Band 7, Heft 1

Factor H (FH) is a natural inhibitor of the alternative pathway (AP) of complement (C) activation, an abundant protein in blood whose reduced level has been associated with proneness for increased C activation. There are also 5 FH-related proteins (FHR), which have different impacts on C function. After brief outlines of the C system and its activation via the AP, this review focuses on FH and FHR, collecting data from the literature that suggest that reduced levels or function of FH is associated with C activation-related hypersensitivity reactions (HSRs), called C activation related pseudoallergy (CARPA). Based on such observations we initiated the measurement of FH in the blood of patients with inflammatory bowel disease (IBD) and rheumatoid arthritis (RA), and examined the correlation between FH levels and HSRs following i.v. administration of PEGylated liposomal prednisolone phosphate (PLPP). ELISA assay of FH was conducted on plasma samples before treatment, immediately after treatment and at follow-up visits up to 7 weeks, and an attempt was made to correlate the FH levels obtained with the presence or absence of HSR that occurred in five of twenty patients. However, the initial data presented here on three reactive and three non-reactive patients showed FH levels >600 μg/mL, while the normal range of FH is 2–300 μg/mL. This unexpected outcome of the test led us to realize that the ELISA we used was based on antibodies raised against the short consensus repeats (SCR) in FH, which are also present in FHR. Thus the kit cannot distinguish these proteins and we most likely measured the combined levels of FH and FHR. These initial data highlighted an unforeseen technical problem in assessing FH function when using a FH ELISA that cross reacts with FHR, information that helps in further studies exploring the role of FH in CARPA.

Complement activation-related pseudoallergy (CARPA) is a hypersensitivity reaction to intravenous administration of nanoparticle-containing medicines (nanomedicines). This review focuses on CARPA in rodent models: rats, mice, guinea pigs and rabbits. Information on all aspects of hypersensitivity reactions caused by known complement activators (zymosan, cobra venom factor) and different nanomedicines (liposomes, other drug carrier nanocarriers) in these species has been compiled and analyzed, trying to highlight the similarities and differences. What is most common in all species’ reactions to i.v. complement activators, liposomes and other nanoparticles is a dose-dependent hemodynamic and cardiopulmonary disturbance manifested in acute, reversible rise or fall of blood pressure and respiratory distress that can lead to shock. Other symptoms include heart rate changes, leukopenia followed by leukocytosis, thrombocytopenia, hemoconcentration due to fluid extravasation (rise of hematocrit) and rise of plasma thromboxane B2. The results of a recent rat study are detailed, which show that rats are 2–3 orders of magnitude less sensitive to liposome-induced CARPA than pigs or hypersensitive humans. It is concluded that CARPA can be studied in rodent models, but they do not necessarily mimic the human reactions in terms of symptom spectrum and sensitivity.

Pigs provide a highly sensitive and quantitative in vivo model for complement (C) activation-related pseudoallergy (CARPA), a hypersensitivity reaction caused by some state-of-art nanomedicines. In an effort to understand the mechanism of the pigs’ unique sensitivity for CARPA, this review focuses on pulmonary intravascular macrophages (PIMs), which are abundantly present in the lung of pigs. These cells represent a macrophage subpopulation whose unique qualities explain the characteristic symptoms of CARPA in this species, most importantly the rapidly (within minutes) developing pulmonary vasoconstriction, leading to elevation of pulmonary arterial pressure. The unique qualities of PIM cells include the following; 1) they are strongly adhered to the capillary walls via desmosome-like intercellular adhesion plaques, which secure stable and lasting direct exposition of the bulk of these cells to the blood stream; 2) their ruffled surface engaged in intense phagocytic activity ensures efficient binding and phagocytosis of nanoparticles; 3) PIM cells express anaphylatoxin receptors, this way C activation can trigger these cells, 4) they also express pattern recognition molecules on their surface, whose engagement with certain coated nanoparticles may also activate these cells or act in synergy with anaphylatoxins and, finally 5) their high metabolic activity and capability for immediate secretion of vasoactive mediators upon stimulation explain the circulatory blockage and other robust physiological effects that their stimulation may cause. These qualities taken together with reports on liposome uptake by PIM cells during CARPA and the possible presence of these cells in human lung suggests that PIM cells may be a potential therapeutic target against CARPA.

Sensitive, specific and rapid diagnosis of infectious diseases is essential for effective and economic medical care. Focused medical treatment of the patient enabled by pathogen-specific diagnosis may benefit the patient, may reduce cost, and may minimize the risk of drug resistance development. The rapid progress in micro and nanotechnologies contributes to the development of novel diagnostic methods. This critical review assesses emerging nanotechnologies for diagnosis of bacterial infection in developed and developing countries on the background of the current state of the art and includes particular challenges and pitfalls posed by a number of specific pathogens.

There has been a great deal of attention and research devoted on nanoparticels (NPs) over the last 10 years. From current knowledge in the field of nanotoxicology, it has become evident that the most NPs, if not all are more toxic than bulk materials. The rapid progress and developing has been leading to concerns about the potential risk associated with the use and application of NPs on human health and the environment. Silver nanoparticles (SNPs) are one of the most available and commercially distributed nanomaterials around the world. In order to understand how human health can be affected by SNPs, quantification and detection of SNPs in biological systems have to be conducted in different models. It seems that respiratory and gastrointestinal systems as well as the skin are the major routes of SNPs penetration into the body. Research on SNPs toxicity is mostly conducted in vitro, and the available human and animal data are relatively limited. This review attempts to focus on the characterization and quantification of the potential harmful effects of SNPs on human health.

Aim: Gold nanoparticles (GNPs) are intended to be used in nanomedicine. Due to nanotechnology innovation GNPs of variable sizes and in different shapes including rods, spheres, cubes, etc., can easily be produced. The aim of the present studies was to evaluate the cyto-and genotoxicity inducible by different shaped GNPs on normal human peripheral blood lymphocytes. Methods: Four different shapes of GNPs including big rod GNPs (BR-GNPs, 50 nm), small rod GNPs (SR-GNPs, 30 nm), sphere GNPs (S-GNPs, 15 nm) and semi-cube GNPs (SC-GNPs, 15 nm) were studied. Cultured human blood lymphocytes were treated with different concentrations of these GNPs for 24 h in vitro. Cytotoxicity was evaluated based on the mitotic index (MI), while genotoxicity was studied by an interphase-fluorescence in situ hybridization (I-FISH) assay. The following genes were studied in I-FISH: TP53, CASP3 , CASP7 , CASP9 , TNF and CRP . The induction of cell death was investigated using the apoptotic-necrotic assay. Results: The lowest concentration of BR-GNPs neither had an effect mitotic activity nor enhanced gain or loss of examined gene signals in a significant manner with I-FSH. Other concentrations of BR-GNPs, SR-GNPs, S-GNPs and SC-GNPs with all concentrations inhibited the mitotic activity of the cells and reduced the cell proliferation highly significantly. The different types of GNPs initiated the duplication of CASP3 , CASP7 and CASP 9 besides TP53 genes; however they reduced the signals of TNF and CRP genes highly significantly as supported by I-FISH results. The apoptotic-necrotic assay demonstrated that small rod, sphere and semi-cube GNPs enhanced the cell death rate through the apoptotic pathway. Conclusion: GNPs at high concentration can reduce the cell proliferation and induce DNA damage. Low concentration of rod-shaped GNPs at 50 nm was safe on human lymphocytes. Further research studies are required to optimize the concentration, shape and size of GNPs before using them in nanomedicine.