Search

Platelets are reportedly causal in hepatitis. We previously showed that in mice, lipopolysaccharide (LPS) induces a reversible and macrophage-dependent hepatic platelet accumulation (HPA), including translocation of platelets into Disse spaces and their entry into hepatocytes. Concanavalin A (ConA), which induces hepatitis in mice via both T cells and macrophages, also induces HPA. Here, we examined the relationship between HPA and ConA-hepatitis. ConA-hepatitis and HPA were evaluated by serum transaminases, hepatic 5-hydroxytryptamine, and/or electron microscopy. Unlike LPS-induced HPA, ConA-induced HPA was only moderately dependent on phagocytic macrophages. Against expectations, platelet-depletion significantly exacerbated ConA-hepatitis, and anti-P-selectin antibody and P-selectin receptor blockade reduced both ConA-induced HPA and hepatitis. Prior induction of HPA by pretreatment with low-dose LPS powerfully reduced ConA-hepatitis. Such protection by LPS-pretreatment was not effective in mice depleted of phagocytic macrophages. In platelet-depleted mice, LPS-pretreatment severely exacerbated ConA-hepatitis. In mice depleted of both macrophages and platelets, neither ConA nor LPS-pretreatment+ConA induced hepatitis. In mice deficient in IL-1α and IL-1β (but not in TNFα), ConA-induced hepatitis was mild, and a protective effect of LPS was not detected. These results suggest that (i) there are causal and protective types of HPA, (ii) the causal type involves hepatic aggregation of platelets, which may be induced by platelet stimulants leaked from injured hepatocytes, (iii) the protective type is inducible by administration of prior low-dose LPS in a manner dependent on phagocytic (or F4/80-positive) macrophages, and (iv) IL-1 is involved in both the causal and protective types., (Copyright © 2011 Elsevier B.V. All rights reserved.)

To examine the potential role of the histamine-forming enzyme, histidine decarboxylase (HDC), in oral inflammation and disease, we studied HDC activity in oral tissue after induction by bacterial agents. Following injection of E. coli-derived lipopolysaccharide (LPS) into mice, we measured the quantitative changes in HDC activity over time in dental pulp and gingiva. Oral tissue taken from individual mice was insufficient for detecting precise HDC activity, thus, we combined dental pulp or gingival tissues from four mice and assayed them over the course of 24 h. Our results indicate that LPS stimulated marked elevations of HDC activity in dental pulp and gingiva. This increase reached a maximum at 6 h after LPS injection and remained detectable at for least 24 h. Since mast cells are known to produce histamine through a difference mechanism than HDC induction, we compared LPS-induced HDC activity in dental pulp and gingiva to that in ear skin (a tissue rich in mast cells) and liver (a tissues lacking in mast cells). LPS also induced a marked increase in the HDC activity in liver and ear skin at 6 h after LPS injection. By contrast, saline injection had no effect on the HDC activity in any of the four tissues, although basal levels of HDC activity in ear skin was markedly higher than basal HDC activity in the other three kinds of tissues. Still, the relative increase in LPS-induced HDC activity in dental pulp and gingiva were much greater than that in ear skin. Since liver are devoid of mast cells and ear skin is considered the tissue richest in mast cells, the differences in HDC activity between tissues indicates that histamine induced by LPS may be produced by cells other than mast cells through another mechanism of action. These results also suggest that histamine produced in oral tissues in response to bacterial agents such as LPS could be involved in development of pulpitis or gingivitis (periodontitis), the most common diseases in the dental clinic, and that efforts to inhibit HDC activity, which elevates histamine levels in oral tissues, might offer the basis for novel treatment strategies.

