Effects of age and pregnancy on the circulatory activin response of sheep to acute inflammatory challenge by lipopolysaccharide

Abstract

The release of activin A in response to intravenous injection of the bacterial cell-wall component lipopolysaccharide (LPS) was investigated in an ovine model of acute inflammatory challenge in newborn and adult sheep, and in non-pregnant and pregnant ewes. Neonatal lambs (<20 days of age) showed a quantitatively similar response in terms of circulating concentrations of activin A, its binding protein follistatin and the cytokine interleukin-6 compared with adult ewes challenged with an equivalent dose (300 ng/kg bodyweight) of LPS. The fever response and plasma tumour necrosis factor-release in response to LPS, however, were significantly (P<0·01) less in lambs than in the adult group. Pregnant ewes in the last trimester of gestation had similar responses to LPS, in all aspects measured, compared with their non-pregnant counterparts, apart from an ablated fever response. Although the adult and neonatal sheep responded to LPS, a similar response was not apparent in the fetal circulation, possibly due to a protective effect of the placenta. A 10-fold increase in the dose of LPS (from 300 ng to 3 µg/kg bodyweight) given to neonatal lambs elicited an increase in several cytokine responses measured, with a significant (P<0·05) increase in follistatin release. In contrast, the amount of activin released by the increased dose of LPS was similar to that invoked by the lower dose. The effect of tolerance to LPS was investigated by giving a second challenge of LPS 5 days after the initial injection. In all animals studied, there was an ablated (P<0·05) response to the subsequent LPS injection, apart from a similar temperature-response profile. These data provide further evidence that activin A concentrations in the bloodstream are acutely responsive to inflammatory challenge in postnatal life and suggest that the response forms a significant component of the innate immune system.

Uteroplacental Inflammation Results in Blood Brain Barrier Breakdown, Increased Activated Caspase 3 and Lipid Peroxidation in the Late Gestation Ovine Fetal Cerebellum

“…data]. Transient fetal hypoxemia, acidemia, and maternal (and therefore, fetal) hyperthermia [22] have been recorded in response to LPS administration, and while it cannot be ruled out that any one or a combination of these could account for the changes, the fetal cerebellum has not hitherto been regarded as being particularly sensitive to these factors. Further work will be necessary to identify the processes that connect the inflammatory reactions in the uterus and placenta to the cells in the fetal brain.…”

“…In the current study, we administered LPS into the uterine artery (UTA) of pregnant sheep. As evidence suggests that LPS does not cross the ovine placenta [22] , we sought evidence for the hypothesis that fetal cerebellar damage can arise as a consequence of uteroplacental inflammation, rather than as a result of the direct effect of the endotoxin on the fetal brain.…”

When versatility matters: activins/inhibins as key regulators of immunity

“…In this context, treatment with exogenous FS has confirmed the important requirement of the early release of activin A to regulate IL-1b, TNF-a and IL-6 secretion induced by LPS. 22,[32][33][34] Moreover, recent evidence has shown that macrophages are able to secrete activin A in response to the activation of TLR2, TLR4 and TLR9 (Figure 1 (1), right panel). [35][36][37][38][39] Accordingly, elevated activin A levels have been observed in a mouse model of endotoxemia and in patients with clinical sepsis condition.…”

Activin A Functions as a Th2 Cytokine in the Promotion of the Alternative Activation of Macrophages

“…T cell-derived cytokines enhanced activin A secretion in monocytes and bone marrow stromal fibroblasts (38). Therefore, it appears that the activation-induced expression of activin A is most likely a common feature in immune (39,40). In Th cells, increased expression of activin A was found only in Th2 cells, but not in Th1 cells, indicating that activin A production is associated with Th2-type immune responses.…”