Acute Lower Respiratory Tract Infection Joseph P. Mizgerd, Sc.D.

1. Acute Lower Respiratory Tract InfectionJoseph P. Mizgerd, Sc.D. N. Engl. J. Med 2008; 358: 716-27

2. Neutrophil Extracellular Traps Kill Bacteria Electron microscopical analysis of resting and activated neutrophils. (A) Resting neutrophils are round and devoid of fibers. (B) Upon stimulation with 25 nM PMA for 30 min, the cells flatten, make many membrane protrusions, and form fibers (NETs), arrows in (B) and (D). (C) TEM analysis of naïve neutrophils in suspension. (D) Ultrathin section of neutrophils stimulated in suspension with 10 ng of IL-8 for 45 min. Bars in (A) to (D) indicate 10 µm. The multilobular nuclei and different granules are clearly visible in both figures. The activated cells in (D) have many pseudopods and show NETs (arrow). (E) High-resolution SEM analysis of NETs that consist of smooth fibers (diameters of 15 to 17 nm, arrowheads) and globular domains (diameter around 25 nm, arrow). Globular complexes can be aggregated to thick bundles or fibers. (F) Ultrathin sections of NETs show that they are not membrane-bound.

3. Neutrophils and Lung Infection Mizgerd J. N Engl J Med 2008;358:716-727

4. The Epithelial Interface and Lung Infection Mizgerd J. N Engl J Med 2008;358:716-727

5. Generation of Acute Inflammation in Infected Lungs • Alveolar macrophages and dendritic cells have a limited abilityto kill microbes, but they are particularly important for sensingmicrobes and passing this information along to other cells,such as epithelial cells and lymphocytes. • These cells then recruitthe effectors of innate immunity, neutrophils.

6. Levels of Soluble Triggering Receptor Expressed on Myeloid Cells (sTREM-1) in Bronchoalveolar-Lavage Fluid from 64 Patients without Pneumonia, 38 Patients with Community-Acquired Pneumonia, and 46 Patients with Ventilator-Associated Pneumonia Gibot S et al. N Engl J Med 2004;350:451-458

7. Inflammation and Acute Lung Injury Survival curves (top) and time to removal of mechanical ventilation (bottom) in patients randomized to hydrocortisone and placebo. Dashed lines represent the placebo group and solid lines represent the hydrocortisone-treated group Confalonieri M, Urbino R, Potena A, et al. Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med 2005;171:242-248

8. Nuclear factor-kB p50 Mortality of p50-deficient mice during Escherichia coli pneumonia. (A) Survival through 7 days after intratracheal instillation of 106 cfu to five wild-type (WT) and five p50-deficient mice. (B) Low-power magnification of postmortem sample from the lungs of a p50-deficient mouse, demonstrating diffuse pulmonary inflammation consistent with acute lung injury. (C) Higher magnification of postmortem sample from the lungs of a p50-deficient mouse demonstrates bacterial rods, particularly in the peribronchial interstitial tissues. Mizgerd JP, Lupa MM, Kogan MS, Warren HB, Kobzik L, Topulos GP. Nuclear factor-kB p50 limits inflammation and prevents lung injury during Escherichia coli pneumonia. Am J Respir Crit Care Med 2003;168:810-817.

9. Responses of Microbes to Inflammation • Acute lower respiratory tract infections can be monomicrobialor polymicrobial, with organisms ranging in virulence from commensalto highly pathogenic • A pneumococcal DNase cleaves NETs and frees bacteria • Preventing the host from detecting pathogens is another strategyoften used by microbes