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1.  Murine Complement Interactions with Pseudomonas aeruginosa and Their Consequences During Pneumonia 
Complement is necessary for defense against lung infection with Pseudomonas aeruginosa in mice. We studied in vitro interactions between complement and P. aeruginosa and in vivo effects of complement depletion to better understand this relationship. In vitro, P. aeruginosa strain UI-18 was resistant to killing by mouse serum. However, C3 opsonized the organism (via the alternative and mannose binding lectin [MBL] pathways), and C5 convertase activity on the bacterial surface was demonstrated. In vivo, compared with normal mice, complement-deficient mice experienced higher mortality and failed to sterilize their bronchoalveolar space within 24 h of inoculation. These changes did not seem to be a result of decreased inflammation because complement-deficient mice had normal neutrophil recruitment, greater lung myeloperoxidase content, and, by 24 h, a 35-fold higher level of the CXC chemokine KC. Lung static pressure-volume curves were abnormal in infected animals but were significantly more so in complement deficient mice. These data indicate that although P. aeruginosa is resistant to serum killing, C3 opsonization and C5 convertase assembly occur on its surface. This interaction in vivo plays a central role in host survival beyond just recruitment and activation of phagocytes and may serve to limit the inflammatory response to and tissue injury resulting from bacterial infection.
PMCID: PMC4153788  PMID: 14500254
2.  Resident murine alveolar and peritoneal macrophages differ in adhesion of apoptotic thymocytes 
Apoptotic cells must be cleared efficiently by macrophages (Mø) to prevent autoimmunity, yet their ingestion impairs Mø microbicidal function. The principal murine resident lung phagocyte, the alveolar Mø (AMø), is specifically deficient at apoptotic cell ingestion, both in vitro and in vivo, compared to resident peritoneal Mø (PMø). To further characterize this deficiency, we assayed static adhesion in vitro using apoptotic thymocytes and resident AMø and PMø from normal C57BL/6 mice. Adhesion of apoptotic thymocytes by both types of Mø was rapid, specific, and cold-sensitive. Antibody against the receptor tyrosine kinase MerTK (Tyro12) blocked phagocytosis but not adhesion in both types of Mø. Surfactant protein A increased adhesion and phagocytosis by AMø, but not to the levels seen using PMø. Adhesion was largely cation-independent for PMø and calcium-dependent for AMø. Adhesion was not inhibited in either Mø type by mAbs against β1 or β3 integrins or scavenger receptor I/II (CD204), but AMø adhesion was inhibited by specific mAbs against CD11c/CD18. Thus, resident murine tissue Mø from different tissues depend on qualitatively disparate receptors systems to bind apoptotic cells. The decreased capacity of murine AMø to ingest apoptotic cells is only partially explained by reduced initial adhesion.
PMCID: PMC4138126  PMID: 14527926
Apoptosis; Adhesion Molecules; Mice; inbred strains; Lung
3.  Cytokine–Chemokine Networks in Experimental Mycobacterial and Schistosomal Pulmonary Granuloma Formation 
Type-1 and type-2 lung granulomas, respectively, elicited by bead immobilized Mycobacteria bovis and Schistosoma mansoni egg antigens (Ags) display different patterns of chemokine expression. This study tested the hypothesis that chemokine expression patterns were related to upstream cytokine signaling. Using quantitative transcript analysis, we defined expression profiles for 16 chemokines and then examined the in vivo effects of neutralizing antibodies against interferon-γ (IFN-γ), interleukin (IL)-4, IL-10, IL-12, and IL-13. Transcripts for CXCL2, −5, −9, −10, and −11 and the CCL chemokine, CCL3, and lymphotactin (XCL1), were largely enhanced by Th1-related cytokines, IFN-γ or IL-12. Transcripts for CCL11, CCL22, CCL17, and CCL1 were enhanced largely by Th2-related cytokines, IL-4, IL-10, or IL-13. Transcripts for CCL4, CCL2, CCL8, CCL7, and CCL12 were potentially induced by either Th1- or Th2-related cytokines, although some of these showed biased expression. IFN-γ and IL-4 enhanced the greatest complement of transcripts, and their neutralization had the greatest anti-inflammatory effect on type-1 and type-2 granulomas, respectively. Th1/Th2 cross-regulation was evident because endogenous Th2 cytokines inhibited type-1, whereas Th1 cytokines inhibited type-2 biased chemokines. These findings reveal a complex cytokine–chemokine regulatory network that dictates profiles of local chemokine expression during T cell–mediated granuloma formation.
PMCID: PMC3677198  PMID: 12600821
4.  Enhancing antitumor immunity perioperatively: a matter of timing, cooperation, & specificity 
PMCID: PMC2640487  PMID: 12707008
Natural Killer cells; macrophages; biological response modifier; innate immunity
5.  Large Conductance Ca2+-Activated K+ Channels Sense Acute Changes in Oxygen Tension in Alveolar Epithelial Cells 
The rise in alveolar oxygen tension (PO2) that occurs as the newborn infant takes its first breaths induces removal of liquid from the lung lumen due to ion transport across the alveolar epithelium and the activity of alveolar Na+ channel (ENaC). In the present study, we have aimed to identify an ion conductance in alveolar epithelial A549 cells that responds to acute changes in PO2. Variation in PO2 did not affect single-channel ENaC activity. However, in these cells we have detected single-channel conductance having properties similar to those of large conductance Ca2+-activated K+ (BKCa) channels. Reverse transcriptase–polymerase chain reaction and Western blotting demonstrated presence of α-BKCa channel subunit and iberiotoxin, a blocker of BKCa channels, inhibited whole cell K+ current. Chronic changes in PO2 did not affect expression, recruitment, or function of BKCa channels in A549 cells. In contrast, acute changes of PO2 regulated the BKCa channel activity by controlling the channel mean open time. This effect of PO2 was insensitive to inhibitor of flavoproteins, diphenylene iodinium. In addition, decrease in PO2 and iberiotoxin induced membrane depolarization and Ca2+ oscillations in A549 cells. We conclude that BKCa channels serve as oxygen sensors in human alveolar A549 epithelial cells.
PMCID: PMC2134978  PMID: 12594063

Results 1-5 (5)