Early indications of monocrotaline pyrrole-induced lung injury in rats

Abstract

Monocrotaline pyrrole (MCTP), a putative metabolite of the naturally occurring plant toxin, monocrotaline (MCT), causes lung injury, pulmonary hypertension, and right cardioventricular hypertrophy when administered intravenously to rats. The lesions caused by MCTP administration are similar to those caused by MCT but appear to occur on a slightly accelerated time course. To explore the onset and development of lung lesions, male Sprague-Dawley rats were treated with a single, intravenous injection of MCTP, and several markers of lung injury were evaluated at early times after administration. Rats received 3.5 mg MCTP/kg or an equal volume of the vehicle, N,N-dimethylformamide (DMF), via the tail vein at time 0 and were killed at 4, 12, 24, 48, 72, or 120 hr after treatment. Beginning at 4 hr, MCTP-treated rats had increased wet lung-to-body-weight ratios (LW/BW). The LW/BW remained elevated at 12 hr, returned to baseline at 24 hr, then increased steadily over the next few days. At 24 hr, the protein concentration of cell-free bronchoalveolar lavage fluid (BALF) was slightly elevated. Lactate dehydrogenase activity in cell-free BALF samples was moderately increased 48 hr after MCTP. Changes in these markers were modest initially but became much more pronounced by 120 hr. Total nucleated cell counts in BALF were variable but were moderately elevated at 120 hr. Cytologic examination of the BALF samples revealed small but significant infiltrates of segmented neutrophils at 4 hr and relatively large infiltrates of segmented neutrophils and small lymphocytes at 120 hr post-treatment. Mature neutrophils had degenerate cytomorphologic characteristics at both 4 and 120 hr. These results confirm that pronounced lung injury is delayed for several days after a single, intravenous administration of MCTP, but they also indicate that subtle lung injury can be detected using quantitative markers quite early after MCTP administration.