RESUMO
Currently, lung transplantation outcome remains inferior compared to other solid organ transplantations. A major cause for limited survival after lung transplantation is chronic lung allograft dysfunction (CLAD). Numerous animal models have been developed to investigate CLAD in order to discover adequate treatments. The murine orthotopic lung transplant model has been further optimized over the last years. However, different degrees of genetic mismatch between donor and recipient mice have been used, applying a single, minor, moderate and major genetic mismatch. This review aims to reassess the existing murine mismatch models and to provide a comprehensive overview, with a specific focus on their eventual histopathologic presentation. This will be crucial to leverage this model and to tailor it according to specific research needs.
RESUMO
Kunitz domain-containing proteins are ubiquitous serine protease inhibitors with promising therapeutic potential. They target key proteases involved in major cellular processes such as inflammation or hemostasis through competitive inhibition in a substrate-like manner. Protease inhibitors from the Kunitz superfamily have a low molecular weight (18-24 kDa) and are characterized by the presence of one or more Kunitz motifs consisting of α-helices and antiparallel ß-sheets stabilized by three disulfide bonds. Kunitz-type inhibitors are an important fraction of the protease inhibitors found in tick saliva. Their roles in inhibiting and/or suppressing host homeostatic responses continue to be shown to be additive or synergistic with other protease inhibitors such as cystatins or serpins, ultimately mediating successful blood feeding for the tick. In this review, we discuss the biochemical features of tick salivary Kunitz-type protease inhibitors. We focus on their various effects on host hemostasis and immunity at the molecular and cellular level and their potential therapeutic applications. In doing so, we highlight that their pharmacological properties can be exploited for the development of novel therapies and vaccines.
Assuntos
Cistatinas , Serpinas , Carrapatos , Animais , Inibidores de Serina Proteinase/farmacologia , Inibidores de Serina Proteinase/uso terapêutico , Inibidores de Serina Proteinase/metabolismo , Serpinas/metabolismo , Saliva/metabolismo , Cistatinas/metabolismoRESUMO
Few studies have examined tick proteomes, how they adapt to their environment, and their roles in the parasite-host interactions that drive tick infestation and pathogen transmission. Here we used a proteomics approach to screen for biologically and immunologically relevant proteins acting at the tick-host interface during tick feeding and, as proof of principle, measured host antibody responses to some of the discovered candidates. We used a label-free quantitative proteomic workflow to study salivary proteomes of (i) wild Ixodes ricinus ticks fed on different hosts, (ii) wild or laboratory ticks fed on the same host, and (iii) adult ticks cofed with nymphs. Our results reveal high and stable expression of several protease inhibitors and other tick-specific proteins under different feeding conditions. Most pathways functionally enriched in sialoproteomes were related to proteolysis, endopeptidase, and amine-binding activities. The generated catalogue of tick salivary proteins enabled the selection of six candidate secreted immunogenic peptides for rabbit immunizations, three of which induced strong and durable antigen-specific antibody responses in rabbits. Furthermore, rabbits exposed to ticks mounted immune responses against the candidate peptides/proteins, confirming their expression at the tick-vertebrate interface. Our approach provides insights into tick adaptation strategies to different feeding conditions and promising candidates for developing antitick vaccines or markers of exposure of vertebrate hosts to tick bites.
Assuntos
Proteínas de Artrópodes , Ixodes , Animais , Proteínas de Artrópodes/genética , Ixodes/genética , Proteoma/genética , Proteoma/metabolismo , Proteômica/métodos , Coelhos , Proteínas e Peptídeos Salivares/genética , Proteínas e Peptídeos Salivares/metabolismo , VertebradosRESUMO
Surgical resection is still the standard treatment for early-stage lung cancer. A multimodal treatment consisting of chemotherapy, radiotherapy and/or immunotherapy is advised for more advanced disease stages (stages IIb, III and IV). The role of surgery in these stages is limited to very specific indications. Regional treatment techniques are being introduced at a high speed because of improved technology and their possible advantages over traditional surgery. This review includes an overview of established and promising innovative invasive loco-regional techniques stratified based on the route of administration, including endobronchial, endovascular and transthoracic routes, a discussion of the results for each method, and an overview of their implementation and effectiveness.