Page 255 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

222 SECTION | II Organ Toxicity

VetBooks.ir (Knight, 2006). Other agents, such as HCl, NH 3 ,NO 2 , unit, e.g., interstitial fibroblasts, myofibroblasts and endo-
thelial cells. If the damage is relatively minor, the lung
and COCl 2 , appear to initiate serum leakage through toxic
may heal with a relatively normal appearance, a higher
effects on epithelial cells or endothelial cells or both.
Highly reactive molecules cause their reactions in a dif- total lung collagen content, and minimal, if any, alteration
ferent manner. It is unlikely that ozone can penetrate fluid of pulmonary function.
layers to cause direct toxicity; it is more likely that reac-
tive molecules initiate a cascade of ROS such as alde- Chronic Responses of the Lung to Injury
hydes and hydroperoxides.
The lung contains most of the metabolizing P450 iso- Fibrosis
enzymes found in other tissues, but often at lower concen-
Healing by secondary intent, often called pulmonary fibro-
trations than in the rest of the body. These P450
sis, may be either reversible or irreversible depending on
isoenzymes are highly inducible. Activation of the
the degree of injury. When a lung injury is too severe, or
enzymes is an initial defensive reaction that may contrib-
persists too long to heal spontaneously, e.g., with high
ute to healing and protecting the lung (Nel et al., 2006).
levels of paraquat, fibroblasts will attempt to fill the void
Although the P450 isoenzymes are clearly activated after
left by type I lung epithelial cell death. Fibroblast prolifer-
exposure, it is not clear whether the response is suffi-
ation may contribute to ventilation perfusion mismatch,
ciently linear and consistent to use them as a biomarker
making the lung less functional than when repaired by
of exposure. Other metabolizing enzymes in the lung
epithelial proliferation. In addition, there would be greater
include glutathione-S-transferase and glutathione peroxi-
alteration of pulmonary architecture and increased num-
dase. In fact, the lung has been found to contain several
bers of interstitial fibroblasts. Increased fibroblasts making
forms of glutathione-S-transferase.
normal amounts of collagen would be expected to collec-
tively make more collagen. If minimal to moderate
Mediators of Lung Toxicosis alterations in pulmonary architecture are present the lung
Cytokines (tumor necrosis factor alpha (TNFα), trans- will spontaneously revert back to normal (Pickrell et al.,
forming growth factor β (TGF-β) and interleukin 1B 1983). If greater alterations have been made to pulmonary
(IL-1B)) are found in respiratory tract lavage fluid, and architecture, the interstitial fibrosis may become irrevers-
are associated with cultured whole lung tissue and of ible and form dense fibrous scars (Pickrell et al., 1983;
specific lung cells (lung epithelial cells and fibroblasts) Witschi and Last, 2001).
(Witschi and Last, 2001). Cytokines can be used in There are over 10 genetically distinct collagen types
studies to signal toxicant-induced lung damage. TNFα in animals and humans. Types I and III are major intersti-
and IL-1B, e.g., signal acute lung injury. TGF-β and the tial collagens in the lung. Type III collagen is more com-
cytokines signaling acute lung injury are part of the path- pliant than type I. An increase in type I relative to type III
ogenesis of pulmonary fibrosis. IL-1, IL-2, IL-5 and IL-8 collagen, which has been shown in experimental models
are thought to be essential components of epithelial lung of fibrosis caused by paraquat and asbestos, makes the
cell injury. Finally, IL-4, IL-5 and IL-13 are thought to be lung even stiffer than if only an increased amount of col-
associated with allergenic responses. lagen was present and the ratios of type I to type III colla-
gen were unchanged (Witschi and Last, 2001).
Cell Proliferation
Toxicants can cause either reversible or irreversible lung Emphysema
changes (Witschi and Last, 2001). Toxic changes that Emphysema has been defined as enlarged air spaces due
cause major alterations in lung architecture usually cause to tissue destruction without fibrosis (Witschi and Last,
irreversible lung injury. Severe tissue injury is followed 2001). The lungs become larger, more compliant, and
by either tissue loss (emphysema) or healing by secondary hyperinflated. Loss of gas exchange surfaces causes a
intent (fibrosis). Although information about the typical reduction in gas exchange potential. Alveoli collapse, air
responses associated with specific toxicants is available, it spaces become distended and irregular, and air may
is still unclear how different responses are triggered. become trapped. This makes it more difficult to expel air
When type I lung epithelial cells are injured and die accumulated in distended alveoli. Patients become emaci-
following exposure to an oxidant gas, some type II lung ated, have increasingly forced expirations and develop
epithelial cells proliferate, and begin to flatten and stretch heave lines due to increasingly difficult and forceful
to cover the denuded area. Clara cells proliferate follow- expirations (Lowell, 1990).
ing type II proliferation (Witschi and Last, 2001). Fibrosis is associated with local, heterogenic, compen-
Migration of blood monocytes to injured areas may trig- satory emphysema. In areas where damage is sufficiently
ger responses from other cells in the parenchymal lung low, the lung heals normally. In areas where injury is