Pulmonary and Systemic Host Response toStreptococcus pneumoniaeandKlebsiella pneumoniaeBacteremia in Normal and Immunosuppressed Mice

Abstract

Mortality related to bacteremic pneumonia remains high, and the role of sepsis in inflammation, pulmonary injury, and death remains unclear, mostly in leukopenic states. In the present study, the microbiology, histopathology, and host response to Streptococcus pneumoniae and Klebsiella pneumoniae infection were determined in an experimental model of bacteremia in immunocompetent and leukopenic mice. Leukocyte depletion by cyclophosphamide did not impair the early clearance of pneumococci from blood but facilitated growth in lungs. By contrast, klebsiellae rapidly grew in blood of leukopenic mice. These observations suggest that tissue-based phagocytes and circulating leukocytes, respectively, play prominent roles in S. pneumoniae and K. pneumoniae eradication. The kinetics of leukocyte recruitment in lungs during S. pneumoniae bacteremia suggested early strong inflammation in immunocompetent mice that is associated with tumor necrosis factor alpha release and histological disorders, including cell debris and surfactant in alveolar spaces. Leukocyte depletion further stimulated pulmonary capillary leakage both in S. pneumoniae and K. pneumoniae bacteremia, which seemed attributable to bacterial virulence factors. Nitric oxide production did not differ significantly among groups. Leukopenia and low platelet counts characterized the late stage of bacteremia for both strains, but only K. pneumoniae altered renal function. Understanding the pathogenesis of bacteremia will help establish beneficial therapies for both sepsis and pneumonia.Bacterial pneumonia is a leading cause of morbidity and mortality in both developed and developing countries, and Streptococcus pneumoniae remains the most common pathogen responsible for community-acquired pneumonia throughout the world. It has been reported that human pneumococcal pulmonary infection when complicated with bacteremia results in two to three fold-higher mortality rates (22). Our previous experimental studies pointed out a direct correlation between bacteremia and mortality in immunocompetent mice suffering from pneumococcal pneumonia (2, 3). In fact, hemodynamic and hemostatic changes and progressive multiple organ failure are the most frequently observed adverse effects of bacteremia in humans. Conversely, sepsis also accounts for as many as half of all cases of acute respiratory distress syndrome (ARDS) (14,17,37). Lung injury apparently occurs at the very onset of bacteremia, this organ often being the first to fail (37). However, the contribution of sepsis to lung injury in the context of bacteremic bacterial pneumonia remains unclear. In various pathological conditions (5,8,11,14,19,24,28,33,39), lung injury induced by bacteremia is characterized by increased microvascular permeability and edema; hence, pathophysiological changes in the alveolar-capillary barrier most likely contribute to mortality resulting from bacteremia.A comparison of bacteremic community-acquired lobar pneumonia due to S. pneumoniae and Klebsiella pneumoniae in an intensive care unit alread...

NKT cells mediate pulmonary inflammation and dysfunction in murine sickle cell disease through production of IFN-γ and CXCR3 chemokines

“…Correction of optical densities (E) for contaminating heme pigments was performed as previously described, using the equation: E 620 (corrected) ϭ E 620 Ϫ (1.426 ϫ E 740 ϩ 0.03). 28 Data were calculated as micrograms EBD per gram lung.…”

Animal Models ofStreptococcus pneumoniaeDisease

“…Several groups have preferred serotype 3 and 6 strains isolated from patients with pneumococcal meningitis and have successfully induced this disease in the mouse, the rat, and the rabbit (26,35,69,76,85,95,145,192,268,269). Clinical isolates of serotypes 3, 6, 9, and 19 have also been employed in laboratory animal models to elucidate features of pneumococcal pneumonia and sepsis (12,14,40,49,196,223,234,251). For experimental otitis media, strains of serotypes 3, 4, 6, 7, 9, 11, 14, 19, and 23, which are the ones most commonly isolated from children with acute otitis, have been used (18,80,81,89,101,154).…”

“…However, outbred mice, such as MF1, CD-1 (Swiss), Swiss-Webster, and NMRI, have increasingly become more popular. They have widely been used for analyzing pathogenicity mechanisms of pneumonia (50,58,114,120,125,131), sepsis (109,131,251), and meningitis (59,95,160,268). In addition, outbred mice have also been employed to evaluate active and passive protection against pneumonia and sepsis (4, 115, 163) and the efficacy of antibiotic therapy against invasive pneumococcal disease (13,141,169,220,223).…”

“…One of the most detailed studies of the pathogenesis of sepsis in the mouse was made by Wang et al, who investigated the systemic host responses to sepsis in normal and immunosuppressed mice infected by the i.v. route (251). A complete analysis of different parameters, such as bacterial loads in blood and lungs, lung injury, biochemical markers, and hematological and inflammatory mediators, was carried out (251).…”

“…route (251). A complete analysis of different parameters, such as bacterial loads in blood and lungs, lung injury, biochemical markers, and hematological and inflammatory mediators, was carried out (251).…”