The roles of interleukin 1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF) in lipopolysaccharide (LPS)-induced fever were investigated in the rat. We used antisera against IL-1 beta and TNF to determine whether we could alter the fever by blocking the action of these cytokines. The intravenous injection of antiserum IL-1 beta 3.5 days before the intraperitoneal injection of LPS resulted in a mean fever that was significantly lower than that seen in rats that had been injected with control serum (0.36 +/- 0.11 vs. 0.82 +/- 0.16 degrees C, P = 0.016). The intravenous injection of antiserum against TNF 3.5 days before the intraperitoneal injection of LPS did not block the fever but significantly enhanced it (1.31 +/- 0.16 vs. 0.82 +/- 0.16 degrees C, P = 0.027). These data support the hypotheses that IL-1 beta is responsible for a significant part of LPS fever and that TNF acts as an endogenous antipyretic to limit the magnitude of LPS fever in the rat.

Septic shock is a cytokine-mediated process typically caused by a severe underlying infection. Toxins generated by the In septic shock, a severe underlying infection triggers a cascade of events leading to intractable hypotension, multiple organ system failure, and high mortality rates (1, 2). The infecting organism stimulates the release of cytokines and vasoactive mediators that ultimately results in vascular smooth muscle relaxation and consequent hypotension. Because several bacterial toxins and a redundant series of receptors and cytokines participate in this process, attempts at therapeutic intervention aimed at a single toxin or mediator have failed (2). Nitric oxide (NO), a potent vasodilator synthesized by nitric oxide synthase (NOS) (3-5), is a key mediator generated late in the sepsis pathway leading to hypotension (6-10). Therefore, NO represents a potentially important target for therapy.In two recent studies, MacMicking et al. (11) and Wei et al. (12) generated mice carrying a disrupted inducible NOS (iNOS) gene. The resistance of these mice to endotoxininduced death underscores the importance of NO in septic shock. Since the overabundance of NO produced during septic shock is generated through the inducible NO pathway, it wouldThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. be beneficial to selectively inhibit this pathway. In fact, investigators have suggested that nonselective inhibition of both the inducible and constitutive (endothelial-cell derived) NO pathways in the treatment of septic shock may be detrimental (9, 13).Transforming growth factor (TGF) (31, which is involved in a number of physiologic processes (14,15), antagonizes the effects of interleukin 1( and tumor necrosis factor a (16-18), two cytokines produced early in the septic shock cascade. TGF-(31 inhibits iNOS gene expression in cultured macrophages (by reducing mRNA stability and translation) (19,20) and in cultured vascular smooth muscle cells (by decreasing the rate of transcription) (21). Because of the critical role of vascular smooth muscle cells in the regulation of vascular tone and the ability of TGF-,B1 to inhibit iNOS after its induction by cytokines in vitro (21), we hypothesized (i) that TGF-,B1 could inhibit iNOS gene expression and protein production after its induction in vivo and (ii) that TGF-131 could block the hypotension of septic shock. We found that TGF-,B1 inhibited iNOS production and arrested hypotension, even after its initiation, in a rat model of septic shock produced by endotoxin. TGF-31 did not increase mean arterial pressure in control rats (not receiving endotoxin), and it did not decrease endothelium-derived constitutive NOS (ecNOS) mRNA in rats receiving endotoxin. These studies suggest that TGF-j31 is an inhibitor of iNOS but not ecNOS during endotoxic shock in vivo. They also suggest that TGF-,B1 may be of benefit in the ...

Chronic exposure of rats to high concentrations of SO2 gas causes pathologic changes in airway similar to those seen in human chronic bronchitis. The purpose of this study was to examine the pulmonary mechanical correlates of these changes and to quantify the extent of mucous hypersecretion by measuring changes in mucous glycoproteins. Female Sprague-Dawley rats were exposed to 250 ppm SO2 gas, 5 h/d, 5 d/wk, for a period of 4 wk. Control rats were exposed to air only. On the day after the last SO2 exposure, rats were anesthetized, instrumented for the measurement of pulmonary resistance (RL) and dynamic compliance (Cdyn), and ventilated. Chronic SO2 exposure caused a small but significant increase in RL and decrease in Cdyn. Airway responsiveness to inhaled aerosolized methacholine was increased in SO2-exposed rats, as indicated by approximately 6.6- and 4.6-fold decreases respectively, in the doses of inhaled methacholine required to double RL or decrease Cdyn to 50% of baseline. SO2 exposure had no effect on the contractile response of the trachea measured in vitro. Tracheae and lungs from SO2-exposed animals exhibited 140 and 535% increases in measured neutral mucous glycoproteins, respectively, and 33 and 37% increases in acid glycoproteins. Our results indicate that this animal model of chronic bronchitis mimics the mucous hypersecretion, airway obstruction, and increased airway responsiveness observed in human bronchitis and may allow us to begin to probe their mechanistic basis.

The role of tumor necrosis factor (TNF, cachectin), a putative endogenous pyrogen, was investigated by comparing fever and plasma TNF levels after the intraperitoneal and intramuscular injection of 10 micrograms/kg lipopolysaccharide (LPS) into male Sprague-Dawley rats and by neutralization of endogenous TNF using TNF antiserum. An intraperitoneal injection of LPS caused a biphasic fever that lasted approximately 6.5 h. TNF levels in these rats peaked at 657 +/- 222 U/ml at 1 h then declined to virtually undetectable levels by the fourth hour. The intramuscularly injected animals showed a lower monophasic fever and low sustained TNF levels (40 +/- 10 U/ml at 1 h, 18 +/- 11 U/ml at 4 h). In a second study, an antiserum that had been shown to neutralize rat TNF was injected intraperitoneally 2 h before the intramuscular injection of 10 micrograms/kg LPS. Control rats were injected with normal rabbit serum before LPS. During the second hour after the injection of LPS, the animals that received the antiserum developed fevers that tended to be lower than those seen in the rats that were injected with control serum (0.33 +/- 0.06 vs. 0.58 +/- 0.1), although this difference was not significant. However, during the third through eighth hours after LPS, the antiserum-injected rats had mean body temperatures that were significantly higher than those of the control rats (1.62 +/- 0.11 vs. 1.07 +/- 0.09; P = 0.0005).(ABSTRACT TRUNCATED AT 250 WORDS)

Experimental autoimmune encephalomyelitis (EAE) is a CD4+ T cell-mediated inflammatory demyelinating disease of the central nervous system (CNS) that serves as a model for multiple sclerosis (MS). Notch receptor signaling in T lymphocytes has been shown to regulate thymic selection and peripheral differentiation. In the present study we hypothesized that Notch ligand–receptor interaction affects EAE development by regulating encephalitogenic T cell trafficking. We demonstrate that CNS-infiltrating myeloid DC, macrophages, and resident microglia expressed Delta-like ligand 4 (DLL4) following EAE induction. Treatment of mice with a DLL4-specific blocking antibody significantly inhibited the development of clinical disease induced by active priming. Furthermore, the treatment resulted in decreased CNS accumulation of mononuclear cells in the CNS. Anti-DLL4 treatment did not significantly alter development of effector cytokine expression by antigen-specific T cells. In contrast, anti-DLL4 treatment reduced T cell mRNA and functional cell surface expression of the chemokine receptors CCR2 and CCR6. Adoptive transfer of antigen-specific T cells to mice treated with anti-DLL4 resulted in decreased clinical severity and diminished antigen-specific CD4+ T cell accumulation in the CNS. These results suggest a role for DLL4 regulation of EAE pathogenesis through modulation of T cell chemokine receptor expression and migration to the CNS.