Enhancement of Antigen-Induced Bronchoconstriction in the Guinea Pig after Intravascular Complement Activation with Cobra Venom Factor

Abstract

The purpose of the present studies was to begin to test the hypothesis that the complement system is important for antigen-induced bronchoconstriction in the guinea pig. The effect of the complement-depleting agent cobra venom factor (CVF) on antigen-induced bronchoconstriction in guinea pigs passively sensitized with IgG or IgE antibody to ovalbumin was determined. Intravenous injection of CVF significantly reduced total hemolytic complement activity (CH₅₀), caused a transient decrease in dynamic lung compliance, an increase in pulmonary resistance, and a decrease in circulating white blood cells with a sustained decrease in platelets. Antigen-induced bronchoconstriction was not inhibited in either IgG- or IgE-sensitized guinea pigs depleted of complement. Thus, a role for the complement system as a contributing factor in antigen-induced bronchoconstriction was not supported. On the contrary, our studies revealed an enhanced antigen-induced bronchoconstriction in guinea pigs depleted of complement with CVF. Our studies were then directed towards characterizing the enhanced response to begin to determine the mechanism responsible. The enhanced antigen-induced bronchoconstriction occurred in both IgG- and IgE-sensitized guinea pigs and was most apparent at lower antigen doses. The enhanced response still occurred in animals treated for 5 min with a dose of CVF (10 U) which caused no demonstrable decrease in CH₅₀, a 30% level of conversion of C3, and a normal response to C5a. These data suggested that the enhanced response was not related to the level of C5a responsiveness of the animal. In addition, CVF-treated animals were normally responsive to various purported mediators of antigen-induced bronchoconstriction: histamine, leukotriene C₄, platelet activating factor, the thromboxane-mimetic U-46,619, and prostaglandin F_2α. The response to prostaglandin D₂ was slightly enhanced. Thus, CVF treatment did not result in a generalized airway hyperreactivity. Since antigen-induced bronchoconstriction was not inhibited in animals depleted of complement, these studies suggest that an intact complement system is not necessary for this antigen-induced event. However, the enhanced antigen-induced bronchoconstriction seen after CVF treatment suggests that complement depletion and/or activation in vivo may be an important modulator or determinant of the severity of a subsequent antigen-induced bronchoconstriction.

The role of complement in the early phase of Leishmania (Leishmania) amazonensis infection in BALB/c mice

“…The efficiency of CVF was confirmed by the significant decrease in complement activity in the sera when comparing depleted and non-depleted groups in the early phase of infection, up to 48 h. The high complement activity by the 7th day of infection in complement-depleted mice compared to non-depleted mice may have occurred due to a high systemic stimulus after intravascular complement activation with CVF, which acts as C3-covertase leading to systemic C3 consumption (21). The complement activity in non-infected, complement-depleted and non-depleted animals did not show significant differences on the 7th day after CVF injection.…”

Systemic Complement System Depletion Does Not Inhibit Cellular Accumulation in Antihistamine Pretreated Allergic Guinea Pig Lung

“…In addition, it is simi lar to our previous result examining the effect of comple ment system activation and/or depletion on antigen-induced bronchoconstriction in the guinea pig. In that study, intra vascular activation of the complement system resulted in se questration of granulocytes in the lung and a much greater bronchoconstriction with intravenous antigen challenge [15]. Certainly our studies suggest that systemic comple ment activation is not a direct contributor to the cellular in filtration but in concert with the antigen antibody reaction will exacerbate the events.…”

“…The remainder of the lung is dried to obtain a wet/dry ratio for the lung. The right and left caudal lobe were processed for EPO and M PO analysis as we previously described [ 17,19].…”

“…To initially test this hypothesis, we utilized the approach of Roska et al [14] and pretreated the guinea pig with CVF. This treatment results in activation of the alternative path way of the complement system, thus depleting the comple ment system in the circulation of the animal [15], In this way. we could determine if the complement system is im portant as a source of mediators for antigen-induced cellular infiltration into the guinea pig lung.…”

Modern Complement Analysis

“…The animals usually tolerate this activation (fairly) well, since only a limited activation of the terminal pathway occurs. Nevertheless, adverse effects from CVF have been reported (38,64), and one should be very cautious with the interpretation of the data from such experiments. A direct inhibition of complement at a certain level is recommended instead of CVF treatment when mechanisms of complement activation are to be studied.…”