212 CHAPTER 42  Mechanisms of Inflammation and Tissue Repair
42  in cells, such as mast cells, and are released or quickly processed and secreted
MECHANISMS OF INFLAMMATION
AND TISSUE REPAIR
GARY S. FIRESTEIN AND STEPHANIE M. STANFORD
  THE INFLAMMATORY RESPONSE
Host defense mechanisms have evolved to recognize pathogens rapidly, render
them harmless, and repair damaged tissue. These complex, highly regulated
events can also be triggered by environmental stimuli such as noxious mechani-
cal and chemical agents. Under normal circumstances, tightly controlled
responses protect against further injury and clear damaged tissue. In disease
states, however, pathologic inflammation can lead to marked extracellular
matrix (ECM) destruction and organ dysfunction.
  Initiation of the Inflammatory Response
When tissue encounters a pathogen, resident cells are stimulated by engage-
ment of pattern recognition receptors that activate an ancient arm of host
defense known as innate immunity. In contrast to adaptive immunity, which
provides exquisite antigen specificity, innate immune responses recognize
common motifs on pathogens (Chapter 39). Additional cytoplasmic receptors
can sense “danger” signals from a toxic environment or cellular stress, such
as urate or adenosine triphosphate (ATP). Innate mechanisms are designed
for rapid responses (minutes to hours) compared with the more leisurely
adaptive system that can take days to weeks to develop. In addition to orches-
trating early events that enable host defense, innate immune cells orchestrate
the subsequent adaptive cascade through generation of chemokines that orga-
nize lymphoid tissue and presentation of antigens to lymphocytes. Innate
immunity provides intergenerational continuity in that the receptors are encoded
in the germline and pass unchanged to progeny to protect the species. In
contrast, each individual must generate his or her own adaptive immune system
through somatic mutations and gene rearrangements. This provides defense
tailored for each member of the species; its complexity and beauty permit
specificity but also provide opportunities for error such as responses against
self-antigens in autoimmunity.1
  PATHOGEN-ASSOCIATED MOLECULAR PATTERN (PAMP) RECOGNITION
Toll-like receptor (TLR) proteins bind common patterns of molecular struc-
tures on microbial pathogens not normally found in mammalian cells.2 The
TLRs are critical members of the innate immune system, serving as sentinels
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that initiate a rapid response. Some are expressed on the cell surface, such as
TLR2, which is activated by bacterial peptidoglycan and lipoproteins, and
TLR4, which is activated by lipopolysaccharide (LPS, or endotoxin). Others
are expressed on the inner leaflet of cytoplasmic vesicles, like TLR9, which
is activated by unmethylated CpG-rich bacterial sequences, or TLR3 and
TLR7, which promote antiviral defense by binding double-stranded and single-
stranded viral RNA, respectively. Some endogenous structures can bind to
TLRs, including heat shock proteins and oxidized low-density lipoproteins
(oxLDLs). The latter are important in the pathogenesis of atherosclerosis,
where LDL activates TLR4 within vascular plaques, inciting local endothelial
cell– and macrophage-derived chemotactic factors to recruit T cells into the
atheroma.
The TLR signal transduction mechanisms integrate environmental stimuli
and generate a broadly antipathogen response that also activates adaptive
responses. TLRs direct dendritic cells (Chapter 39) to migrate from peripheral
tissues to central lymphoid organs. Dendritic cells produce cytokines and,
after maturation, present antigens to T cells in the context of class II major
histocompatibility molecules and surface costimulatory proteins. The activated
T cells then migrate to the tissue to enhance and amplify the host response.
  ENVIRONMENTAL STRESS AND DANGER-ASSOCIATED MOLECULAR
PATTERNS (DAMPS)
Danger-associated molecular pattern molecules (DAMPs), also known as
“alarmins,” serve to detect and respond to microenvironment damage. Tissue
injury due to trauma or noxious stimulus initiates an inflammatory response
and is associated with microvascular damage, extravasation of leukocytes, and
leakage of plasma and proteins into the tissue. Alarmins are often preformed
in response to stress. Endogenous proteins including ATP receptors, S100
proteins, heat shock proteins, and high mobility-group box 1 (HMGB1)
mediate release of molecules that reflect cellular toxicity and induce a cellular
response. Other alarmins include products of cell damage, such as ATP or
uric acid. Cell surface acid-sensitive ion channels (ASICs) can also detect
environmental stress by sensing decreased tissue pH. ASICs can mediate a
variety of cellular functions, including cell death through apoptosis or pain
responses that lead to adaptive pain behaviors, limiting further exposure to
noxious stimuli.
