Endogenous humoral mediators

There is an accumulating amount of evidence supporting the hypothesis that the induction of iNOS by endotoxin in vivo is secondary to the release of cytokines and other humoral mediators, including TNF, IL-1, and PAF (see above). For example, pretreatment of rats with monoclonal antibodies to TNF, with endogenous IL-l,a, or with PAF antagonists attenuates the delayed circulatory failure (hypotension and vascular hyporeactivity to vasoconstrictor agents) as well as the induction of iNOS in the lung. Similarly, inhibition of iNOS induction can be achieved by pretreatment with antiinflammatory cytokines, such as IL-4 or IL-10. Certain polyamines, such as spermine, are potent inhibitors of iNOS induction in vitro. However, no data are available as to whether polyamines are able to inhibit the induction of iNOS in vivo. 

Histamine also induces antinociceptive (i.e. pain-relieving) responses in animals after microinjection into several brain regions [73, 74]. H, and H2 mechanisms are significant and both neuronal and humoral mechanisms may be involved. Brain H2 receptors appear to mediate some forms of endogenous analgesic responses, especially those elicited by exposure to stressors [75]. Many of the modulatory actions of histamine discussed above appear to be activated as part of stress responses. For reasons that remain unclear, histamine releasers, such as thioperamide, show only mild, biphasic antinociceptive actions, even though histamine is a potent and effective analgesic substance. Outside the brain, both H and H3 receptors exist on certain types of sensory nerves and activation of these receptors promotes and inhibits, respectively, peripheral nerve transmission related to pain and/or inflammation [76,77]. 

The interaction between an antimicrobial and a pathogen in the laboratory does not take normal host defense systems into account. Humoral and cell-mediated immune systems play a major role in pathogen eradication their contribution is underestimated in susceptibility reports. Antimicrobial agents act in concert with endogenous microbial inhibitors such as immunoglobulins, T lymphocytes, phagocytes, complement components, lactoferrin, lactoperoxidase and lysozymes. 

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