Neutrophil elastase inhibitor sivelestat ameliorates gefitinib-naphthalene-induced acute pneumonitis in mice

Abstract

Gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), is an effective therapeutic agent for non-small cell lung cancer with EGFR mutations. It can cause severe acute pneumonitis in some patients. We previously demonstrated that mice with naphthalene-induced airway epithelial injury developed severe gefitinib-induced pneumonitis and that neutrophils played important roles in the development of the disease. This study aimed to investigate the effects of the neutrophil elastase inhibitor sivelestat on gefitinib-induced pneumonitis in mice. C57BL/6J mice received naphthalene (200 mg/kg) intraperitoneally on day 0. Gefitinib (250 or 300 mg/kg) was orally administered to mice from day -1 until day 13. Sivelestat (150 mg/kg) was administered intraperitoneally from day 1 until day 13. Bronchoalveolar lavage fluid (BALF) and lung tissues were sampled on day 14. Sivelestat treatment significantly reduced the protein level, neutrophil count, neutrophil elastase activity in BALF, and severity of histopathologic findings on day 14 for mice administered with 250 mg/kg of gefitinib. Moreover, sivelestat treatment significantly improved the survival of mice administered with 300 mg/kg of gefitinib. These results indicate that sivelestat is a promising therapeutic agent for severe acute pneumonitis caused by gefitinib.

Neutrophil Elastase Subverts the Immune Response by Cleaving Toll-Like Receptors and Cytokines in Pneumococcal Pneumonia

“…In the present study, 40 mg/kg sivelestat were intraperitoneally administered to mice every 6 h, resulting in significantly decreased NE activity in BALF and markedly reduced mortality of mice inoculated with S. pneumoniae compared with untreated control mice. Yanagihara et al demonstrated that administration of sivelestat (30 mg/mL per 12 h) resulted in moderately delayed mortality in pneumococcal pneumonia mouse model ( 14 ), whereas Mikumo et al reported that administration of 150 mg/kg/day of sivelestat ameliorates pneumonitis and that there is significant improvement in the survival of mice administered naphthalene and gefinitib ( 46 ). Higher dose or increased frequency of administration could have effectively blocked NE activity in the present study.…”

Linking tyrosine kinase inhibitor-mediated inflammation with normal epithelial cell homeostasis and tumor therapeutic responses

“…Furthermore, the alveolar epithelium is able to contribute to the immune landscape of the lung by generating pro-inflammatory cytokines like CXCL10 and CCL2 when stimulated with IFNλ [46] . Studies to investigate the effects of gefitinib on airway repair after injury demonstrated that mice treated with gefitinib after naphthalene induced airway injury developed severe pneumonitis driven primarily by infiltrating neutrophils [47,48] . Bronchial epithelial cells harvested from these mice demonstrated an increase in proinflammatory genes.…”

Combination of sivelestat and N-acetylcysteine alleviates the inflammatory response and exceeds standard treatment for acetaminophen-induced liver injury

“…Pharmacologic inhibition of NE has been shown to successfully reduce the inflammatory response and disease severity in different pathologies mediated by acute inflammation . As we and others demonstrated a pronounced acute inflammatory response in AILI, and given the increased production of NE, we hypothesized that NE inhibition may be protective against AILI.…”

“…injected with PBS or 300 mg/kg of APAP (Sigma, Diegem, Belgium) dissolved in warmed PBS, after overnight fasting. Two hours after APAP injection, mice received either PBS vehicle, sivelestat (150 mg/kg i.p., dissolved in PBS, Tocris, Abingdon, United Kingdom), NAC (200 mg/kg i.p., dissolved in PBS, Sigma), or the combination of sivelestat and NAC (separate injections), creating five study groups ( n = 8 in each group). Dose regimens were based on published protocols.…”

“…In addition to its proteolytic action, NE causes organ damage by direct cytotoxicity and by inducing the release of proinflammatory mediators . The therapeutic potential of sivelestat, a highly specific NE inhibitor, has been studied in different pathologies mediated by acute inflammation, mainly in the field of pulmonology . Both preclinical and clinical studies indicate beneficial effects in acute lung injury, with less severe lung damage and improved clinical outcome .…”