Translational mini-review series on complement factor H: structural and functional correlations for factor H.

The 155-kDa glycoprotein, complement factor H (CFH), is a regulator of complement activation that is abundant in human plasma. Three-dimensional structures of over half the 20 complement control protein (CCP) modules in CFH have been solved in the context of single-, double- and triple-module segments. Proven binding sites for C3b occupy the N and C termini of this elongated molecule and may be brought together by a bend in CFH mediated by its central CCP modules. The C-terminal CCP 20 is key to the ability of the molecule to adhere to polyanionic markers on self-surfaces where CFH acts to regulate amplification of the alternative pathway of complement. The surface patch on CCP 20 that binds to model glycosaminoglycans has been mapped using nuclear magnetic resonance (NMR), as has a second glycosaminoglycan-binding patch on CCP 7. These patches include many of the residue positions at which sequence variations have been linked to three complement-mediated disorders: dense deposit disease, age-related macular degeneration and atypical haemolytic uraemic syndrome. In one plausible model, CCP 20 anchors CFH to self-surfaces via a C3b/polyanion composite binding site, CCP 7 acts as a 'proof-reader' to help discriminate self- from non-self patterns of sulphation, and CCPs 1-4 disrupt C3/C5 convertase formation and stability.

Effects of immobilization restraint on Syrian golden hamsters.

Rodent nose-only inhalation toxicology systems comprise whole-body immobilization in plastic restraint tubes. This method of restraint is known to have a variety of effects on animals. In the studies reported here, two independent toxicology laboratories examined the effects of inhalation tube restraint in Syrian golden hamsters, a species that has recently gained importance in inhalation studies of fibrous particulates. Body weight, food and water consumption, core body temperature, and plasma cortisol and corticosterone concentrations were assessed in animals immobilized in nose-only inhalation tubes, and the results were compared with those from unrestrained cage-control animals. Animals were immobilized for either 6 h/ day, 5 days/week for 13 weeks (subchronic), or 4 h/day for 14 consecutive days (subacute), mimicking exposure conditions commonly used in nose-only inhalation studies. Tube restraint was found to induce a marked decrease in body weight, which increased in response to cessation of restraint. The body weight decrement was associated with significant differences in food and water consumption between the restrained and control groups in the subacute study and only food consumption in the subchronic study. During the restraint period, core body temperature in the immobilized animals increased slightly but not above the normal range for this species. Plasma cortisol and corticosterone concentrations were not significantly increased with use of restraint, compared with values in controls. Immobilization-associated body weight depression in Syrian golden hamsters is important for the evaluation of nose-only inhalation study results because many normal physiologic parameters, as well as toxicant-induced effects, are associated with body weight status.

Inflammation and recruitment of immune cells into the lung.

The mechanisms responsible for recruitment of antibody-forming cells (AFC) into lung lobes exposed to antigen are not known. Because instillation of antigen induces inflammation, AFC may enter immunized lung lobes by changes in vascular permeability and/or in response to the release of mediators. The purposes of this study were to evaluate inflammatory responses produced by particulate antigens or interleukin-1 (IL-1) and to examine the recruitment of AFC and lymphocytes into the lung in response to these inflammatory stimuli. Two peaks of inflammation were observed in the lung lobes of dogs exposed to sheep red blood cells (SRBC), one at 1 day and the second around 9 days after instillation. Lymphocytes did not enter the lung during the first inflammatory response. However, lymphocytes and anti-SRBC AFC did enter immunized lung lobes during the second inflammatory response. AFC and lymphocytes also entered a lung lobe instilled with rabbit red blood cells (RRBC) at 6 days after immunization with SRBC. The observation that lymphocytes did not enter at 1 day after instillation of SRBC, but did enter the RRBC lung lobe at 1 day after instillation of RRBC, suggested that a population of lymphocytes, including AFC, were present in blood several days after immunization with SRBC that were capable of entering sites of inflammation in the lung. Instilled IL-1 was chemotactic in vivo for neutrophils and induced inflammation in the lung. However, IL-1 was not directly chemotactic for AFC or lymphocytes in vivo.