Role of p38 Mitogen-Activated Protein Kinase in a Murine Model of Pulmonary Inflammation

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-α 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-α and MIP-2. Systemic inhibition of p38 MAPK resulted in significant decreases in the release of TNF-α 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-α 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.

Migration across the sinusoidal endothelium regulates neutrophil mobilization in response to ELR + CXC chemokines

“…To investigate the importance of neutrophil chemotaxis in the mobilization of neutrophils by MIP-2, we examined the effect of inhibiting this response on neutrophil mobilization. It has previously been shown that the chemotaxis of neutrophils to several inflammatory mediators is inhibited in vitro by p38 MAP kinase inhibitors (Zu et al, 1998;Nick et al, 2000;Cara et al, 2001). Consistent with these results, we show here that the specific p38 MAP kinase inhibitor, SB202190, significantly reduced neutrophil chemotaxis stimulated by MIP-2 in vitro.…”

“…However, we cannot rule out potential effects of the p38 inhibitor on endothelial cell function, although importantly we did not observe (i) an effect of SB202910 on the basal release of neutrophils or other leucocytes (Fig 4 and data not shown) or (ii) any changes in the endothelial morphology as observed by TEM following infusion of the p38 inhibitor (data not shown). The antiinflammatory effects of p38 MAP kinase inhibitors have been demonstrated in a variety of in vivo models (Badger et al, 1996;Jackson et al, 1998;Nick et al, 2000) and have also been evaluated in clinical trials (Herlaar & Brown, 1999;Branger et al, 2002). However, this is the first study to demonstrate that a potential anti-inflammatory effect of p38 MAP kinase inhibition arises from the direct inhibition of neutrophil mobilization from the bone marrow.…”

Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: Potential proinflammatory mechanisms

“…Significant effects of potent, selective p38 inhibitors have been observed in models of pulmonary inflammation (29), rat and mouse CIA, and rat adjuvant-induced arthritis (30). These studies and others have amply demonstrated the significant therapeutic potential of p38 inhibitors in treating chronic inflammatory conditions such as RA, and indeed, a number of clinical trials have been initiated to explore the efficacy and safety of this therapeutic approach in RA.…”

cAMP elevators inhibit LPS-induced IL-12 p40 expression by interfering with phosphorylation of p38 MAPK in Murine Peritoneal Macrophages

“…In response to microbes and their products, such as LPS (lipopolysaccharides), macrophages can secret a number of pro-inflammatory cytokines, including IL-12, IL-1, IL-6 and TNF-α [1][2][3][4][5]. They can also produce a number of anti-inflammatory cytokines, such as TGF-β, IL-10 and IL-1Rα [6][7][8].…”