PURPOSE: Type 1 angiotensin II (AT1) receptor antagonists have anti-inflammatory effects in vitro and in patients. The purpose of this study was to investigate whether losartan (LOS), an AT1 receptor antagonist, reduces lung damage by inhibiting the induction of high mobility group box 1 (HMGB1) protein and cytokines by lipopolysaccharide (LPS; serotype: O127:B8) in a rat model. METHODS: We used male Wistar rats. Control group rats received a 0.9% NaCl solution. The LOS + LPS group rats received LOS (50 mg kg(-1)) before LPS (7.5 mg kg(-1)) administration. LPS group rats received injection of LPS (7.5 mg kg(-1)). MEASUREMENTS AND RESULTS: We performed immunohistochemistry, ELISA, and western blot analysis to examine the suppressive effects of LOS on LPS-induced cytokine induction. Plasma concentrations of cytokines (IL-6 and TNF-alpha) and HMGB1 (p < 0.05) were markedly reduced in the LOS + LPS group compared to the LPS group. LOS also inhibited the LPS-mediated decrease in angiotensin-converting enzyme 2 (ACE2) activity (p < 0.05). Immunohistochemical analysis revealed positive staining for ACE2 in lungs from both control and LOS + LPS groups. The intensity and degree of ACE2 labeling in lung tissue sections from the LPS group were markedly reduced compared to the control and LOS + LPS groups (p < 0.05). Additionally, RAW264.7 murine macrophages were stimulated with LPS, with or without simultaneous LOS treatment, resulting in inhibition of IkappaB phosphorylation. CONCLUSIONS: Treatment with LOS improved lung injury in an endotoxin shock model system by an anti-inflammatory action that inhibits reduction of ACE2.
PURPOSE: Type 1 angiotensin II (AT1) receptor antagonists have anti-inflammatory effects in vitro and in patients. The purpose of this study was to investigate whether losartan (LOS), an AT1 receptor antagonist, reduces lung damage by inhibiting the induction of high mobility group box 1 (HMGB1) protein and cytokines by lipopolysaccharide (LPS; serotype: O127:B8) in a rat model. METHODS: We used male Wistar rats. Control group rats received a 0.9% NaCl solution. The LOS + LPS group rats received LOS (50 mg kg(-1)) before LPS (7.5 mg kg(-1)) administration. LPS group rats received injection of LPS (7.5 mg kg(-1)). MEASUREMENTS AND RESULTS: We performed immunohistochemistry, ELISA, and western blot analysis to examine the suppressive effects of LOS on LPS-induced cytokine induction. Plasma concentrations of cytokines (IL-6 and TNF-alpha) and HMGB1 (p < 0.05) were markedly reduced in the LOS + LPS group compared to the LPS group. LOS also inhibited the LPS-mediated decrease in angiotensin-converting enzyme 2 (ACE2) activity (p < 0.05). Immunohistochemical analysis revealed positive staining for ACE2 in lungs from both control and LOS + LPS groups. The intensity and degree of ACE2 labeling in lung tissue sections from the LPS group were markedly reduced compared to the control and LOS + LPS groups (p < 0.05). Additionally, RAW264.7murine macrophages were stimulated with LPS, with or without simultaneous LOS treatment, resulting in inhibition of IkappaB phosphorylation. CONCLUSIONS: Treatment with LOS improved lung injury in an endotoxin shock model system by an anti-inflammatory action that inhibits reduction of ACE2.
Authors: S M Opal; C J Fisher; J F Dhainaut; J L Vincent; R Brase; S F Lowry; J C Sadoff; G J Slotman; H Levy; R A Balk; M P Shelly; J P Pribble; J F LaBrecque; J Lookabaugh; H Donovan; H Dubin; R Baughman; J Norman; E DeMaria; K Matzel; E Abraham; M Seneff Journal: Crit Care Med Date: 1997-07 Impact factor: 7.598
Authors: Christine Krämer; Julia Sunkomat; Jana Witte; Maren Luchtefeld; Michael Walden; Boris Schmidt; Dimitrios Tsikas; Rainer H Böger; Wolf-Georg Forssmann; Helmut Drexler; Bernhard Schieffer Journal: Circ Res Date: 2002-04-19 Impact factor: 17.367
Authors: Daniel E Leisman; Jamie R Privratsky; Jake R Lehman; Mabel N Abraham; Omar Y Yaipan; Mariana R Brewer; Ana Nedeljkovic-Kurepa; Christine C Capone; Tiago D Fernandes; Robert Griffiths; William J Stein; Marcia B Goldberg; Steven D Crowley; Rinaldo Bellomo; Clifford S Deutschman; Matthew D Taylor Journal: Proc Natl Acad Sci U S A Date: 2022-08-15 Impact factor: 12.779
Authors: Massimo Antonelli; Elie Azoulay; Marc Bonten; Jean Chastre; Giuseppe Citerio; Giorgio Conti; Daniel De Backer; François Lemaire; Herwig Gerlach; Goran Hedenstierna; Michael Joannidis; Duncan Macrae; Jordi Mancebo; Salvatore M Maggiore; Alexandre Mebazaa; Jean-Charles Preiser; Jerôme Pugin; Jan Wernerman; Haibo Zhang Journal: Intensive Care Med Date: 2010-01-28 Impact factor: 17.440