Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 544

When abnormal conditions are sustained, inflammation can become maladaptive.
Chronic inflammation can result from: (1) defective elimination of pathogens with
formation of granulomas (local accumulation of macrophages and lymphocytes) and
tertiary lymphoid tissues; (2) undegradable foreign bodies (e.g., silica and asbestos
particles); and (3) autoimmunity [ 997 ]. Chronic allergic inflammation occurs at sites
of persistent or repetitive exposure to allergens.
The inflammatory pathway comprises [ 997 ]: (1) exogenous non-microbial (al-
lergens, irritants, foreign bodies, and toxics) and microbial (pathogen-associated
molecular patterns recognized by host pattern-recognition receptors and virulence
factors) as well as endogenous (coagulation factor-XII and other inflammatory
mediators, oxidized lipoproteins, crystals of monosodium urate, and calcium py-
rophosphate dihydrate, products of matrix proteins, etc.) inducers; (2) sensors
(TLRs, IgE, NALPs, etc.); (3) mediators (vasoactive amines [histamine and sero-
tonin], vasoactive peptides [substance-P, kinins, fibrinopeptide-A and -B, and
fibrin degradation products], fragments of complement components [anaphylatoxins
C3a, C4a, and C5a], lipid mediators [eicosanoids and platelet-activating factors],
cytokines [TNF , IL1, IL6, etc.], chemokines, and proteolytic enzymes [cathepsins

and matrix metallopeptidases]); and (4) effectors (endothelial and smooth muscle
cells, leukocytes, neuroendocrine cells, etc.).
Activated endothelium allows a selective extravasation of leukocytes, as it
impedes the transmigration of erythrocytes. Leukocyte diapedesis (Sect. 9.7 ) relies
on adhesion molecules of leukocytes that connect to those of endothelial cells, and
then to proteins of the extracellular matrix with its newly deposited plasma proteins.
In the case of infection, migrating neutrophils are activated by contact with
pathogens or secreted cytokines to kill invading microbes by releasing granular
content (reactive oxygen and nitrogen species, peptidase-3, cathepsin-G, and elas-
tase) [ 997 ]. Resolution and repair phases follow the elimination of infectious agents
that is mainly done by tissue-resident and recruited macrophages. Pro-inflammatory
prostaglandins give rise to anti-inflammatory lipoxins for the transition from inflam-
mation to resolution. Lipoxins impede the recruitment of neutrophils and promote
that of monocytes to remove dead cells and initiate tissue remodeling in cooperation
with resolvins, protectins, and growth factors produced by macrophages.
Endothelial cells of the microvascular bed at a site of inflammation regulate each
stage of inflammation. Two modes of endothelial cell activation exist that [ 998 ]:
(1) increase blood flow, hence leukocyte delivery; (2) cause leakage of plasma
proteins into the tissue that creates a matrix for leukocyte migration; and (3) promote
recruitment, binding, and activation of leukocytes for extravasation.
Endothelial cell activation mode 1 associated with acute inflammation arises
rapidly in response to microbes or injured tissue and transiently (duration
10-20 mn). It is mediated by Gq-coupled receptors such as histamine H 1 receptors.
It recruits and activates neutrophils to kill pathogens and remove cellular debris.
Successful, acute inflammation restores normal tissue architecture or forms a
connective tissue scar.
Endothelial cell activation mode 2 during persistent inflammation is mediated by
cytokines, such as tumor-necrosis factor and interleukin-1. It is slow, as it depends

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