be a promising means of alleviating lung inflammation without increasing susceptibility to infection in ALI/ARDS during neutropenia recovery.
Authors: R William Vandivier; Valerie A Fadok; Peter R Hoffmann; Donna L Bratton; Churee Penvari; Kevin K Brown; Joseph D Brain; Frank J Accurso; Peter M Henson Journal: J Clin Invest Date: 2002-03 Impact factor: 14.808
Authors: A Murat Kaynar; A McGarry Houghton; Esther H Lum; Bruce R Pitt; Steven D Shapiro Journal: Am J Respir Cell Mol Biol Date: 2008-02-14 Impact factor: 6.914