Nebulized C1-Esterase Inhibitor does not Reduce Pulmonary Complement Activation in Rats with Severe Streptococcus Pneumoniae Pneumonia

Abstract

Complement activation plays an important role in the pathogenesis of pneumonia. We hypothesized that inhibition of the complement system in the lungs by repeated treatment with nebulized plasma-derived human C1-esterase inhibitor reduces pulmonary complement activation and subsequently attenuates lung injury and lung inflammation. This was investigated in a rat model of severe Streptococcus pneumoniae pneumonia. Rats were intra–tracheally challenged with S. pneumoniae to induce pneumonia. Nebulized C1-esterase inhibitor or saline (control animals) was repeatedly administered to rats, 30 min before induction of pneumonia and every 6 h thereafter. Rats were sacrificed 20 or 40 h after inoculation with bacteria. Brochoalveolar lavage fluid and lung tissue were obtained for measuring levels of complement activation (C4b/c), lung injury and inflammation. Induction of pneumonia was associated with pulmonary complement activation (C4b/c at 20 h 1.24 % [0.56–2.59] and at 40 h 2.08 % [0.98–5.12], compared to 0.50 % [0.07–0.59] and 0.03 % [0.03–0.03] in the healthy control animals). The functional fraction of C1-INH was detectable in BALF, but no effect was found on pulmonary complement activation (C4b/c at 20 h 0.73 % [0.16–1.93] and at 40 h 2.38 % [0.54–4.19]). Twenty hours after inoculation, nebulized C1-esterase inhibitor treatment reduced total histology score, but this effect was no longer seen at 40 h. Nebulized C1-esterase inhibitor did not affect other markers of lung injury or lung inflammation. In this negative experimental animal study, severe S. pneumoniae pneumonia in rats is associated with pulmonary complement activation. Repeated treatment with nebulized C1-esterase inhibitor, although successfully delivered to the lungs, does not affect pulmonary complement activation, lung inflammation or lung injury.

Pulmonary complement depositions in autopsy of critically ill patients have no relation with ARDS

“…The findings of this study are remarkable, as they are contrasting findings of several preclinical studies in animals [3–6, 14] and two clinical investigations [7, 8]. Indeed, all these earlier studies showed an association between pulmonary complement activation and ARDS.…”

“…A specific therapy is presently lacking. Preclinical studies using various models of lung injury [3–6], as well as human investigations in intensive care unit (ICU) patients with ARDS, have shown complement activation in the lung [7, 8]. It is uncertain, though, whether this finding is unique for ARDS and also whether the extent of complement activation depends on ARDS severity and ventilator settings at the moment of sampling.…”

Human plasma-derived C1 esterase inhibitor concentrate has limited effect on house dust mite-induced allergic lung inflammation in mice

“…In addition, recently, de Beer et al . reported no effect of C1-INH treatment in two different rat pneumonia models[ 29 , 30 ].…”

The effects of resuscitation with different plasma products on endothelial permeability and organ injury in a rat pneumosepsis model

“…The left inferior lobe of the right lung was fixed in 10% formaldehyde and embedded in paraffin, after which 4-µm-thick sections were cut and stained with haematoxylin and eosin (H&E). A pathologist blinded for treatment allocation evaluated the lung tissue for the presence of oedema, bronchitis, endothelialitis, interstitial inflammation and thrombi formation on a scale of 0–4 (0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe), as described previously [ 25 , 26 ]. For the full scoring list, see the supplement (Additional file 1 : Table S1).…”