Tissue damage target cells

In general, biotransformation reactions are beneficial in that they facilitate the elimination of xenobiotics from pulmonary tissues. Sometimes, however, the enzymes convert a harmless substance into a reactive form. For example, CYP-mediated oxidation often results in the generation of more reactive intermediates. Thus, many compounds that elicit toxic injury to the lung are not intrinsically pneumotoxic but cause damage to target cells following metabolic activation. A classic example of this is the activation of benzo(a)pyrene, which is a constituent of tobacco smoke and combustion products, and is... 

In most, if not all, chronic inflammatory diseases endothelial cells are prominently involved in the disease process. This is demonstrated by an increased expression of adhesion molecules and production of cytokines, and their pro-angiogenic behaviour. This leads to continuous recruitment of leucocytes into the inflamed area, without (detectable) antigen present in the affected tissue, resulting in a vicious circle of tissue damage and leucocyte recruitment. Targeting inhibitory agents (in)to the endothelial cell may interrupt in this process by controlling the activation status of this cell type. 

Whereas the normally functioning immune response can successfully neutralize toxins, inactivate viruses, destroy transformed cells, and eliminate pathogens, inappropriate responses can lead to extensive tissue damage (hypersensitivity) or reactivity against self antigens (autoimmunity) conversely, impaired reactivity to appropriate targets (immunodeficiency) may occur and abrogate essential defense mechanisms. 

The result of this is accumulation of phospholipids, or phospholipidosis, in the tissues where accumulation of the drug occurs. Active uptake of a toxic compound into the target tissue may also occur. For example, the herbicide paraquat is actively accumulated in the lung, reaches toxic concentrations in certain cells, and then tissue damage occurs (see chap. 7). 

Thus, the susceptibility is the result of accumulation of the drug in the target organ to reach concentrations not achieved in other tissues. This is then followed by what is probably a combination of events such as formation of a reactive intermediate, possibly a free radical, stimulation of lipid peroxidation and depletion of GSH, and then peroxidative damage to cell membranes and mitochondria. Whether metabolic activation by cytochromes P-450, or chemical rearrangement, or reductive activation, or all the three are involved is not currently clear. 

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