Nitrogen-containing bisphosphonates (N-BPs), powerful anti-bone-resorptive drugs, have inflammatory side effects, while histamine is not only an inflammatory mediator, but also an immuno-modifier. In murine models, a single intraperitoneal injection of an N-BP induces various inflammatory reactions, including the induction of the histamine-forming enzyme histidine decarboxylase (HDC) in tissues important in immune responses (such as liver, lungs, spleen, and bone marrow). Lipopolysaccharide (LPS) and the proinflammatory cytokines IL-1 and TNF are also capable of inducing HDC. We reported previously that in mice, (i) the inflammatory actions of N-BPs depend on IL-1, (ii) N-BP pretreatment augments both LPS-stimulated IL-1 production and HDC induction, and (iii) the co-administration of clodronate (a non-N-BP) with an N-BP inhibits the latter's inflammatory actions (including HDC induction). Here, we add the new findings that (a) pretreatment with alendronate (a typical N-BP) augments both IL-1- and TNF-induced HDC elevations, (b) LPS pretreatment augments the alendronate-induced HDC elevation, (c) co-administration of clodronate with alendronate abolishes these augmentations, (d) alendronate does not induce HDC in IL-1-deficient mice even if they are pretreated with LPS, and (e) alendronate increases IL-1beta in all tissues tested, but not in the serum. These results suggest that (1) there are mutual augmentations between alendronate and immuno-stimulants (IL-1, TNF, and LPS) in HDC induction, (2) tissue IL-1beta is important in alendronate-stimulated HDC induction, and (3) combination use of clodronate may have the potential to reduce the inflammatory effects of alendronate (we previously found that clodronate, conveniently, does not inhibit the anti-bone-resorptive activity of alendronate).

Intravenous injection of Klebsiella O3 lipopolysaccharide (LPS) into BALB/c mice induces an anaphylaxis-like shock within minutes. Using 5-hydroxytryptamine as a marker for platelets, we previously suggested that a rapid platelet accumulation in the liver and lung precedes the shock, and that a complement-dependent platelet-degradation is involved in the shock. Here, we examined (i) the effect of platelet-depletion (using an anti-platelet monoclonal antibody) on the shock and (ii) the contribution of macrophages to the platelet-accumulation in those organs. LPS-induced platelet-accumulations in the liver and lung were confirmed by immunostaining. In platelet-depleted mice, the shock was largely prevented. The number of F4/80-positive macrophages was much greater in liver than in lung, and the hepatic macrophages were largely lost in mice given clodronate-encapsulated liposomes. In mice treated with such liposomes, both the LPS-induced accumulation of platelets in the liver (but not in the lung) and the shock were largely prevented, and repopulation of hepatic macrophages restored these LPS-induced responses. These results suggest that (i) platelets are indeed involved in the shock, (ii) Kupffer cells mediate the hepatic platelet accumulation, and (iii) preventing this hepatic accumulation can largely prevent rapid shock being induced by LPS (at the dose used here).

Within a few minutes of an intravenous injection of a lipopolysaccharide (LPS) into mice, platelets accumulate, largely in the lung. At higher doses, LPS induces rapid shock (within 10 min), leading to death within 1 h. This type of shock differs from so-called endotoxin shock, in which shock signs and death occur several hours or more later. Here, we found that platelet depletion (by a monoclonal anti-platelet antibody) prevented LPS-induced rapid shock, but increased delayed lethality. In Japan, glycyrrhizin (GL), a compound isolated from licorice, is daily and slowly infused intravenously into chronic hepatitis C patients. A single bolus intravenous injection into mice of GL (200 mg/kg or less) shortly before (or simultaneously with) LPS injection reduced the pulmonary platelet accumulation and the severity of the rapid shock, and prevented death in both the early and later periods. GL itself, at 400 mg/kg, produced no detectable abnormalities in the appearance or activity of mice. Intraperitoneal injection of aspirin or dexamethasone had only marginal effects on LPS-induced platelet responses and lethality. These results suggest that platelets play important roles in the development of both the rapid and delayed types of shock induced by LPS. Although the mechanism by which GL suppresses platelet responses and delayed lethality remains to be clarified, GL might provide a strategy for alleviating the acute respiratory distress syndrome seen in sepsis. Our results may also support the proposal by Cinatl et al. [Cinatl J, Morgenstern B, Bauer G, Chandra P, Ravenau H, Doerr HW. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet 2003; 361: 2045-6.] that GL may be an effective drug against severe acute respiratory syndrome.

