Trimellitic anhydride-induced allergic response in the lung: role of the complement system in cellular changes

Abstract

Trimellitic anhydride (TMA) is a small molecular weight industrial compound that will cause asthma-like symptoms in humans. Some of these TMA-induced symptoms can be reproduced in the guinea pig. In the guinea pig model of TMA-induced asthma, intratracheal instillation of TMA coupled to guinea pig serum albumin causes an immediate bronchoconstriction and increase in airway microvascular leakage with concomitant decrease in circulating platelets and white blood cells and subsequent cellular infiltration of mononuclear cells, neutrophils and eosinophils into the bronchoalveolar lavage fluid. In addition, in the lung tissue an increase in eosinophil peroxidase activity (a measure of eosinophil numbers) occurs. The purpose of this study was to determine whether complement system activation was essential for any of these TMA-induced events. Guinea pigs pretreated with cobra venom factor (CVF) had significantly reduced amounts of complement component C3 in the lavage fluid 24 hours after TMA conjugated to guinea pig serum albumin challenge indicating that the CVF treatment was successful in depleting complement proteins. Pretreatment with CVF did not affect the immediate TMA-induced bronchoconstriction nor the TMA-induced microvascular leakage. In animals depleted of the complement system by pretreatment with CVF the TMA-induced increase in mononuclear cells, total white blood cells, red blood cells, and EPO activity in the bronchoalveolar lavage was significantly reduced. Thus, our results suggest that in the guinea pig, the complement system is an important source of mediators for cellular infiltration into the lung after exposure to this acid anhydride and that inhibiting complement activation may be useful in preventing the inflammatory cell infiltration in TMA-induced asthma.

Fig. 1

Effect of CVF pretreatment on the percent increase in pulmonary resistance and percent decrease in dynamic lung compliance induced by intratracheal instillation of TMA-GPSA. TMA-GPSA is given at zero time. Values represent the mean ± S.E. of the percent change from control before instillation. Experiments were conducted in five guinea pigs in each experimental group.

Fig. 2

Effect of CVF pretreatment on the numbers of circulating WBC and platelets after intratracheal instillation of TMA-GPSA. TMA-GPSA was given intratracheally at time zero and blood samples were taken at various time points postinjection. Values represent the mean ± S.E. of five guinea pigs in each group. *P < .05 when compared to TMA-GPSA.

Fig. 3

Effect of CVF pretreatment on the numbers of WBC recovered in the BAL 24 hr after intratracheal instillation of GPSA or TMA-GPSA. Values represent the mean ± S.E. of 12 to 14 guinea pigs in each group. *P < .05 when compared to GPSA. ^†P < .05 when compared to TMA-GPSA

Fig. 4

Effect of CVF pretreatment on the numbers of mononuclear cells, neutrophils and eosinophils recovered in the BAL 24 hr after intratracheal instillation of GPSA or TMA-GPSA. Values represent the mean ± S.E. of 12 to 14 guinea pigs in each group. *P < .05 when compared to GPSA for each cell type. ^†P < .05 when compared to TMA-GPSA.

Fig. 5

Effect of CVF pretreatment on MPO and EPO activities recovered in the BAL 24 hr after intratracheal instillation of GPSA or TMA-GPSA. *P < .05 when compared to GPSA. ^†P < .05 when compared to TMA-GPSA.

Fig. 6

Effect of CVF pretreatment on protein recovered in the BAL 24 hr after intratracheal instillation of GPSA or TMA-GPSA. Values represent the mean ± S.E. of 12 to 14 guinea pigs in each group. *P < .05 when compared to GPSA.

Fig. 7

Effect of CVF pretreatment on the number of red blood cells in the BAL 24 hr after intratracheal instillation of GPSA or TMA-GPSA. O.D.₄₁₂ of lysed red blood cells was used as an estimate of cell numbers. Values represent the mean ± S.E. of 12 to 14 guinea pigs in each group. *P < .05 when compared to GPSA. ^†P < .05 when compared to TMA-GPSA.

Fig. 8

Effect of CVF pretreatment on C3 recovered in the BAL 24 hr after intratracheal instillation of GPSA or TMA-GPSA. Values represent the mean ± S.E. of 12 to 14 guinea pigs in each group. *P < .05 when compared to GPSA.