Transcript Acute Lower Respiratory Tract Infection Joseph P. Mizgerd

Acute Lower Respiratory Tract Infection
Joseph P. Mizgerd, Sc.D.
N. Engl. J. Med 2008; 358: 716-27
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.
Neutrophils and Lung Infection
Mizgerd J. N Engl J Med 2008;358:716-727
The Epithelial Interface and Lung Infection
Mizgerd J. N Engl J Med 2008;358:716-727
Generation of Acute Inflammation in
Infected Lungs
• Alveolar macrophages and dendritic cells
have a limited ability to kill microbes, but
they are particularly important for sensing
microbes and passing this information
along to other cells, such as epithelial cells
and lymphocytes.
• These cells then recruit the effectors of
innate immunity, neutrophils.
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 VentilatorAssociated Pneumonia
Gibot S et al. N Engl J Med 2004;350:451-458
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 communityacquired pneumonia: a preliminary randomized
study. Am J Respir Crit Care Med 2005;171:242-248
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 p50deficient mice. (B) Low-power magnification of
postmortem sample from the lungs of a p50deficient mouse, demonstrating diffuse
pulmonary inflammation consistent with acute
lung injury. (C) Higher magnification of
postmortem sample from the lungs of a p50deficient 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.
Responses of Microbes to
Inflammation
• Acute lower respiratory tract infections can
be monomicrobial or polymicrobial, with
organisms ranging in virulence from
commensal to highly pathogenic
• A pneumococcal DNase cleaves NETs and
frees bacteria
• Preventing the host from detecting
pathogens is another strategy often used
by microbes