Infiltration, Inflammatory cells leads to Inflammation, Liver

Immune cells such as polymorphonuclear neutrophils (PMNs) or monocytes, circulate in the blood and become attracted towards a gradient of secreted pro-inflammatory cytokines. PMNs have a life span of only 7-12 hours. Therefore, around 1-2 x 1011 PMN are produced daily in the human body. They account for about 50-70 % of all blood leukocytes in the human body ^[1][2]. Upon an inflammatory event, neutrophil production is upregulated, and its lifetime increases as a response to platelet activating factor (PAF), granulocyte-colony stimulating factor (G-CSF) or various pro-inflammatory cytokines, such as interleukin 1ß (IL-1ß) ^[2]. In sterile tissue injury, for example as the result of apoptosis, there is no need for PMNs to function as antimicrobial effectors; instead, they clear debris and initiate the wound-healing process. Released damage-associated molecular patterns (see Relationship:924) stimulate Kupffer cells to produce IL-1ß which leads to intercellular adhesion molecular-1 (ICAM-1) upregulation on sinusoidal endothelial cells ^[3]. ICAM-1 in turn mediates neutrophil adhesion to endothelial cells, as it interacts with ß2 integrin, which is expressed on the surface of PMNs. Subsequent to adhesion, neutrophils begin to migrate across the endothelium and towards the affected tissue ^[4][5]. The transition of neutrophils from a resting state, as during circulation in the blood, to an activated state at the site of infection is triggered by an ordered sequence of signals from cytokines^[3].

The aberrant activation of neutrophils and their extended lifespan upon an inflammatory stimulus can increase the probability of extracellular damage. PMNs are potent phagocytes, but they also lead to pathogen destruction upon oxidative bursting. The oxidative burst is marked by an increased consumption of molecular oxygen, resulting in the production of reactive oxygen species (ROS) such as H2O2 and OH•, and reactive nitrogen species (RNS)^[6]. In general, the acute inflammatory response, as in the liver, is bi-phasic. The initial phase is characterised by a macrophage (Kupffer cell)-mediated phase, with the generation of reactive oxygen species aggravating the organ damage. The activated macrophages and subsequent infiltrating lymphocytes produce additional cytokines that further promote the inflammatory response, leading to a second phase, during which neutrophils become fully activated and secrete ROS, complement components, proteases, CXCL-1 and CXCL-2^[3]. The role of IL-1 and IL-17A in neutrophil activation and subsequent induction of inflammation has been confirmed by the use of knock-down models, showing that the absence of these mediators prevent neutrophil infiltration and subsequent onset of inflammation, inhibition of the latter also being shown by direct depletion of neutrophils^[7].

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

Inhibition of messengers for the infiltration of inflammatory cells leads to a strong reduction of these. Furthermore, direct inhibition of neutrophils prevents the onset of liver inflammation.

^[8][7]: mouse ^[9]: human