Nebulized Cl-esterase inhibitor treatment does not attenuate pulmonary complement activation in a rat model of severe Streptococcus pneumoniae pneumonia

Introduction

While complement protein deficiencies are associated with severe and recurrent pulmonary infections, excessive complement activation plays a role in the pathogenesis of lung injury. We hypothesized that inhibition of the complement system by repetitive treatment with nebulized plasma-derived human C1-esterase inhibitor (C1-INH) reduces pulmonary complement activation and subsequently attenuates lung injury and lung inflammation in a model of severe Streptococcus pneumoniae pneumonia.

Methods

Thirty-two male rats were intratracheally challenged with S. pneumoniae to induce pneumonia. Rats were repeatedly exposed to nebulized C1-INH or saline, 30 minutes before induction of pneumonia and every 6 hours thereafter. Rats were sacrificed 20 or 40 hours after inoculation to investigate early and late effects. BALF and lung tissue were obtained for measuring levels of complement activation (C4b/c in BALF), lung injury (total protein levels in BALF), and inflammation (IL-6 levels in lung tissue).

Results

Pneumonia was characterized by bilateral macroscopic infiltrates, bacterial outgrowth in the lung and clinical signs of illness. Pneumonia was associated with pulmonary complement activation. In rats treated with nebulized C1-INH, a functional fraction of C1-INH was detectable in BALF. However, C1-INH treatment did not affect pulmonary complement activation (Figure 1A), lung injury (Figure 1B) or inflammation (Figure 1C).

Figure 1

(abstract P315)

Conclusion

Severe S. pneumoniae pneumonia is associated with pulmonary complement activation in rats. Nebulized C1-INH treatment, in an attempt to reduce pulmonary complement activation, neither affects pulmonary complement activation or lung injury and inflammation.