A promising therapeutic approach for reducing aberrant leukocyte − endothelial adhesion during pathological inflammation is to inhibit pro-inflammatory (e.g., tumor necrosis factor-α (TNF−α)) induced endothelial cell adhesion molecule (ECAM) expression at the transcriptional level. Over the past decade, several compounds have been shown to reduce leukocyte adhesion via inhibition of cytokine induced ECAM expression by suppressing the activity of transcription factors.
The majority of prior studies have tested the effects of transcription inhibitors under a narrow range of conditions. We extensively investigated the effects of a representative transcription inhibitor, the proteasome inhibitor lactacystin, on single and multi-cytokine treatment of cultured endothelial cells. Our results provide evidence that a proteasome inhibitor can reduce concurrent, sequential and long term interleukin−1β (IL−1β and TNF−α induced ECAM expression and myeloid cell adhesion.
In a separate study, we explored the anti-inflammatory properties of a novel compound i.e., phenyl methimazole. We found that phenyl methimazole reduces TNF−α induced monocytic cell adhesion to endothelial cells by predominantly inhibiting vascular cell adhesion molecule−1 (VCAM−1) expression at the transcriptional level. Thus, phenyl methimazole holds promise as an anti-adhesion therapeutic.
The transcription inhibitors, if administered systemically, can potentially affect all cells causing adverse side effects. The non-specific action of transcription inhibitors leads to the idea of targeting the delivery of these compounds using ligand-coated drug carriers. Since transcription inhibitors act within the cell, it is relevant to study the endocytosis of drug carriers. Our findings reveal that ligand-coated nanospheres are endocytosed by selectin presenting cellular monolayers.
The complexities of the in vivo haemodynamic environment will complicate the targeted delivery of drug carriers to inflamed endothelium. An engineering analysis of this system can reveal significant insights into the interdependent relationship of the various parameters that affect in vivo targeted drug delivery. We have taken the first step towards the development of a mathematical model that predicts particle deposition to inflamed endothelium and have identified some of the key parameters for selective adhesion of targeted drug carriers.
Combined, the above four studies represent a significant step towards the rational development of transcription inhibitors for the treatment of pathological inflammation.