ABSTRACT
Gram-negative bacterial pneumonia is a common and dangerous infection with diminishing treatment options due to increasing antibiotic resistance among causal pathogens. The mononuclear phagocyte system is a heterogeneous group of leukocytes composed of tissue-resident macrophages, dendritic cells, and monocyte-derived cells that are critical in defense against pneumonia, but mechanisms that regulate their maintenance and function during infection are poorly defined. M-CSF has myriad effects on mononuclear phagocytes but its role in pneumonia is unknown. We therefore tested the hypothesis that M-CSF is required for mononuclear phagocyte-mediated host defenses during bacterial pneumonia in a murine model of infection. Genetic deletion or immunoneutralization of M-CSF resulted in reduced survival, increased bacterial burden, and greater lung injury. M-CSF was necessary for the expansion of lung mononuclear phagocytes during infection but did not affect the number of bone marrow or blood monocytes, proliferation of precursors, or recruitment of leukocytes to the lungs. In contrast, M-CSF was essential to survival and antimicrobial functions of both lung and liver mononuclear phagocytes during pneumonia, and its absence resulted in bacterial dissemination to the liver and hepatic necrosis. We conclude that M-CSF is critical to host defenses against bacterial pneumonia by mediating survival and antimicrobial functions of mononuclear phagocytes in the lungs and liver.
Subject(s)
Klebsiella Infections/immunology , Liver/immunology , Lung/immunology , Macrophage Colony-Stimulating Factor/immunology , Mononuclear Phagocyte System/immunology , Phagocytes/immunology , Pneumonia, Bacterial/immunology , Animals , Antibodies, Neutralizing/administration & dosage , Antibodies, Neutralizing/immunology , Bone Marrow/immunology , Bone Marrow Cells/drug effects , Bone Marrow Cells/immunology , Klebsiella Infections/microbiology , Klebsiella pneumoniae/immunology , Liver/cytology , Liver/microbiology , Liver/pathology , Lung/cytology , Lung/microbiology , Lung/pathology , Macrophage Colony-Stimulating Factor/deficiency , Macrophage Colony-Stimulating Factor/genetics , Macrophage Colony-Stimulating Factor/pharmacology , Mice , Monocytes/immunology , Monocytes/microbiology , Pneumonia, Bacterial/microbiologyABSTRACT
Acute kidney injury (AKI) contributes to progressive kidney disease. Although significant advances have been made in the understanding of mechanisms of AKI, less is known about the biological basis that links the initial injury to progressive interstitial fibrosis, tubular dysfunction, and capillary rarefaction. The round table discussion focused on mechanisms of renal recovery and fibrosis following AKI. The knowledge gained by understanding these pathways will serve to identify novel therapeutic targets in the future.
