Induction of Pulmonary Inflammation by Components of the Pneumococcal Cell Surface^1–2

Abstract

Using a rabbit model of experimental pneumonitis, the components on the surface of the pneumococcus that incite pulmonary inflammation were identified. Rabbits were challenged intratracheally with live pneumococci, capsular polysaccharide, purified cell walls, or cell wall subcomponents. Leukocytosis and elevation of protein concentration was quantitated in bronchial lavage fluid during the first 24 h after challenge. Of the pneumococcal surface components tested, cell wall preparations had the highest specific activity in inducing inflammation; abnormalities in bronchial lavage fluid cytochemistry appeared rapidly and in a dose-dependent manner. Cell wall building blocks and the products of penicillin-induced hydrolysis of the cell wall were also highly inflammatory, indicating that inflammation can be generated by disruption of the cell wall during lysis of bacteria by beta-lactam antibiotics. Administration of inhibitors of arachidonic acid metabolism suggested that inhibition of the lipoxygenase pathway reduced inflammation associated with cell walls. We propose that pulmonary inflammation during pneumococcal pneumonia arises in large part from the interaction of the bacterial cell wall with complement and noncomplementmediated host defenses.

Microbiological and Clinical Significance of a New Property of Defective Lysis in Clinical Strains of Pneumococci

“…The cryptic nature of infection with the lysisdefective strain would contribute to higher morbidity and mortality from this type of infection. It is known that antibiotic-induced lysis and subsequent release of cell wall-degradation products contribute to generating inflammation in the CNS and the lung [10,16,17]. By this criterion, the lysis-defective strains would be expected to generate less inflammation, particularly during antibiotic-induced cell death in vivo.…”

Bordetellafilamentous hemagglutinin plays a critical role in immunomodulation, suggesting a mechanism for host specificity

“…In vitro studies suggest that FHA functions as an adhesin (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28), and several binding domains have been identified. A heparin-binding domain promotes attachment to sulfated polysaccharides (29), a carbohydrate-recognition domain facilitates bacterial binding to ciliated respiratory epithelial cells and macrophages (30), and an arg-gly-asp (RGD) triplet interacts with the leukocyte-response integrin͞integrin-associated protein (LRI͞IAP) complex on monocytes͞macrophages, resulting in up-regulation of complement-receptor-3-binding activity (23) and, with very late antigen-5 on epithelial cells, stimulating the up-regulation of intercellular adhesion molecule-1 via an NF-B signaling pathway (19,31).…”

Impact of antibiotic therapy on systemic cytokine expression in pneumococcal pneumonia

“…A possible explanation for the differences observed in the pattern of systemic cytokine production over time is that -lactam cell wall activity causes the release of cell wall components which act as potent inflammatory inducers [27][28][29][30]. One hypothesis is that 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 11 combination therapy offers more rapid microbial killing due to the presence of quinolones and hence shortens the exposure of the host to microbial products.…”