Model illustrating the activation of acute phase response and the release of acute phase proteins (APP) in blood of dairy cattle triggered by sub-acute rumen acidosis
(SARA) due to unbalanced feeding. The feeding of imbalanced diets (i.e., diets rich in grain and low in physically effective fiber) increases the risk of SARA and causes
disturbances in the rumen ecosystem such as shifts in favor of Gram-negative bacteria (GNB), resulting in the release of cell-free lipopolysaccharide (LPS) in the rumen milieu.
Free LPS can also be available in the hindgut during intensive fermentation, when large amounts of fermentable substrate bypass the rumen due to SARA. Low pH values,
ischemia, high luminal osmolality, as well as the presence of certain strains of pathogenic GNB and their products (most likely cell-free LPS, biogenic amines, ethanol) is
assumed to contribute in the increase of permeability by disrupting the tight-junctions and other cell adhesion proteins such as desmosomes of stratified squamous epithelia
(SSE) of reticulorumen. There are two pathways of the translocated LPS to reach systemic circulation that involve the lymphatic ducts and portal vein. Once translocated, the
serum component LPS-binding protein (LBP) complexes LPS and catalyses its transfer to CD14 (membrane bound or often soluble; sCD14), which then associates with TLR-4
and forms together with the protein myeloid differentiation-2 (MD-2), which results in the activation of macrophages (in the liver Kuppfer cells). The activated macrophages
release different pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8, tumor-necrosis factor (TNF)-alpha. These cytokines initiate an inflammatory response,
stress, fever, apathy, and the production of different APP from hepatocytes and different cells of other organs including the gut. Hepatocytes make the most important
quantitative site of the production of APP. The APR in cattle is also expressed through general signs like fever, lowered feed intake, changes in the metabolism, lipolysis, and
stress.