ABSTRACT
Patients undergoing surgery can suffer from various complications, including post-operative bleeding, local or systematic infection, and neurologic disorders. Major surgery can initiate innate immune responses and trigger overproduction of inflammatory mediators, which can contribute to organ dysfunction. Inflammasomes are innate immune complexes, which are connected to the pathogenesis of various diseases, including atherosclerosis, hemorrhagic brain injury, and Alzheimer's disease. In the present study, we hypothesized that nucleotide-binding oligomerization domain-containing-like receptor protein (NLRP) inflammasomes may have a role in the pathological effects of surgery. Therefore, we designed a protein inhibitor of nuclear factor kappa B (NF-κB) p65 transcripts, called nt-p65-TMD (nuclear transducible (nt) transcription modulated domain (TMD) of RelA (p65)), that can penetrate the nucleus, and evaluated its therapeutic efficacy for dampening surgery-induced inflammasome activation. It was found that the nt-p65-TMD significantly reduced the NLRP1 inflammasome complex components (NLRP1, ASC, and Caspase-1) and interleukin (IL)-1ß and IL-18 productions in the spleen after surgery. In the spleen, specific cell population and selective mediators were altered after surgery with/without nt-p65-TMD treatment. Also, we found that treatment of nt-p65-TMD decreased cell death in the spleen after surgery. Therefore, nt-p65-TMD is a potential novel strategy for reducing surgery-induced NLRP1 inflammasome and complications.
Subject(s)
Drug Delivery Systems/methods , Inflammasomes/metabolism , Intranuclear Space/metabolism , Postoperative Complications/drug therapy , Postoperative Complications/metabolism , Transcription Factor RelA/administration & dosage , Abdomen/surgery , Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Adaptor Proteins, Signal Transducing/metabolism , Animals , Apoptosis Regulatory Proteins/antagonists & inhibitors , Apoptosis Regulatory Proteins/metabolism , Inflammasomes/antagonists & inhibitors , Intestines/surgery , Intranuclear Space/drug effects , Male , Mice , Mice, Inbred ICR , Postoperative Complications/etiologyABSTRACT
Atopic dermatitis (AD) has high morbidity and poor prognosis because safe and effective treatments are scarce. Recently, short interfering RNA (siRNA) has shown promise as an effective treatment for targeting specific aberrantly expressed genes. However, naked siRNAs are too inefficient because of various enzymatic, membrane, and cellular barriers. We previously reported that a Tat analog acting as a cell-penetrating peptide, combined with AT1002, which reversibly increases paracellular transport of molecules across the epidermal barrier in epidermis-disrupted mice and enhances the skin permeation of water-soluble siRNA. In the present study, to develop a novel treatment for AD, we determined the intradermal permeation of siRNAs and the antiallergic effects of a siRNA that silences RelA, a member of the nuclear factor-κB family, using Tat and AT1002 peptides in an AD mouse model. We first showed that the Tat analog and AT1002 delivered siRNA into the skin of ICR mice and, upon topical application to the AD-induced ears of NC/Nga mice, changed zonula occludens protein 1 expression. In addition, the silencing effects on the mRNA of RelA in JAWS II cells transfected with siRNA oligonucleotides for mouse RelA, complexed with Tat, were as effective as a commercial vector. Furthermore, the ear thickness, clinical skin severity, topical cytokine levels, and serum IgE production in AD model mice treated with anti-RelA siRNA with Tat and AT1002 were improved.
