Role of CC Chemokines (Macrophage Inflammatory Protein-1β, Monocyte Chemoattractant Protein-1, RANTES) in Acute Lung Injury in Rats

Abstract

The role of the CC chemokines, macrophage inflammatory protein-1β (MIP-1β), monocyte chemotactic peptide-1 (MCP-1), and RANTES, in acute lung inflammatory injury induced by intrapulmonary deposition of IgG immune complexes injury in rats was determined. Rat MIP-1β, MCP-1, and RANTES were cloned, the proteins were expressed, and neutralizing Abs were developed. mRNA and protein expression for MIP-1β and MCP-1 were up-regulated during the inflammatory response, while mRNA and protein expression for RANTES were constitutive and unchanged during the inflammatory response. Treatment of rats with anti-MIP-1β Ab significantly decreased vascular permeability by 37% (p = 0.012), reduced neutrophil recruitment into lung by 65% (p = 0.047), and suppressed levels of TNF-α in bronchoalveolar lavage fluids by 61% (p = 0.008). Treatment of rats with anti-rat MCP-1 or anti-rat RANTES had no effect on the development of lung injury. In animals pretreated intratracheally with blocking Abs to MCP-1, RANTES, or MIP-1β, significant reductions in the bronchoalveolar lavage content of these chemokines occurred, suggesting that these Abs had reached their targets. Conversely, exogenously MIP-1β, but not RANTES or MCP-1, caused enhancement of the lung vascular leak. These data indicate that MIP-1β, but not MCP-1 or RANTES, plays an important role in intrapulmonary recruitment of neutrophils and development of lung injury in the model employed. The findings suggest that in chemokine-dependent inflammatory responses in lung CC chemokines do not necessarily demonstrate redundant function.

TRALI – Definition, mechanisms, incidence and clinical relevance

“…RANTES (Regulated upon activation, normal T-cell expressed and presumably secreted) evokes the release of histamine from basophils, may be related to allergic reactions. There are conflicting data regarding the role of RANTES in animal models of lung injury (40,41). TGF-β1 is mostly bound in an inactive form to extracellular components, but there is evidence of a link to ALI (42).…”

Activation of Monocytic Cells Through Fcγ Receptors Induces the Expression of Macrophage-Inflammatory Protein (MIP)-1α, MIP-1β, and RANTES

“…Moreover, MIP-1␣ is rapidly induced by factors that activate macrophages, thus belonging to the class of rapid-response or immediate-early genes (19). Studies addressing the transcriptional regulation of both MIP-1␣ (20) and MIP-1␤ (21) have indicated a strong dependence on short proximal promoter sequences containing activating transcription factor/CREB, CCAAT/enhancer-binding protein ␤ (C/EBP␤), c-Ets, and B sites, thus explaining the rapid and cell-specific induction of these chemokines in macrophages by LPS, serum, and cycloheximide (18,22,23). However, these data cannot be readily extended, because some studies have been conducted on murine cells, and promoter analyses have been conducted with early databases.…”

“…In this connection, RANTES has been characterized as a chemoattractant for monocytes and lymphocytes, which has been implicated in several clinical conditions such as allergic inflammation (12), endotoxemia (13), the cytotoxic activity of human HIV-specific CD8 ϩ T cells (14), and ulcerative colitis (15). The role of MIP-1␣ and MIP-1␤ deserves detailed attention, because these chemokines form a doublet and are involved in the development of the acute lung injury induced by IC (16,17) and endotoxin (18), as it has been shown in experimental studies by using specific Ab against these molecules. Moreover, MIP-1␣ is rapidly induced by factors that activate macrophages, thus belonging to the class of rapid-response or immediate-early genes (19).…”

Decreased alveolar oxygen induces lung inflammation

“…Cytokines are best known for their leukocyte chemoattractant activity, whereas chemokines orchestrate the complex cellular interactions and mediate different steps of migration of leukocytes through the endothelium (11). It has been shown that macrophage inflammatory protein-1␤ (MIP-1␤) plays a key role in the IgG immune complex-induced lung injury, whereas monocyte chemoattractant protein-1 (MCP-1) dominates the regulation of IgA immune complex-induced lung injury (5,14). An important signal transduction element is the transcriptional factor nuclear factor-B (NF-B).…”