  PROTEASES, COAGULATION, AND INFLAMMATION
Although the coagulation system’s primary function is to maintain vascular
integrity, proteases that regulate coagulation also promote early responses to
tissue damage and inflammation. For example, plasminogen is a circulating
proenzyme that can be cleaved to plasmin by enzymes in the coagulation
pathway, including Factor XIa and XIIa. Tissue plasminogen activating factor
and kallikrein also have this capacity. Once activated, the serine protease
plasmin can digest fibrin, fibronectin, thrombospondin, and laminin as well
as activate pro-matrix metalloproteinases like collagenase (MMP1). By remod-
eling the extracellular matrix, this system can regulate cell recruitment and
tissue damage.
Thrombus formation at the site of vascular damage can begin the inflam-
matory cascade through the release of vasoactive amines (e.g., serotonin),
release of lysosomal proteases, and formation of eicosanoid products. The
platelets can also later regulate healing with release of growth factors such as
platelet-derived growth factor (PDGF) and transforming growth factor-β
(TGF-β).
  INFLAMMASOME
The inflammasome is among the best-characterized mechanisms for sensing
danger and includes the 22-family-member human Nod-like receptor (NLR)
family of cytoplasmic proteins.3 Activated NLR proteins recruit additional
proteins to form a complex with caspase-1 and adaptor molecule apoptosis-
associated specklike protein (ASC). Activation of caspase-1 is a key function
of inflammasomes, with resultant cleavage and activation of interleukin-1
(IL-1), IL-18, and the alarmin IL-33.
Disorders of the inflammasome are associated with a group of conditions
known as autoinflammatory diseases (Chapter 245). The prototypic syndromes
known as familial cold autoinflammatory disease, Muckle-Wells disease, and
neonatal-onset multisystem inflammatory disease (NOMID) are due to non-
conserved mutations in the NLR gene that encodes cryopyrin (also known as
NALP3). These rare diseases are characterized by abnormal inflammasome
activation with aberrant release of processed IL-1β. The critical role of IL-1
has been proved by studies using treatment with IL-1 inhibitors, which prevent
 CHAPTER 42  Mechanisms of Inflammation and Tissue Repair
 
212.e3

ABSTRACT KEYWORDS
Sensing danger from foreign pathogens is a complex process involving a series inflammation
of coordinated events that quickly recognize pathogens, alert other cells and cellular responses
tissues to the danger, and eliminate the threat. These processes, which can cytokines
also be triggered by environmental stimuli including pathogens, mechanical tissue damage
stress, and chemical agents, involve an early inflammatory response followed resolution of inflammation
by a second wave. The initial response involves stimulation of innate immune tissue repair
cells through molecular pattern recognition mechanisms, followed by propaga- extracellular matrix
tion involving systems such as proteases, coagulation factors, inflammasome
components, complement, and neutrophil extracellular traps. The second wave
involves immune cell infiltration into tissues, followed by responses of tissue
resident cells, which include production of soluble mediators of inflammation
like inflammatory cytokines, eicosanoids, and mast cell products, stimulation
of cell metabolism, and epigenetic changes that modify gene expression. This
program of events can contribute to tissue destruction, largely mediated through
generation of reactive oxygen and nitrogen species, proteases, and extracellular
matrix damage. Consequently, resolution of inflammation, repair of the result-
ing tissue damage, and prevention of further injury are required to restore
homeostasis. Inflammatory cells are eliminated through production of anti-
inflammatory soluble mediators, antioxidants, and protease inhibitors, and
deactivation of intracellular signaling pathways. Normally, these intricate
responses enable host response to environmental triggers while mitigating
tissue damage. In disease states, however, inadequately controlled inflamma-
tion can lead to extracellular matrix damage, exacerbation of disease, and
ultimately to organ dysfunction.

