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A "Zip Code" for Lymphocyte Infiltration in Inflammatory Sites
Lymphocytes are recruited into inflammatory sites by a complex process that involves rolling of the cells and their passage through the microvascular post-capillary endothelium into the tissue. L-selectin and its glycosylated ligands are important participants in the initial stages of extravasation. L-selectin recognizes several endothelial ligands decorated by glycans such as sialyl Lewis x (sLex) and sulfo sLex. Induction of sLex or sulfo sLex decorated L-selectin ligands in post-capillary endothelium occurs in heart and kidney allograft rejection, both in humans and rodents. Renkonen et al (Am J Pathol 2002, 161:543–550) extended these observations and investigated the pattern of expression of endothelial sLex and sulfo sLex in various inflammatory diseases including ulcerative colitis, myocarditits, and psoriasis among others. Endothelium of non-inflamed tissue did not express these glycans, but in marked contrast, endothelium of inflamed tissues expressed an abundant amount of sLex and sulfo sLex epitopes. For every inflammatory tissue examined there was a specific pattern of expression of these epitopes creating a kind of "zip code" that might direct lymphocyte traffic to a given organ. These "zip code" glycans could be useful as targets for specific inhibition of leukocyte infiltration.
Epidermal Growth Factor Reduces Intestinal Damage in Ischemia/Reperfusion Injury
Multiple organ failure (MOF) is a frequent cause of death after systemic infections, burns, and trauma. Both ischemia as well as ischemia/reperfusion are important triggering events for MOF, which involves hypoperfusion of the splanchnic circulation, increased intestinal permeability, and endotoxemia. There is great interest in developing or identifying agents that may counteract the initiating events that lead to MOF. Berlanga et al (Am J Pathol 2002, 161:373–379) hypothesized that epidermal growth factor (EGF) could have a protective effect because it stimulates cell proliferation in the gastrointestinal tract and may act as a cytoprotective agent. Berlanga et al produced ischemia/reperfusion injury in rats by clamping the superior mesenteric artery for 60 minutes followed by a 60-minute period of reperfusion. Ischemia/reperfusion injury caused macroscopic damage affecting 56% of small intestine length, which include intraluminal bleeding. Other indices of damage were an eightfold increase in malondialdehyde levels and a 15-fold increase in myeloperoxidase activity (markers for free radical release and presence of inflammatory infiltrate, respectively). In contrast, animals that received EGF before vessel clamping had reduced injury (11% of length), no intestinal bleeding, and a 60 to 90% reduction in malondialdehyde and myeloperoxidase levels. Although these are preliminary studies, the results suggest that EGF might be an effective therapy for preventing intestinal damage and MOF resulting from splanchnic hypoperfusion.
COX-2 Activity Protects the Lung against Inflammation and Fibrosis
Cyclooxygenases 1 and 2 (COX-1 and -2) are important components of prostaglandin synthesis from arachidonic acid. Both enzymes are constitutively expressed in the lung, but COX-2 is induced by several proinflammatory cytokines and is thought to be a mediator of lung fibrogenesis. However, the role of COX-2 and prostaglandin E2 (PGE2) in pulmonary fibrosis has not been established. Bonner et al (Am J Pathol 2002, 161:459–470) used COX-1 and COX-2 deficient mice to investigate lung inflammation and fibrosis after intratracheal instillation of vanadium pentoxide (V205), a metal released from burned fuel oil that can cause airway injury in humans and rodents. Both wild-type and COX-1 knockout mice showed a transient inflammatory response after V205 exposure. In contrast, the inflammation persisted and led to lung fibrosis in COX-2 knockout mice, 2 weeks after V205 exposure. PGE2 and TNF levels in bronchoalveolar lavage fluids were respectively not altered and elevated in COX-2 knockout mice while PGE2 was increased in COX-1 knockouts. The results suggest that COX-2 but not COX-1 activity protects against lung inflammation and fibrosis and that TNF may play an important role in the susceptibility of COX-2 deficient mice to pulmonary fibrosis.
