Leukocyte inflammatory mediators and lung pathophysiology: an update

LEUKOCYTE RECRUITMENT TO THE LUNG is characteristic of lung inflammation. A variety of environmental factors, such as lipopolysaccharide (LPS), initiate this process, which requires mediators such as cytokines and chemokines. In spite of extensive research and progress made in the past decade, there continues to be a great interest in the mechanisms underlying cytokine and chemokine expression and their biological mechanisms in lung inflammation. This issue of the American Journal of Physiology-Lung Cellular and Molecular Physiology features four research articles and an editorial focus article on the topic of cytokine gene expression and chemokine-mediated recruitment of leukocytes to the lung.

Land and Darakhshan (9) demonstrate that thymulin, a nonapeptide neuroendocrine hormone secreted by thymic epithelia cells (18), has an effect on fetal mesenchyme-epithelial differentiation during exposure to Escherichia coli LPS. It has been previously shown that thymulin in its Zn2+-conjugated form augments the expression of factors that regulate T cell development and migration into lymphoid tissues (18). Through a series of carefully conducted experiments, the authors provided evidence that thymulin inhibits TNF-{alpha} synthesis through a posttranscriptional suppression mechanism, and this suppression is accompanied by elevated IL-6 expression and CCAAT/enhancer-binding protein-{beta}-dependent mesenchyme proliferation (9). These findings have potential implication in regenerative repair in the fetal lung and suggest that immunomodulation by thymulin may influence the process of lung damage during infection.

Monocyte chemotactic protein-1 (MCP-1; CCL2) is a CC chemokine produced by several types of cells, including monocytes, macrophages, and endothelial cells. Several studies have shown that MCP-1 expression follows hyperoxia in newborn animals treated with 95% O2 (3, 4). Vozzelli and colleagues (20) demonstrate that, in newborn rats, inhibition of hyperoxia-induced MCP-1 by neutralizing anti-MCP-1 antibody significantly reduces infiltration of macrophages and neutrophils. Whereas macrophages may be attracted to the lung by MCP-1, neutrophil infiltration is believed to result from elevated levels of cytokine-induced neutrophil chemoattractant (CINC)-1 and possibly other neutrophil chemokines. Although the authors did not test the level of macrophage inflammatory protein-2 (MIP-2), it is likely that this chemokine also plays a role in attracting neutrophils to the hyperoxia-exposed lung.

Evidence supporting a role of monocytes and macrophages in recruitment of neutrophils also came from a recent study by Maus and coworkers (14). These authors demonstrated that depletion of resident alveolar macrophages not only suppressed alveolar cytokine release but also neutrophil and monocyte recruitment upon combined fibroblast immediate-early response gene product (JE)/MCP-1/LPS stimulation. In a separate study employing CC chemokine receptor 2 (CCR2) knockout mice, it was shown that recruitment of neutrophils did not depend on the MCP-1 receptor CCR2, but the presence of CCR2-bearing monocytes could facilitate neutrophil accumulation (15). On the basis of these findings, there is significant cross talk between alveolar monocytes/macrophages and neutrophils, and chemokines secreted by monocytes/macrophages are mediators for this cell-cell communication. Signaling through CCR2 possibly plays a role in autocrine stimulation of chemokine secretion by alveolar monocytes/macrophages, as evidenced by the much decreased alveolar neutrophil accumulation by JE/LPS in mice lacking CCR2 or with blocked CCR2 function by an antibody (13).

Pulmonary and activation-regulated chemokine (PARC, DC-CK1, MIP-4) is a CC chemokine (CCL18) produced by dendritic cells and macrophages (1, 8). Unlike most other chemokines, PARC is primarily produced in the lung and serves to attract T cells. Schraufstatter and colleagues (19) in this issue reported identification of additional sources of and targets for this chemokine. Based on RT-PCR and antibody detection, they found that eosinophils prepared from individuals with mild eosinophilia also produce PARC. This finding is of interest because PARC has been recently identified to be an antagonist for the eosinophil receptor CCR3, which binds and responds to several chemokines, including eotaxin (CCL11) (16). The antagonism exerted by PARC can possibly serve as a negative regulatory mechanism for eosinophil activation by eotaxin and related chemokines, and this regulation may affect eosinophil function during allergic inflammation.

Another interesting finding by Schraufstatter and colleagues (19) is that primary monocytes acquire the ability to respond to PARC in chemotaxis and calcium mobilization assays after 3-4 days of culture. This observation appears to contradict with previous reports that PARC attracts naïve T cells but not monocytes (1, 6, 7). However, these previous studies were performed using freshly prepared monocytes that also failed to respond to PARC in the current study. Because monocytes may be desensitized by the chemokine they produce, it is unclear how the cells acquire the ability to respond to PARC after being cultured for a few days. It is likely that the culture process induces the expression of a receptor for PARC. The results reported in this article (19) may help to identify the PARC receptor based on differential expression of genes in cultured vs. fresh monocytes. PARC expression in monocytes is inducible by LPS stimulation. The study by Schraufstatter et al. demonstrated that IL-8, which is highly expressed in the lung during acute inflammation, could stimulate PARC production by monocytes. On the basis of antibody blocking and selective binding of GRO-{alpha} by CXCR2 but not CXCR1, the authors showed that CXCR1 is responsible for this effect of IL-8. It is conceivable that IL-8 helps to maintain the basal level of PARC in the lung and contributes to its induced expression during inflammation.

Whereas MCP-1 is a monocyte chemoattractant and PARC primarily attracts naïve T cells and possibly monocytes into the lung, a significant event of acute inflammation is neutrophil infiltration. MIP-2, IL-8, GRO-{alpha}, keratinocyte-derived growth factor, and CINC are major chemokines for neutrophil recruitment. Although these chemokines share many functional properties and they all interact with CXCR2, there is a great deal of interest in the differences between these chemokines. Quinton and colleagues (17) in this issue demonstrate that CINC and MIP-2 are quite different in their ability to move to systemic circulation when expressed in the lung or instilled into the airways. The rapid appearance of CINC in systemic circulation (within 5 min after intratracheal administration) precludes the possibility of de novo protein synthesis, and the lack of MIP-2 in systemic circulation when similarly administered suggests that MIP-2 is selectively retained in the lung, whereas CINC is not.

A second finding by Quinton and colleagues (17) is that CINC in systemic circulation facilitates MIP-2-mediated neutrophil recruitment in the lung, whereas intravenously administered MIP-2 does not potentiate CINC-mediated recruitment of neutrophils. The mechanism for this "priming" effect by CINC has not been delineated. In consideration of previous reports that intravenously administered IL-8 inhibits neutrophil adhesion and transmigration (5, 7, 11, 12), it is possible that these chemokines produce different effects on the same receptor: the less potent chemokine produces a priming effect while the chemokine with higher potency desensitizes the receptor. It is also possible that the gradient of chemokines between lung (CINC and MIP-2) and systemic circulation (CINC) influences neutrophil migration to the lung (2). This and other possibilities are discussed more extensively in an editorial focus by Klaus Ley (10).

Since the discovery of chemokines in the 1980s, tremendous progress has been made in our understanding of this diverse group of mediators and their receptors. The four papers in this issue represent part of the ongoing progress in cytokine and chemokine research with respect to lung physiology and pathophysiology. Along with the rapid accumulation of knowledge in these inflammatory mediators, new questions have been raised that challenge existing models. We anticipate another wave of new discoveries on the role of cytokines and chemokines in leukocyte recruitment and activation in the lung.

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Richard D. Ye, Associate Editor




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