The Prophylactic Effects of U75412E Pretreatment in a Smoke‐Induced Lung Injury Rabbit Model

Abstract

The effects of the lazaroid analogue U75412E (21-[4-(3-ethylamino-2-pyridinyl)-1-piperazinyl]-16 alpha-methylpregna-1,4,9]-(11)-triene-3,20-dione) were examined in an acute lung injury rabbit model. Standard doses of 0, 8 and 16 mM U75412E were aerosolized and ventilated into the lungs for 3 min. via an endotracheal tube. A 60 tidal volume dose of diesel fuel-polycarbonate plastic smoke was then instilled, followed by mechanical ventilation for one hour. Pretreatment with 16 mM U75412E significantly increased blood PaO2 and pH values, and decreased blood PaCO2 as compared to smoke only exposures. It also significantly decreased the total cell counts and granulocytes in bronchoalveolar lavage fluid, and the ability of pulmonary alveolar macrophages to produce tumour necrosis factor-alpha in vitro after cell isolation and culture. Histopathology indicated that 16 mM U75412E pretreatment attenuated increases in wet lung/body weight ratios, inflammatory focus, and interstitial oedema associated with smoke insult. In summary, U75412E pretreatment may possess the potential to improve acute smoke-induced lung injury, in part, through modulation of tumour necrosis factor-alpha production from pulmonary alveolar macrophages.

Early Alterations of Lung Injury Following Acute Smoke Exposure and 21-Aminosteroid Treatment

“…This finding is consistent with results of previous work that utilized the pretreatment of smoke-exposed animals with U75412E (34,35). Lazaroid treatment prevented smoke-induced changes in blood Pa02, PaC02, pH, and COHb°lo.…”

“…Administration of aerosolized lazaroid, U75412E, significantly attenuated smoke-induced changes in alveolar hypoventilation, BAL total protein and 6-keto-PGF1-a levels, and epithelial injury. U75412E appears to preserve respiratory epithelial cell structure possibly through modulating AA metabolism, in addition to its characterized antioxidative mechanisms (4,5,34).…”

“…In vivo efficacy of lazaroids has been documented in animal models of lung injuries induced by endotoxins (17), silica (16), oxidants (11), phorbol esters (22), and bleomycin (21). In an established rabbit model, lazaroid U75412E attenuated chemical mediators after smoke insult (34,35). These studies suggest that lazaroids may exert their protective action not only by a direct antioxidant activity (1,19,29,30) and inhibition of lipid peroxidation (17) but also by suppressing the expression and/or release of cytokines (28), such as interleukin-8 (22) and tumor necrosis factor-a (TNF-a) (35).…”

A Free Radical Scavenger (Lazaroid U75412E) Attenuates Tumor Necrosis Factor-Alpha Generation in a Rabbit Model of Smoke-Induced Lung Injury

“…Previous studies in our laboratory with this model have demonstrated that smoke-induced lung injury was involved in a complex series of events in the lung includ ing the time-phase changes of PAM 03 production, PAM TNF-a release, and lung permeability [12,[26][27][28], We found that PAM 03 production cx vivo decreases 2 h and conversely, increases 24 h after cell isolation and culture in a 1-hour smoke experiment [32]. Therefore, this inves tigation was designed fora comparison between pretreat ment and posttreatment with U75412E in this model, due to a biphasic response of PAM O] production.…”

Substance P and neutral endopeptidase in development of acute respiratory distress syndrome following fire smoke inhalation

“…Our FS exposure protocol and the chemical characteristics of this particular type of smoke have been described in detail in previous studies (44,48). Briefly, 30 ml of diesel fuel were placed in a ceramic crucible and burned in a stainless steel smoke chamber.…”