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Macrophage-conditioned medium and interleukin 1 suppress vascular contractility
T M McKenna1, D W Reusch, C O Simpkins
1Casualty Care Research Department, Naval Medical Research Institute, Bethesda, Maryland 20814-5055.
Abstract:
Isolated rat aortas, after incubation in medium conditioned by endotoxin-stimulated peritoneal macrophages, exhibited diminished contraction to norepinephrine (maximal contraction: control medium = 713 +/- 37 (SE) mg tension/mg tissue; medium conditioned by macrophages = 437 +/- 38, P less than .001). Medium containing endotoxin alone or medium conditioned by nonstimulated macrophages had no effect on aortic tissue response to norepinephrine. Stimulation of peritoneal macrophages in vivo by sterile silica particles also induced diminished contractile responses to norepinephrine by subsequently isolated aortas. Incubation of rat aortas with human monocyte-derived interleukin 1 or recombinant human tumor necrosis factor resulted in diminished aortic contraction and sensitivity to norepinephrine, and gel filtration of medium conditioned by endotoxin-stimulated macrophages yielded suppressive activity at a molecular weight equivalent to interleukin 1 and tumor necrosis factor. The data suggest that mononuclear phagocytes may contribute to altered vascular function in sepsis via the release and vascular modulatory effects of interleukin 1 and tumor necrosis factor.
Insights
Macrophages stimulated by endotoxin release factors that impair blood vessel function. These findings suggest a role for mononuclear phagocytes in sepsis-induced vascular dysfunction through interleukin 1 and tumor necrosis factor.
Area of Science:
- Immunology
- Physiology
- Pharmacology
Background:
- Sepsis can lead to significant alterations in vascular function.
- Mononuclear phagocytes, including macrophages, play a key role in the inflammatory response during sepsis.
Purpose of the Study:
- To investigate the effect of endotoxin-stimulated macrophages on rat aortic contractility.
- To identify potential mediators released by macrophages that affect vascular function.
Main Methods:
- Isolated rat aortas were incubated in medium conditioned by endotoxin-stimulated or nonstimulated macrophages.
- Aortic contractile responses to norepinephrine were measured.
- The effects of interleukin 1 and tumor necrosis factor on aortic contractility were assessed.
- Gel filtration was used to determine the molecular weight of suppressive factors.
Main Results:
- Medium conditioned by endotoxin-stimulated macrophages significantly reduced aortic contraction to norepinephrine.
- Endotoxin alone or medium from nonstimulated macrophages had no effect.
- Silica particle stimulation of macrophages in vivo also led to diminished aortic contractility.
- Interleukin 1 and tumor necrosis factor mimicked the suppressive effects of conditioned medium, with suppressive activity found at molecular weights corresponding to these cytokines.
Conclusions:
- Endotoxin-stimulated macrophages release factors, including interleukin 1 and tumor necrosis factor, that impair aortic contractility.
- Mononuclear phagocytes may contribute to sepsis-induced vascular dysfunction through the release of these cytokines.