The Role of Arachidonic Acid Metabolites in Mononuclear Phagocytic Cell Interactions

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65162/1/j.1365-4362.1986.tb04543.x.pd

Two strikes: limited NIH R55 and R56 retooling funds and abolishment of the A2 grant mechanism

The U.S. National Institutes of Health (NIH) are facing significant budgetary challenges as a result of the current economic climate. The recent sunset of investigator‐initiated R01‐type research grants after one revised submission, coupled with the present lack of an NIH retooling funding mechanism for such grant applicants, creates a concerning risk that talented and well‐trained investigators may be forced to give up their research careers. Existing NIH retooling mechanisms include the R55 Shannon Award, which was established in 1991 and was essentially replaced in 2005 by the R56 award. There is an urgent need to either significantly expand the R55/R56 mechanisms and definition of NIH grant bridging/retooling support for unfunded meritorious proposals or introduce a new mechanism that provides specific support to investigators with competitive but unfunded R01 revised grants. An expanded retooling funding mechanism deserves implementation during continuing assessment of whether allowance of only one revision of research proposals has achieved its initial intended goals. Omary, M. B., Offhaus, H., Kunkel, S. L. Two strikes: limited NIH R55 and R56 retooling funds and abolishment of the A2 grant mechanism. FASEB J. 25, 4108–4110 (2011). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154267/1/fsb2fj11188052.pd

The Role of Interleukin-8 in the Infectious Process a

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73887/1/j.1749-6632.1994.tb44245.x.pd

Notch system in the linkage of innate and adaptive immunity

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142014/1/jlb0059.pd

Role of CC chemokine CCL6/C10 as a monocyte chemoattractant in a murine acute peritonitis.

The aim of this study was to determine the role of CC chemokine CCL6/C10 in acute inflammation. Intraperitoneal injection of thioglycollate increased peritoneal CCL6, which peaked at 4 h and remained elevated at 48 h. Neutralization of CCL6 significantly inhibited the macrophage infiltration (34-48% reduction), but not other cell types, without decreasing the other CC chemokines known to attract monocytes/macrophages. CCL6 was expressed in peripheral eosinophils and elicited macrophages, but not in elicited neutrophils. Peritoneal CCL6 level was not decreased in granulocyte-depleted mice where eosinophil influx was significantly impaired. Thus, CCL6 appears to contribute to the macrophage infiltration that is independent of other CC chemokines. Eosinophils pre-store CCL6, but do not release CCL6 in the peritoneum in this model of inflammation

Monokine Secretion in Aging and Protein Malnutrition

Aged and protein‐malnourished hosta have diminished febrile responses and increased morbidity and mortality from infection that could be due to deficiencies in the production of certain monokines. In this study, the ability of peritoneal macrophages from aged and protein‐malnourished rats to produce IL‐1 and TNF was explored. Aged rats fed a standard diet produced less IL‐1 and TNF, as measured by the thymocyte proliferation and L929 cytotoxicity assays, than young and middle‐aged rats. Monokine production was not diminished by protein malnutrition in any age group. No synergistic decline in IL‐1 or TNF production was seen with increasing age in malnourished rats. Diminished IL‐1 and TNF production may partially explain the severity of infection seen in the elderly patient, but not the malnourished host. The role of other cytokines such as IL‐6 and cytokine inhibitors in aging and malnutrition should be explored.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141681/1/jlb0510.pd

C‐C chemokine‐induced eosinophil chemotaxis during allergic airway inflammation

The production of eosinophil‐specific chemotactic factors during allergic airway responses may be a pivotal event resulting in eosinophil accumulation, activation, and airway damage. Recent studies have identified specific chemokines that may play crucial roles in recruitment of eosinophils to the site of allergic reactions. In this study we have utilized an established model of schistosome egg antigen (SEA)‐mediated allergic responses to examine the role of specific C‐C chemokines [macrophage inflammatory protein‐1α (MIP‐1α), RANTES, and monocyte chemoattractant protein‐1 (MCP‐1)] in eosinophil recruitment. We have previously identified a role for MIP‐1α in eosinophil accumulation in the lung and airway during allergic airway inflammation. We extend those studies using in vitro eosinophil chemotaxis to establish that both MIP‐1α and RANTES are potent eosinophil chemotactic factors in lungs during allergic airway responses. Morphometric analysis demonstrated a peribronchial accumulation of eosinophils within the lungs beginning at 8 h, peaking at 24 h, and plateauing at 48–96 h after allergen (SEA) challenge. Utilizing whole‐lung homogenates from allergen‐challenged mice, in vitro eosinophil chemotactic assays demonstrated significant increases in eosinophil chemotactic activity with 8‐h lung homogenates and peak activity with samples from 24‐h lung homogenates. These data correlated with the morphometric analysis of peribronchial eosinophil accumulation in situ. When lung homogenates from allergen‐challenged mice were preincubated in vitro with antibodies specific for MIP‐1α, RANTES, or MCP‐1, a significant reduction in eosinophil chemotaxis was observed with only MIP‐1α and RANTES neutralization. Altogether, these studies indicate that RANTES and MIP‐1α are major eosinophil chemotactic factors produced during allergic airway responses. J. Leukoc. Biol. 60:573–578; 1996.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141543/1/jlb0573.pd

Arachidonic acid metabolites regulate interleukin-1 production

We have investigated the role of arachidonic acid metabolites in the regulation of interleukin-1 production by murine peritoneal macrophages. Indomethacin a potent inhibitor of prostaglandin synthesis caused a dose-dependent augmentation of lipopolysaccharide induced interleukin production (up to 7-fold at 5 [mu]M). In contrast, lipoxygenase inhibitors, nordihydroguarietic acid and nafazatrom had no effect at doses that did not significantly decrease prostaglandin synthesis. Added to lipopolysaccharide stimulated cultures, PGE2 suppressed interleukin in a dose-dependent manner. Zymosan induced interleukin was also augmented by indomethacin but unlike lipopolysaccharide treated cultures was suppressed by nordihydroguarietic acid. These data suggest that arachidonate metabolites may be potent autoregulators of macrophage interleukin-1 production.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25698/1/0000252.pd