Activation of 5-Lipoxygenase Pathways in Human Pancreatic Cancer an Pancreatic Cancer Lines
Lipoxygenase pathways play an important role in fat metabolism and in the regulation of pancreatic cancer cell proliferation. Among the components of the 5-lipoxygenase (5-Lox) pathway are leukotriene B4 (LTB4) and its receptor. 5-Lox expression has been detected in cell lines from prostate, lung, and colon carcinoma as well as in pancreatic acinar cells. Hennig et al (Am J Pathol 2002, 161:421–428) investigated the patterns of expression of 5-Lox and B4 receptors in ducts of normal and neoplastic pancreas as well as in pancreatic cancer cell lines. 5-Lox mRNA and protein expression was detectable in pancreatic cancer cell lines but not in normal pancreatic ductal cells. Immunohistochemistry analyses revealed that 5-Lox was expressed in ductal components of the tumors but not in ducts of normal pancreas. LTB4 was also highly expressed in pancreatic cancers. The authors suggest that 5-Lox inhibitors may be a potential target for inhibiting the growth of pancreatic cancers.
Remodeling of Splenic Marginal Zone by Tumor Necrosis Factor during Infection
The splenic marginal zone constitutes the boundary between the red pulp and areas of lymphocyte accumulation in the white pulp. It contains two special populations of macrophages as well as dendritic cells and B cells. The development of the splenic marginal zone is dependent on lymphotoxin 
(LT) and, to a much lesser extent, tumor necrosis factor (TNF). The marginal zone is disrupted in chronic inflammatory diseases but little information is available about the role of cytokines in marginal zone remodeling during these processes. Engwerda et al (Am J Pathol 2002, 161:429–437) investigated remodeling of splenic marginal zone and cytokine involvement in mice injected with Leishmania donovani. In chronic L. donovani infection, marginal zone macrophages are lost and lymphocyte traffic into the white pulp is impaired. These abnormalities were not present in TNF knockout mice injected with L. donovani, or infected wild-type mice that received anti-TNF antibodies. This report demonstrates conclusively that cytokines involved in the development of normal lymphoid architecture play a role in marginal zone remodeling during chronic infection and that TNF has an important role in the remodeling.
Hepatocyte Replacement by Bone Marrow Cells Is a Slow and Rare Event
The demonstration that bone marrow of humans and rodents contain cells that can differentiate into hepatocytes or hepatocyte precursors (oval cells) has generated great interest. The main implications of the findings are that hemopoietic stem cells may participate in liver repopulation after injury, and that these cells can be used in transplantation procedures both in humans and in animal experiments. The most direct demonstration that hemopoietic stem cells can repopulate damaged livers has been presented by M. Grompe and his colleagues, using fumarylacetoacetate hydrolase (FAH) knockout mice. Grompe’s group (Wang et al, Am J Pathol 2002, 161:565–574) has now investigated in detail the frequency and kinetics of hepatocyte replacement after complete hemopoietic reconstitution in these animals. They show that hepatocyte nodules derived from hemopoietic cells appeared slowly, becoming detectable only at 11 weeks after transplantation and produced incomplete repopulation. The frequency of hepatocyte production was very small, estimated as being 10-4 to 10-6. In contrast to hemopoietic stem cell repopulation, hepatocyte repopulation in FAH knockout mice was rapid and efficient. It reached approximately 40% frequency in 21 days and more than 80% repopulation at 40 days. The data demonstrate that compared to hepatocytes, adult hemopoietic stem cells have very low efficiency for liver transplantation and repopulation. A Commentary on this paper also appears in this issue (Am J Pathol 2002, 161:349–350).
Related articles in Am J Pathol:
in Remodeling the Splenic Marginal Zone during Leishmania donovani Infection
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