Intravenously injected lipopolysaccharides (LPS) rapidly induce pulmonary platelet accumulation (PPA) and anaphylaxis-like shock (ALS) in mice. Macrophages reportedly release catecholamines rapidly upon stimulation with LPS. Here, we examined the involvement of macrophage-derived catecholamines in LPS-induced PPA and ALS. A catecholamine or Klebsiella O3 (KO3) LPS was intravenously injected into mice, with 5-hydroxytryptamine in the lung being measured as a platelet marker. The tested catecholamines induced PPA, leading to shock. Their minimum shock-inducing doses were at the nmol/kg level. The effects of epinephrine and norepinephrine were inhibited by prazosin (α1 antagonist) and by yohimbine (α2 antagonist), while dopamine's were inhibited only by prazosin. Use of synthetic adrenergic α1- and/or α2-agonists, platelet- or macrophage-depleted mice, a complement C5 inhibitor and C5-deficient mice revealed that (a) α2-receptor-mediated PPA and shock depend on both macrophages and complements, while α1-receptor-mediated PPA and shock depend on neither macrophages nor complements, (b) the PPA and ALS induced by KO3-LPS depend on α1- and α2-receptors, macrophages, and complements, and (c) KO3-LPS-induced PPA is preceded by catecholamines decreasing in serum. Together, these results suggest the following. (i) Catecholamines may stimulate macrophages and release complement C5 via α2-receptors. (ii) Macrophage-derived catecholamines may mediate LPS-induced PPA and ALS. (iii) Moderate PPA may serve as a defense mechanism to remove excess catecholamines from the circulation by promoting their rapid uptake, thus preventing excessive systemic effects. (iv) The present findings might provide an insight into possible future pharmacological strategies against such diseases as shock and acute respiratory distress syndrome. [ABSTRACT FROM AUTHOR]

Abstract: IL-1 and TNF-α are thought to be important bone-remodeling regulators. However, mice lacking either them or their receptors reportedly grow healthily. Here, we examined the roles of IL-1 and TNF-α in bone. Although a significant IL-1 level was detected in the tibia of non-stimulated wild-type (WT) mice, no significant physicochemical, morphological, or histological defects were detected in the tibias in mice lacking IL-1 (both α and β types) (IL-1KO) or lacking both IL-1 and TNF-α (IL-1/TNF-αKO). Injection of sub-lethal doses of lipopolysaccharide (LPS) into WT mice induced a transient hypocalcemia, increased IL-1 (in the plasma and markedly in the tibia), and increased TNF-α (markedly in the plasma, but only slightly in the tibia). LPS-induced hypocalcemia was modest in IL-1KO mice, and not detected in IL-1/TNFαKO mice. IL-1α (but not TNFα) induced hypocalcemia in both WT and IL-1KO mice. In both WT and IL-1KO mice treated with clodronate (osteoclast inhibitor), the LPS-induced hypocalcemia was markedly augmented. Nifedipine (inhibitor of both voltage-activated and capacitative Ca2+-entry) reduced the LPS-induced hypocalcemia. These results suggest that in mice: (i) IL-1 and TNF-α may contribute little to physiological bone-formation, and (ii) a time-lag between IL-1- and TNF-α-stimulated Ca2+-entry into cells throughout the body from the circulation and IL-1-stimulated Ca2+-release from the bone may cause the observed transient LPS-induced hypocalcemia. Thus, the prime role of bone IL-1 may reside in the supply of Ca2+ from the bone to cells throughout the body when the need is urgent. [Copyright &y& Elsevier]