| dc.description.abstract | Nano- and submicron particles, inflammation and asthma Inflammation is an underlying condition of many diseases that represent important public health problems ranging from e.g. asthma to cancer. Particle exposure affects important regulators of the inflammatory process, i.e. cytokines that are signalling substances of the immune system, and thus particles may be toxic per se. There are several possible ways particles can interact with cells of the immune system. Particles administered alone may induce production of one set of cytokines that is different from those produced after concomitant exposure to microorganisms. In this way particles may influence upon the natural immune responses to bacteria. The phagocytic cell intracellular cooperative mechanisms of particles and microorganisms are poorly described. The particles may in one way act as a whole bacterium when the active substances of the bacterium, e.g. LPS from Gram negative bacteria, are covalently bound to the particles. In another way the particles may act separately from the active substances of the bacterium when the particles and LPS are not conjugated. LPS binds to receptors, TLR4, on the cell membrane of immune cells or to TLR4 in the phagosome. This binding in different compartments of the cells activates different signalling cascades within the cell and production of different sets of cytokines; IFN- when binding in the endosomes and TNF- when binding on the plasma membrane. However, it is not known which signalling route is the most important for particles with conjugated LPS or with LPS not conjugated. As part of these processes the particles may activate the inflammasome and by that route start the inflammation by activating caspase-1 which transforms pro IL-1 and pro IL-18 to biologically active cytokines. This mechanism is only partly described and needs further investigations. However, there are clear indications that some particles and crystals i.e. cholesterol crystals, silica and asbestos activate the inflammasome by disrupting the phagosome membrane. Also there are indications that particles both via the inflammasome and via receptor-independent membrane binding may activate the metabolism of arachidonic acid to prostaglandin E2 which is important for a Th2 cell response and allergy. As there is shown in mice that small particles to a higher degree than larger ones augment an allergic response one may expect that submicron and nano particles will induce a cytokine response that is different from that induced by micrometer sized particles by the intracellular mechanisms indicated above. The complement system is also shown to be involved in the inflammation in asthma and we also want to study the effects of the various sized particles in human whole blood These processes may be studied in monocytes and whole blood by assessing the different cytokines produced and their relative amounts after various exposure combinations of particles and LPS and activation of complement. Smaller projects within this research field will study monocytes and whole blood, LPS and uniform particles in the size range from 50 nanometer to 1 micrometer as well as diesel exhaust particles, and analyze cytokines with ELISA, and multiplex and possibly PCR as well as complement factors. The particle sizes must be determined by scanning or transmission electron microscopy, preferably high resolution scanning electron microscopy in the NanoLab. | nb_NO |