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212.e4 CHAPTER 42  Mechanisms of Inflammation and Tissue Repair
 

Signaling by TLR2 and TLR4 progresses through adaptor proteins and

often converges on the kinase MyD88, which orchestrates several downstream E-TABLE 42-1 EXAMPLES OF INFLAMMATION PATHWAYS IN
cascades. IκB kinase-β (IKKβ) phosphorylation activates nuclear factor-κB DISEASE
(NF-κB), a master switch for inflammatory genes. NF-κB nuclear transloca-
DISEASE ACTIVATED PATHWAYS
tion stimulates production of cytokines (e.g., interleukin-6 [IL-6], IL-8, and
tumor necrosis factor [TNF]), the machinery for prostaglandin release (e.g., Atherosclerosis Toll-like receptor activation (e.g., oxLDL)
cyclooxygenase 2 [COX2]), and genes that regulate the ECM (e.g., metal- Chemokine-mediated leukocyte recruitment (e.g.,
MCP-1)
loproteinases). MyD88-independent pathways also exist; for instance, TLR3
engagement activates a separate pathway involving IKKβ and interferon regu- Cancer Reactive oxygen and nitrogen intermediate-induced
lating factor-3 (IRF-3). IRF-3, in combination with other transcription factors, mutations
Cyclooxygenase 2–mediated neoplasia (e.g., colon,
induces expression of genes, such as interferon-β (IFN-β), that establish an breast)
antiviral state. NF-κB prolonging survival of damaged cells
These genes offer protection against pathogens by initiating key defense
Asthma IgE-mediated mast cell activation
mechanisms. However, these same pathways can create a hazardous milieu TH2 cytokine-mediated leukocyte activation
that is toxic to host cells through production of oxygen radicals, nitric oxide, Leukotriene-induced bronchospasm
and other reactive intermediaries. These molecules can damage DNA and Protease-induced airway remodeling
harm bystander cells, or lead to neoplasia (E-Table 42-1). Rheumatoid arthritis Toll-like receptor activation (e.g., peptidoglycan)
Macrophage/fibroblast cytokine production,
including IL-1, TNF, and IL-6
Non-TLR cytoplasmic sensors serve a similar purpose. RIG-1 and MDA5 Cyclooxygenase 2 induction
can detect RNA viruses and intiate an inflammatory response. These are, in Protease-mediated cartilage destruction
some cases, partially redundant with TLR3 and 7 and can activate similar Synovial complement activation
signaling mechansisms. Systemic lupus erythematosus Complement activation in multiple organs
α-Interferon production and interferon signature
Autoinflammatory diseases Inflammasome activation, including production of
Sepsis can cause dysregulation of the hemostatic system and lead to dis- IL-1, IL-18 and IL-33
seminated intravascular coagulation. Thus, targeting this pathway could poten- Psoriasis TH17 cell activation
tially provide therapeutic benefit. As a proof of concept, recombinant human IL-17A, IL-12, and IL-23 mediated inflammation
thrombomodulin, which reduces thrombin-mediated clotting, reduces mortality IgE = immunoglobulin E; MCP-1 = monocyte chemoattractant protein 1; NF-κB = nuclear
in sepsis and has been approved for use in the United States. factor-κB; oxLDL = oxidized low-density lipoprotein; TH2 = helper T lymphocyte type 2; TH17 =
helper T lymphocyte type 17; TNF = tumor necrosis factor.

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 CHAPTER 42  Mechanisms of Inflammation and Tissue Repair
flares and can reverse end-organ damage. The inflammasome also participates
in gout (Chapter 257), in which urate crystals can activate the inflammasome.
  IMMUNE COMPLEXES AND COMPLEMENT
The complement system (Chapter 44) is another ancient defense mechanism
that links innate immunity and the humoral arm of adaptive immunity. Both
the classical complement pathway, activated by immunoglobulin G (IgG)- and
IgM-containing immune complexes, and the alternative pathway, activated
by bacterial products, converge at the third component of complement, C3,
with proteolytic release of fragments that amplify the inflammatory response
and mediate tissue injury. C3a and C5a directly increase vascular permeability
and contraction of smooth muscle. C5a induces mast cell release of histamine,
thereby indirectly mediating increased vascular permeability. C5a also activates
leukocytes and enhances their chemotaxis, adhesion, and degranulation, with
release of proteases and toxic metabolites. C5b attaches to the surface of cells
and microorganisms and is the first component in the assembly of the C5b-9
membrane attack complex.
  NEUTROPHIL EXTRACELLULAR TRAPS
Neutrophils contribute to microbe elimination through phagocytosis, genera-
tion of reactive oxygen species, and degranulation. Another more recently
discovered antimicrobial activity is their extrusion of chromatin fibers contain-
ing antimicrobial peptides and enzymes, called neutrophil extracellular traps
(NETs).5 These structures immobilize and kill invading microorganisms. They
may also contribute to autoimmune and inflammatory disorders by binding and
displaying extracellular autoantigens or as a stimulus for thrombus formation.
  Second Wave of the Inflammatory Response
Activation of innate immunity quickly leads to the robust influx of inflamma-
tory cells. Resident cells, such as vascular endothelial cells, mast cells, dendritic
cells, and interstitial fibroblasts, respond by releasing soluble mediators, includ-
ing eicosanoids and pro-inflammatory cytokines (E-Table 42-2). These media-
tors amplify the inflammatory response and recruit additional leukocytes.
