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1.
J Trauma Acute Care Surg ; 73(4): 861-8, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22914078

ABSTRACT

BACKGROUND: Patients with multiple injuries surviving the initial insult are highly susceptible to secondary pneumonia, frequently progressing into sepsis and multiorgan failure. However, the underlying mechanisms of posttraumatic immunosuppression are poorly understood. We hypothesized that dysregulated p38 mitogen-activated protein kinase (MAPK) signaling accounts for impaired lung protective immunity in a model of trauma/hemorrhage (T/H) and subsequent pneumococcal pneumonia in mice. METHODS: C57BL6/N mice were subjected to trauma by midline laparotomy, and T/H was induced by midline laparotomy followed by cannulation of femoral arteries and veins to induce hemorrhage. Subsequently, mice were infected with Streptococcus pneumoniae. In selected experiments, mice were treated with a p38 MAPK inhibitor or vehicle control immediately after induction of T/H. RESULTS: Mice subjected to T/H showed significantly increased p38 MAPK activation in their lungs, which was accompanied by a reduced Escherichia coli phagocytosis by macrophages from T/H mice in vitro and an impaired pneumococcal killing activity of T/H mice in vivo, overall resulting in increased mortality of T/H mice after infection with S. pneumoniae. Application of p38 MAPK inhibitor BIRB796 immediately after T/H induction improved the bacterial phagocytosis activity of macrophages from T/H mice in vitro and lung pneumococcal killing in vivo but did not improve the survival of T/H mice challenged with S. pneumoniae. CONCLUSION: T/H triggers sustained p38 MAPK activation in the lungs of mice, which attenuates lung macrophage antibacterial activities and renders mice more susceptible to pneumococcal pneumonia. However, no major role for dysregulated p38 MAPK to affect survival of T/H mice after pneumococcal challenge was detected, suggesting that dysregulated p38 MAPK activity may possibly play only a limited role in posttraumatic immunosuppression in mice.


Subject(s)
Enzyme Activation/immunology , Immune Tolerance/immunology , Immunocompromised Host , Pneumonia, Pneumococcal/immunology , Wounds and Injuries/immunology , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Disease Models, Animal , Female , Macrophages, Alveolar/enzymology , Macrophages, Alveolar/immunology , Mice , Mice, Inbred C57BL , Pneumonia, Pneumococcal/enzymology , Pneumonia, Pneumococcal/etiology , Signal Transduction/immunology , Streptococcus pneumoniae/immunology , Wounds and Injuries/complications , Wounds and Injuries/enzymology , p38 Mitogen-Activated Protein Kinases/immunology
2.
Infect Immun ; 79(12): 4893-901, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21911460

ABSTRACT

Neutrophil serine proteases cathepsin G (CG), neutrophil elastase (NE), and proteinase 3 (PR3) have recently been shown to contribute to killing of Streptococcus pneumoniae in vitro. However, their relevance in lung-protective immunity against different serotypes of S. pneumoniae in vivo has not been determined so far. Here, we examined the effect of CG and CG/NE deficiency on the lung host defense against S. pneumoniae in mice. Despite similar neutrophil recruitment, both CG knockout (KO) mice and CG/NE double-KO mice infected with focal pneumonia-inducing serotype 19 S. pneumoniae demonstrated a severely impaired bacterial clearance, which was accompanied by lack of CG and NE but not PR3 proteolytic activity in recruited neutrophils, as determined using fluorescence resonance energy transfer (FRET) substrates. Moreover, both CG and CG/NE KO mice but not wild-type mice responded with increased lung permeability to infection with S. pneumoniae, resulting in severe respiratory distress and progressive mortality. Both neutrophil depletion and ablation of hematopoietic CG/NE in bone marrow chimeras abolished intra-alveolar CG and NE immunoreactivity and led to bacterial outgrowth in the lungs of mice, thereby identifying recruited neutrophils as the primary cellular source of intra-alveolar CG and NE. This is the first study showing a contribution of neutrophil-derived neutral serine proteases CG and NE to lung-protective immunity against focal pneumonia-inducing serotype 19 S. pneumoniae in mice. These data may be important for the development of novel intervention strategies to improve lung-protective immune mechanisms in critically ill patients suffering from severe pneumococcal pneumonia.


Subject(s)
Cathepsin G/metabolism , Leukocyte Elastase/metabolism , Lung/immunology , Pneumonia, Pneumococcal/immunology , Streptococcus pneumoniae/physiology , Animals , Bronchoalveolar Lavage Fluid , Cathepsin G/genetics , Leukocyte Elastase/genetics , Lung/metabolism , Mice , Mice, Knockout , Neutrophils/physiology , Oxygen/blood , Peptide Hydrolases/metabolism , Permeability , Streptococcus pneumoniae/immunology
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