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Role of p38 mitogen-activated protein kinase in a murine model of pulmonary inflammation
J A Nick1, S K Young, K K Brown
1Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206, USA. nickj@njc.org
Abstract:
Early inflammatory events include cytokine release, activation, and rapid accumulation of neutrophils, with subsequent recruitment of mononuclear cells. The p38 mitogen-activated protein kinase (MAPK) intracellular signaling pathway plays a central role in regulating a wide range of inflammatory responses in many different cells. A murine model of mild LPS-induced lung inflammation was developed to investigate the role of the p38 MAPK pathway in the initiation of pulmonary inflammation. A novel p38 MAPK inhibitor, M39, was used to determine the functional consequences of p38 MAPK activation. In vitro exposure to M39 inhibited p38 MAPK activity in LPS-stimulated murine and human neutrophils and macrophages, blocked TNF-alpha and macrophage inflammatory protein-2 (MIP-2) release, and eliminated migration of murine neutrophils toward the chemokines MIP-2 and KC. In contrast, alveolar macrophages required a 1000-fold greater concentration of M39 to block release of TNF-alpha and MIP-2. Systemic inhibition of p38 MAPK resulted in significant decreases in the release of TNF-alpha and neutrophil accumulation in the airspaces following intratracheal administration of LPS. Recovery of MIP-2 and KC from the airspaces was not affected by inhibition of p38 MAPK, and accumulation of mononuclear cells was not significantly reduced. When KC was instilled as a proinflammatory stimulus, neutrophil accumulation was significantly decreased by p38 MAPK inhibition independent of TNF-alpha or LPS. Together, these results demonstrate a much greater dependence on the p38 MAPK cascade in the neutrophil when compared with other leukocytes, and suggest a means of selectively studying and potentially modulating early inflammation in the lung.
Insights
The p38 mitogen-activated protein kinase (MAPK) pathway is crucial for early lung inflammation, particularly in neutrophils. Inhibiting p38 MAPK selectively reduces neutrophil recruitment, offering a potential target for modulating inflammatory responses.
Area of Science:
- Immunology
- Cellular Signaling
Background:
- Early inflammatory responses involve cytokine release and immune cell accumulation.
- The p38 mitogen-activated protein kinase (MAPK) pathway is a key regulator of cellular inflammation.
Purpose of the Study:
- To investigate the role of the p38 MAPK pathway in initiating pulmonary inflammation using a murine model.
- To evaluate the effects of a novel p38 MAPK inhibitor, M39, on inflammatory responses.
Main Methods:
- Utilized a lipopolysaccharide (LPS)-induced lung inflammation model in mice.
- Administered M39 in vitro and systemically to assess p38 MAPK activity, cytokine release, and immune cell migration.
- Measured levels of TNF-alpha, MIP-2, and KC, and quantified neutrophil and mononuclear cell accumulation.
Main Results:
- M39 inhibited p38 MAPK activity and blocked TNF-alpha and MIP-2 release in neutrophils and macrophages.
- Neutrophil migration towards MIP-2 and KC was inhibited by M39.
- Systemic p38 MAPK inhibition significantly reduced TNF-alpha release and neutrophil accumulation in LPS-induced lung inflammation.
- p38 MAPK inhibition's effect on neutrophil accumulation was independent of TNF-alpha or LPS when KC was the stimulus.
Conclusions:
- The p38 MAPK cascade is more critical for neutrophil function than other leukocytes in early lung inflammation.
- Selective inhibition of p38 MAPK in neutrophils presents a potential strategy for modulating early pulmonary inflammation.