Locally stimulated cells, along with the newly arrived inflammatory cells,
release toxic reactive intermediates of nitrogen and oxygen as well as a myriad
of proteases, principally matrix metalloproteinases (MMPs), serine proteases,
and cysteine proteases. In most situations, the normal physiologic response
is an exquisitely coordinated program that uses proteolytic enzymes to remodel
the ECM and promote a supportive environment for wound healing rather
than tissue damage.
  CELLULAR RESPONSE
Inflammatory cell infiltration at the site of tissue damage begins with release
of chemokines and soluble mediators from resident cells, including interstitial
fibroblasts, mast cells, and vascular endothelial cells. Signaling from these
events alters the local adhesion molecule profile and creates a chemotactic
gradient that recruits cells from the blood stream. Mast cells act as sentinels
that degranulate within seconds after ligation of immunoreceptors and activa-
tion of the signaling molecule spleen tyrosine kinase (Syk) to release vasoactive
amines. In acute responses, polymorphonuclear leukocytes (PMNs) are usually
the first inflammatory cells to arrive at the site of injury, followed later by
mononuclear cells.
  SOLUBLE MEDIATORS
  Pro-Inflammatory Cytokines
Pro-inflammatory cytokines, often derived from macrophages and fibroblasts,
are mediators that activate the immune system. The pro-inflammatory members
of the IL-1 family (IL-1α, IL-1β, IL-18, and IL-33) and TNF have pleiotropic
activities and can enhance adhesion molecule expression on endothelial cells,
induce proliferation of endogenous cells, and stimulate antigen presentation.
IL-1 and TNF increase expression of matrix-degrading enzymes, such as col-
lagenase and stromelysin, and stimulate synthesis of other inflammatory
mediators such as prostaglandins from fibroblasts. TNF inhibitors (Chapter
33) are effective in inflammatory diseases such as psoriasis, RA, and inflam-
matory bowel disease, and IL-1 inhibitors are beneficial in genetic diseases
such as the cryopyrinopathies.
  Eicosanoids
Local inflammatory responses lead to release of lipid-derived eicosanoids.
These molecules are produced adjacent to sites of injury, and their half-lives
range from seconds to minutes. Eicosanoids, such as prostanoids and leukot-
rienes, are produced de novo from membrane lipids when cell activation by
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213
mechanical trauma, cytokines, growth factors, or other stimuli leads to release
of free arachidonic acid from membrane phospholipids mainly via the action
of cytosolic phospholipase A2 (cPLA2). Prostanoids, including prostaglandins,
prostacyclins, and thromboxanes, are produced from free arachidonic acid by
cyclooxygenases and specific isomerases. These molecules act at peripheral
sensory neurons and central sites within the spinal cord and brain to evoke
pain and hyperalgesia. Their production is increased in most acute inflamma-
tory conditions, including exacerbations of arthritis and inflammatory bowel
disease. In response to exogenous and endogenous pyrogens, PGE2 derived
from cyclooxygenase 2 (COX2) mediates a central febrile response. Prosta-
glandins, a type of prostanoid, synergize with bradykinin and histamine to
enhance vascular permeability and edema.7 Prostaglandin levels are usually
very low in normal tissues and increase rapidly with acute inflammation, well
before leukocyte recruitment. COX2 induction with inflammatory stimuli
most likely accounts for the high levels of prostanoids in chronic inflammation.
COX2 plays a key role in platelet-endothelial cell interactions by increasing
production of prostacyclin (PGI2) in endothelial cells. Increased risk of myo-
cardial infarction associated with the use of selective COX2 inhibitors might
be related to unopposed production of thromboxane A2 by COX1 in platelets.
Prostacyclin also protects against atherosclerosis in mice, and COX2 blockade
abrogates this beneficial effect. Thus, COX inhibitors can potentially increase
thrombotic events.
A distinct set of enzymes direct arachidonic acid metabolites toward the
synthesis of leukotrienes. Their relative importance depends on the specific
target organ of an inflammatory response. For instance, leukotriene receptor
antagonists are effective in asthma, whereas similar approaches have been
less impressive in RA. Unlike prostaglandins, leukotrienes are primarily pro-
duced by inflammatory cells such as neutrophils, macrophages, and mast
cells. 5-Lipoxygenase transforms released arachidonic acid into the epoxide
leukotriene A4 (LTA4) in concert with 5-lipoxygenase-activating protein
(FLAP). LTA4 can be hydrolyzed by cytosolic LTA4 hydrolase to LTB4, a
potent neutrophil chemoattractant and stimulator of leukocyte adhesion to
endothelial cells. LTA4 can also conjugate with glutathione to form LTC4 by
LTC4 synthase at the nuclear envelope. LTC4 can be metabolized extracellularly
to LTD4 and LTE4. These leukotrienes promote plasma leakage from postcapil-
lary venules, upregulation of expression of cell surface adhesion molecules,
and bronchoconstriction.
