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A. Los límites internos y externos
In Chapter 2, the pathophysiological changes occurring in H FW animals were reported and a possibly, immune-dependent mechanism of resilience for the HFW lambs was suggested. Peripheral eosinophilia was consistently lower in HFW animals and now a lower tissue eosinophilia has also been demonstrated.
3.4.1 . 1 Tissue
High fleeceweight sheep, in spite of a similar worm burden, had a significantly less pronounced tissue eosinophilia on Day 8 p.i. in comparison with control sheep. Thus the H FW hosts either were able to actively suppress eosinophil recruitment into the mucosa early in infection or the p roduction following appropriate stimuli of eosinophils by their bone marrows was reduced. The latter seems more likely, since blood eosinophils in HFW lambs stayed low throughout the whole experiment. There was l imited evidence that I L-5 1evels in
95 H FW animals were lower and this itself would be s ufficient to explain the lower eosinoph ilia.
I nflammatory cells, like eosinophils, are known to p roduce and release a variety of substances, e.g. cytokines and leukotrienes, able to injure the integrity of the gastrointestinal mucosal layer (Rothenberg et al., 2001 ) . Similarly, a detrimental effect of mucosal eosinophils was suspected in the gastrointestinal mucosa, when ewes with the highest dag score also displayed an abundance of mucosal eosinoph ils (Larsen et al., 1 994).
Other cells of the immune/inflammatory response, e.g. lymphocytes and globule leucocytes were also prominent and certainly could play significant parts in the pathogenesis of parasitism, but given the known deleterious effects of eosinophils in diseases such as asthma (Hamelmann & Gelfand, 2001 ), the presence of large n umbers of these cells in any d isease is always going to be important.
The ability to suppress the eosinophilic inflammatory response supports the resilient status of the H FW lambs. If resilience is seen as the ability to maintain productivity while parasitised, then a redu ced inflammatory response is desirable. As a consequence, H FW sheep would experience reduced losses and need to invest less in compensation and/or reconstruction and thus productivity would be less affected by parasitism.
3.4.1 .2 Mucosal Thickness
lt is likely that the inflammatory process is linked to the re-structuring of the mucosa. In the larval infection experiment, mucosal thickness and tissue eosinophilia were both maximal 1 0 days p.i. In the h igh fleeceweight experiment, the H FW lambs had thinner mucosae than did the controls, 8 days p.i. and this was potentially linked to more mild inflammatory changes. The fact that the H FW lambs retain a more normal gastrointestinal structure when parasitised provides additional support for their resilient status.
I n humans, diagnosed with H. pylori associated enlarged fold gastritis, pro inflammatory cytokines like I L- 1 J3, and HGF, appear to trigger increases in
mucosal thickness (Yasunaga et al., 1 996, 1 997). The clinical picture of this latter gastropathy is very similar to that of abomasal parasitism and includes many of the same features of parasitism, n amely, hypoacidity, mucosal hyperplasia via increased foveolar length as well as inflammatory infiltration (Murayama et al., 1 999).
Factors known to stimulate mucosal hyperplasia also include TGF-a, a known epithelial mitogen having an additional regulatory role in cell differentiation (reviewed by Salomon et al., 1 990), which is highly expressed in healing tissue (Konturek et al., 1 997). A possible source of TGF-a could have been mucous cells themselves, since a strong signal was found in some mucous cells, particularly later in infection (Figure 3.26). Hyperplasia was, however, present focally in Day 5 animals and was more generalized on Day 1 0 when immunohistchemical staining of the tissues rather suggested that the mucosal content of TGF-a had declined.
Another possible source of TGF-a is the eosinophil (Eiovic et al., 1 990; Walz et
al., 1 993), but in no instance did eosinophils stain for the growth factor. Nevertheless, a contribution of TGF-a can still be considered, since a low sensitivity of the antibody employed cannot be excluded. Moreover, m RNA levels in tissues were not measured, which could give an indication of the production of TGF-a.
Hypergastrinaemia is consistently present during abomasal parasitism and different forms of gastrin have been shown to enhance cell proliferation (reviewed by Dockray et al., 2001 ) . A possible role for gastrin as a trophic agent was perhaps demonstrated in Sheep #50, one of the Day 30 animals. This animal had extremely high serum gastrin concentrations that occurred far later in the experiment than was seen in other animals. This sheep also had a severely thickened mucosa (Figure 3 .3 1 ) in comparison with that in the other sheep of this group, although it also had markedly fewer parietal cells than other members of the gro up.
lt may be impossible to exclude TGF-a or gastrin as acting as trophic agents, and perhaps there is a combined effect of both. Transgenic mice over-
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expressing amidated gastrin , which display similar mucosal changes to those reported here, also show an increase in TGF-a production (Wang et al., 2000).
As mentioned earlier, the closest parallel to abomasal parasitism is enlarged fold gastritis in humans, due to H. pylori infection in the fundus. This type of gastritis also features gastric inflammation accompanied by reduced acid secretion and hypergastrinaemia is secondary to this. In addition it has also been demonstrated that as the mucosal levels of cytokines such as I L -1 J3 increase, the mucosal content of TG F-a decreases (Russo et al., 1 998).
This leads to other work which shows that simply losing the parietal cell is
sufficient stimulus for hyperplasia to occur (Li et al., 1 996), most likely due to
the lower mucosal levels of TG F-a that result from parietal cell loss thus confirming that interference with the parietal cell plays a pivotal role in parasitic infections and other forms of gastritis.