Abstract
During infection or certain metabolic disorders, neutrophils can escape from blood vessels, invade and attach to other tissues. The invasion and adhesion of neutrophils is accompanied and maintained by their own secretion. We have previously found that adhesion of neutrophils to fibronectin dramatically and selectively stimulates the release of the free amino acid hydroxylysine. The role of hydroxylysine and lysyl hydroxylase in neutrophil adhesion has not been studied, nor have the processes that control them. Using amino acid analysis, mass spectrometry and electron microscopy, we found that the lysyl hydroxylase inhibitor minoxidil, the matrix metalloproteinase inhibitor doxycycline, the PI3K/Akt pathway inhibitors wortmannin and the Akt1/2 inhibitor and drugs that affect the actin cytoskeleton significantly and selectively block the release of hydroxylysine and partially or completely suppress spreading of neutrophils. The actin cytoskeleton effectors and the Akt 1/2 inhibitor also increase the phenylalanine release. We hypothesize that hydroxylysine release upon adhesion is the result of the activation of lysyl hydroxylase in interaction with matrix metalloproteinase, the PI3K/Akt pathway and intact actin cytoskeleton, which play important roles in the recruitment of neutrophils into tissue through extracellular matrix remodeling.
Highlights
Neutrophils, normally circulating in the bloodstream, are able to penetrate the walls of blood vessels and invade infected tissues
We compared the effects of minoxidil and doxycycline on neutrophil morphology and free amino acid release during adhesion
We have previously found that neutrophils secrete branched chain, aromatic and positively charged free amino acids when incubated over an adhesive or non-adhesive substrate at the same conditions
Summary
Neutrophils, normally circulating in the bloodstream, are able to penetrate the walls of blood vessels and invade infected tissues. In the focus of infection, neutrophils phagocytose and kill microbes with the help of special bactericidal agents that are secreted into the formed phagosomes, and enter the extracellular environment. Aggressive products of neutrophil secretion can induce the development of inflammations that damage the surrounding tissues. Recruitment of neutrophils into the tissue can occur even in the absence of infection. The release of aggressive bactericidal agents by recruited neutrophils causes the development of vascular and tissue pathologies during reperfusion after ischemia, myocardial infarction or diabetes [1,2,3]. Understanding the biochemical processes that carry out the invasion of neutrophils can serve as the basis for the development of new means for the prevention of inflammatory processes caused by the penetration of neutrophils into tissue
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