Toxicity, mechanisms inflammatory responses

LPDI nanoparticles are homogenous, self-forming spheres between 100 and 200 nm in diameter that are formed from the spontaneous rearrangement of a lipid bilayer around a polycation condensed DNA core. The LPDI particles (lipopolyplexes) have benefits over lipoplexes, which are composed of liposomes and DNA. Homogenous particles are formed during preparation and thus allow a more consistent production of particles, as required by the FDA for clinical use. The LPDI particles also have a lower toxicity associated with them as opposed to lipoplexes, which can generate severe systemic inflammatory responses, most likely to the increased DNA content on the surface of the particles. The internalization of DNA inside the LPDI also has a benefit of DNA protection. The DNA is not nearly as accessible to nuclease attack and mechanical stress. Therefore, a lower quantity of DNA is used because it is protected inside of the LPDI for delivery. 

Host cells are killed by cytotoxic T-ceUs or natural kiUer cells by the processes of necrosis or apoptosis. Necrosis leads to release of cell contents that can sufficiently disturb the tissue to initiate a local inflammatory response. However, the cell killed by apoptosis is then phagocytosed, which does not cause local disturbance, so that inflammation does not occur (Chapter 20). Apoptosis is achieved by two mechanisms release of toxic granules by the cytotoxic cells or by the binding of the cytotoxic ceU to the host ceU, via its death receptor protein (see below). 

The mechanism of action of sulfur mustard is multifaceted and complex, and has been reviewed in some detail by Papirmeister et al. (1991), Hurst and Smith (2008), and Smith et al. (2008). Efforts to understand the mechanisms of sulfur mustard toxicity are ongoing. Basically, sulfur mustard disrupts the interface of the epidermis and basement membrane causing blistering between the epidermis and dermis. Both immediate (immediate cell membrane damage) and delayed phases (secondary effects resulting from inflammatory responses, DNA damage, vascular leakage) have been described for sulfur mustard-induced dermal effects (Somani and Babu, 1989). Many of the toxic effects of sulfur mustard can be attributed to oxidative stress. 

The pathogenesis of drug-induced pancreatitis does not appear to differ from other causes of AP. Exactly how medications induce AP is unknown, but postulated mechanisms include immune-mediated inflammatory response, direct cellular toxicity, pancreatic duct... 

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