Original article: general thoracic
β-chemokine function in experimental lung ischemia-reperfusion injury

https://doi.org/10.1016/S0003-4975(03)01600-XGet rights and content

Abstract

Background

Although chemokines are functionally important in models of ischemia-reperfusion injury, little is known about their role in lung ischemia-reperfusion injury (LIRI). This study examined the role of the β-chemokines, macrophage inflammatory protein (MIP)-1α, monocyte chemoattractant protein (MCP)-1, and regulated upon activation normal T cells expressed and secreted (RANTES) in LIRI.

Methods

Left lungs of Long-Evans rats underwent normothermic ischemia for 90 minutes and reperfusion for up to 4 hours. Treated animals received anti–MIP-1α, anti–MCP-1, or anti-RANTES antibodies before reperfusion. Changes in lung vascular permeability were measured with iodine 125–labeled bovine serum albumin. Neutrophil accumulation in the lung parenchyma was determined by myeloperoxidase activity, and bronchoalveolar lavage was performed to measure leukocyte cell counts. Western blots, Northern blots, and ribonuclease protection assays assessed β-chemokine messenger RNA and protein levels.

Results

Animals receiving anti–MIP-1α demonstrated reduced vascular permeability compared with controls (p < 0.001). Attenuation of permeability was less dramatic in animals treated with anti–MCP-1 and anti-RANTES antibody, which demonstrated permeability decreases of 15% and 16%, respectively (p < 0.02). Lung neutrophil accumulation was reduced in animals receiving anti–MIP-1α antibody (p < 0.005) but was unchanged in animals receiving either anti–MCP-1 or anti-RANTES. Bronchoalveolar lavage leukocyte content was also reduced by treatment with anti–MIP-1α (p < 0.003) and was unchanged in anti–MCP-1–treated and anti-RANTES–treated animals. MIP-1α treatment decreased tumor necrosis factor-α messenger RNA in injured left lungs.

Conclusions

MIP-1α is functionally significant in the development of LIRI. It likely exerts its effects in part by mediating the expression of proinflammatory and antiinflammatory cytokines and influencing tissue neutrophil recruitment. MCP-1 and RANTES seem to play relatively minor roles in the development of direct LIRI.

Section snippets

Reagents

Polyclonal rabbit antibodies to rat MIP-1α, MCP-1, RANTES, and nonspecific IgG were purchased from Peprotech Industries (Rocky Hills, NJ). All other reagents were purchased from Sigma Chemical (St. Louis, MO) unless otherwise specified.

Animal model

Pathogen-free Long-Evans rats (Simonsen Labs, Gilroy, CA) weighing 280 to 320 g were used for all experiments. The University of Washington Animal Care Committee approved all experimental protocols. All animals received humane care in accordance with the Guide

Lung vascular permeability

The PI in animals undergoing thoracotomy alone (0.18 ± 0.02) was double that seen in unmanipulated, negative control lungs (0.09 ± 0.006). The increase in permeability seen with thoracotomy and ventilation was statistically significant (p < 0.04). The difference in permeability between thoracotomy-alone animals and those that underwent 90 minutes of ischemia without reperfusion (0.22 ± 0.005) was not statistically significant (p = 0.2). However, a significant increase in permeability was seen

Comment

MIP-1α is unique among the β-chemokines in that it is also chemotactic for neutrophils. Initial studies indicated that MIP-1α was a potent chemoattractant for both CD4 and CD8 lymphocytes [11]. Subsequently, other investigators demonstrated in vitro that MIP-1α was a potent macrophage chemoattractant and activator [12]. These activities of MIP-1α are currently being investigated in human trials, where a genetically engineered analogue of MIP-1α has demonstrated safety in clinically relevant

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