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Published on: May 2, 2018
Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase
J D MacMicking1, C Nathan, G Hom
1Beatrice and Samuel A. Seaver Laboratory, Department of Medicine, Cornell University Medical College, New York, New York 10021, USA.
Abstract:
Mice deficient in inducible nitric oxide synthase (iNOS) were generated to test the idea that iNOS defends the host against infectious agents and tumor cells at the risk of contributing to tissue damage and shock. iNOS-/-mice failed to restrain the replication of Listeria monocytogenes in vivo or lymphoma cells in vitro. Bacterial endotoxic lipopolysaccharide (LPS) caused shock and death in anesthetized wild-type mice, but in iNOS-/-mice, the fall in central arterial blood pressure was markedly attenuated and early death averted. However, unanesthetized iNOS-/-mice suffered as much LPS-induced liver damage as wild type, and when primed with Propionobacterium acnes and challenged with LPS, they succumbed at the same rate as wild type. Thus, there exist both iNOS-dependent and iNOS-independent routes to LPS-induced hypotension and death.
Insights
Mice lacking inducible nitric oxide synthase (iNOS) show impaired defense against Listeria and lymphoma. While iNOS deficiency protects against LPS-induced shock, it does not prevent liver damage or death in all cases.
Area of Science:
- Immunology
- Pathophysiology
Background:
- Inducible nitric oxide synthase (iNOS) plays a role in host defense.
- iNOS activity may contribute to tissue damage and shock during infection and inflammation.
Purpose of the Study:
- To investigate the role of iNOS in host defense against Listeria monocytogenes and lymphoma.
- To determine the contribution of iNOS to lipopolysaccharide (LPS)-induced shock, hypotension, and mortality.
Main Methods:
- Generation of iNOS-deficient (iNOS-/-) mice.
- In vivo assessment of Listeria monocytogenes replication.
- In vitro evaluation of lymphoma cell growth.
- Measurement of central arterial blood pressure in anesthetized and unanesthetized mice following LPS challenge.
- Assessment of LPS-induced liver damage and mortality in iNOS-/- and wild-type mice, with and without Propionobacterium acnes priming.
Main Results:
- iNOS-/- mice exhibited uncontrolled replication of Listeria monocytogenes and lymphoma cells.
- Anesthetized iNOS-/- mice showed attenuated hypotension and delayed death after LPS administration compared to wild-type mice.
- Unanesthetized iNOS-/- mice experienced similar LPS-induced liver damage as wild-type mice.
- iNOS-/- mice succumbed to LPS challenge at rates comparable to wild-type mice when primed with Propionobacterium acnes.
Conclusions:
- iNOS is crucial for host defense against certain infectious agents and tumor cells.
- iNOS-dependent pathways contribute significantly to LPS-induced hypotension and death.
- iNOS-independent mechanisms also mediate LPS-induced pathology, including liver damage and mortality under specific conditions.
