Dose- and time-dependent effects of lipopolysaccharide on technetium-99-m-labeled diethylene-triamine pentaacetatic acid clearance, respiratory system mechanics and pulmonary inflammation

Abstract

Intratracheal administration of lipopolysaccharide (LPS) in animals is a commonly used model of acute lung injury, characterized by increased alveolar-capillary membrane permeability causing protein-rich edema, inflammation, deterioration of lung mechanical function and impaired gas exchange. Technetium-99-m-labeled diethylene-triamine pentaacetatic acid (99mTc-DTPA) scintigraphy is a non-invasive technique to assess lung epithelial permeability. We hypothesize that the longer the exposure and the higher the dose of LPS the greater the derangement of the various indices of lung injury. After 3, 6 and 24 h of 5 or 40 μg LPS intratracheally administration, 99mTc-DTPA was instilled in the lung. Images were acquired for 90 min with a γ-camera and the radiotracer clearance was estimated. In another subgroup, the mechanical properties of the respiratory system were estimated with the forced oscillation technique and static pressure-volume curves, 4.5, 7.5 and 25.5 h post-LPS (iso-times with the end of 99mTc-DTPA scintigraphy). Bronchoalveolar lavage (BAL) was performed and a lung injury score was estimated by histology. Lung myeloperoxidase (MPO) activity was measured. 99mTc-DTPA clearance increased in all LPS challenged groups compared with control. DTPA clearance presented a U-shape time course at the lower dose, while LPS had a declining effect over time at the larger dose. At 7.5 and 25.5 h post-LPS, tissue elasticity was increased and static compliance decreased at both doses. Total protein in the BAL fluid increased at both doses only at 4.5 h Total lung injury score and MPO activity were elevated in all LPS-treated groups. There is differential time- and dose-dependency of the various indices of lung injury after intratracheally LPS instillation in rats.