Medical Aspects of Chemical Warfare (2008) - The Black Vault

Medical Aspects of Chemical Warfaretion, and fragmentation. 55Lung tissue and cellular responses to inhalationexposure can also be manifested in the form of cellmembrane destruction. This can be measured to somedegree by determining the extent of lipid peroxidation,an indicator of oxidative stress caused by theabundance of free radicals. Lipid peroxidation is aprocess whereby the rigid lipid bilayer of the membranebecomes more fluid, resulting in the activationof intracellular metabolic pathways regulated byaltered enzyme function. One of the more importantpathways is the arachidonic acid (AA) pathway, whichleads to the production of mediators of inflammationand edema such as the leukotrienes. The othermetabolic arm of the AA pathway leads to vasoactivecompounds such as prostaglandins, which are in partresponsible for vascular tone. Both leukotrienes andprostaglandins have been implicated in toxic-gas–inducedacute lung injury. 56–59 Adenlyate cyclase is yetanother injury-activated enzyme system responsiblefor the cleavage of adenosine triphosphate to formadenosine 3’,5’-cyclic monophosphate (cAMP), whichis required for endothelial and epithelial tight-junctionformation. The initial step in this process is damage tomembrane surface β-adrenergic receptors, which aid inthe regulation of cAMP formation. With the deactivationof cAMP formation, tight junctions become morepermeable and allow the passage of fluid or waterinto intracellular and extracellular spaces. DecreasedcAMP production and the resultant pulmonary edemahave been implicated in toxic-gas–induced acute lunginjury. 39Acute exposure to nitrogen dioxide causes a rangeof pathological effects characterized by increasedepithelial permeability and the proliferation of Claraand type II epithelial cells. 60 Chronic exposure inducesbronchiolitis, alveolar bronchiolarization, ciliatedcysts, and emphysema. Exposure effects may be morepronounced in those with preexisting compromisedlung function such as asthma. In experiments in anasthmatic population exposed to 1 ppm nitrogen dioxide,increased levels of mediators of inflammation andvasoactive compounds were measured in the BALF. 61Metabolites of the cyclooxygenase pathway of the AAcascade, such as 6-keto-prostaglandin F 1-α (responsiblefor bronchodilation) were decreased; however, bothprostaglandin D 2and thromboxane B 2(responsible forbronchoconstriction) were increased. Elevated levels ofleukotrienes such as C 4, D 4, and E 4, which are productsof the lipoxygenase pathway of the AA cascade relatedto bronchial hyperresponsiveness, were also involvedin the inflammatory response.Exposure to smoke has been shown to cause sufficientlysevere acute lung injury to ultimately resultin death. In human smoke-related fatalities, the lungswere shown to exhibit soot staining in the tracheobronchialmucosa, and they were heavy (edematous) andhyperemic. Light microscopy indicated pulmonarycongestion, and electron microscopy revealed carbonparticles as well as interstitial and intraalveolaredema. 62Inflammatory PathwaysInflammation is a critical result of toxic-gas–inhalation injury. Many studies have demonstrateda decrease in the number of macrophages, which areimportant in clearance mechanisms, and an increasein neutrophils, which aid in detoxification of toxicmediators and metabolites. These shifts in cell populationsgenerally occur over time and are usually afunction of the gas involved, the depth of inhalation,the concentration, and the duration of exposure. Inthe case of some inhaled gases, the chemical reactionin the tissue can produce deleterious amounts of freeradicals. These radicals in turn can damage migratingcells such as neutrophils, causing them to dumptheir toxic proteases, proinflammatory cytokines andchemokines, and additional toxic free radicals suchas the hydroxyl species •OH and superoxide anionO 2 - into the intracellular environment, causing greaterdamage. This additive effect may account for some ofthe latent injury responses seen following inhalationof gases such as phosgene and possibly other irritants,some of which have well-described latency (1–24hours) effects.Markers of inflammation and the timing of theirrelease after exposure can provide useful informationabout the potential therapeutic window for eventualand successful treatment. Many studies have focusedon cytokines, which are produced by a variety of whitecells, fibroblasts, and epithelial and endothelial cells,to assess the inflammatory response. Cytokines canhave a wide range of proinflammatory and antiinflammatoryeffects in tissue injury responses. Thesecompounds serve as important mediators of tissue andinjury repair processes and as such represent suitablemarkers of inflammation injury and signal transductionpathways (Table 10-5). 63For example, in phosgene-exposed mice, BALF cytokineand chemokine analysis over 72 hours clearlydemonstrated that the cytokine interleukin-6 and thechemokine macrophage inflammatory protein-2, theanalog in mice for human interleukin-8, were both significantlyincreased within 4 to 8 hours of exposure. 64Both interleukin-1β and tumor necrosis factor-α weresignificantly increased 24 to 72 hours after exposure.The data support the postulation that tumor necrosis350