  Mast Cell Products
Histamine is a vasoactive amine produced by basophils and mast cells (Chapter
240) that markedly increases capillary leakage. In basophils, histamine is
released in response to bacterial formylmethionyl-leucyl-phenylalanine (f-MLP)
sequences, complement fragments C3a and C5a, and IgE. The resultant edema
can be readily observed clinically in urticaria (Chapters 237 and 411) and
allergic rhinitis (Chapter 398). The stimulus for release of histamine from
mast cell granules is the same as in basophils, except for the absence of f-MLP
receptors in this cell type. Histamine also synergizes with locally produced
LTB4 and LTC4. In addition, histamine enhances leukocyte rolling and firm
adhesion and induces gaps in the endothelial cell lining, enhancing leukocyte
extravasation.
Despite the production of histamine in asthma and in acute synovitis, cur-
rently available histamine blockers have minimal therapeutic effect in these
conditions. Targeting the histamine type 4 receptor (HR4), which has a variety
of immunomodulatory effects on bone marrow derived cells, suggests that more
precise inhibition of this novel histamine pathway might have greater success.
Tryptase is a neutral serine protease released by mast cells in response to
allergens and is used as a biomarker of mastocytosis and systemic anaphylaxis.8
Tryptase can also contribute to inflammation by promoting angiogenesis.
  Kinins
Kinins induce vasodilation, edema, and smooth muscle contraction, as well
as pain and hyperalgesia, through stimulation of C fibers.9 They are formed
from high- and low-molecular-weight kininogens by the action of serine pro-
tease kallikreins in plasma and peripheral tissues. The primary products of
kininogen digestion are bradykinin and lysyl-bradykinin. These products have
high affinity for the widely expressed B2 receptor. The peptides desArg-BK
and Lys-desArg-BK are generated by carboxypeptidases and bind the kinin
B1 receptor subtype, which is not expressed in normal tissues but is rapidly
upregulated by TLR ligands and cytokines. Kinin actions are associated with
secondary production of other mediators of inflammation, including nitric
oxide, mast cell–derived products, and the pro-inflammatory cytokines IL-6
and IL-8.
 CHAPTER 42  Mechanisms of Inflammation and Tissue Repair
 
213.e1
Individuals with abnormalities of early complement components, especially
C1q, C2, and C4, usually have a minimally increased incidence of infection E-TABLE 42-2 SIGNALS FOR INDUCTION AND REPAIR
but demonstrate enhanced risk of developing autoimmune diseases such as OF INFLAMMATION
systemic lupus erythematosus (SLE) (Chapter 250), possibly due to inefficient
INFLAMMATION RESOLUTION AND TISSUE REPAIR
clearance of immune complexes. Enhanced activation and consumption of
complement proteins can also occur in SLE accompanied by low plasma C3 CYTOKINES AND GROWTH FACTORS
and C4 levels, especially in association with disease exacerbations. C3 or C5 TNF TGF-β
deficiency increases susceptibility to bacterial infections, whereas defects in IL-1 family (IL-1, IL-18, IL-33) IL-10
the late components that form the membrane attack complex result in an IL-6 family (IL-6, IL-11, LIF, FGF
increased incidence of Neisseria sp bacteremia. Blocking formation of the osteopontin)
membrane attack complex may, however be used to treat paroxysmal nocturnal
IL-4, IL-13 Osteoprotegerin
hemoglobinuria (PNH) by protecting red blood cells from complement-
mediated intravascular hemolysis.4 An antibody directed against C5 was also IL-15 IL-1RII
effective in several PNH clinical trials. IL-17 family (IL-17A-F) IL-1Ra
IL-12 family (IL-12, IL-23, IL-27) Soluble TNF-R
VEGF IL-18 binding protein
Most tissue fibroblasts and vascular endothelial cells are quiescent before
migration of PMNs into the tissue. However, these resident cells can be trig- Chemokines
IL-8
gered to proliferate and migrate toward the site of injury and synthesize cyto- MCP-1
kines, proteases, and ECM components. Growth factors are released, such as RANTES
basic fibroblast growth factor (bFGF) and vascular endothelial growth factor IL-16
(VEGF), stimulating new blood vessel formation. Together with granulocyte- CCL2
macrophage colony-stimulating factor (GM-CSF), these growth factors con- CXL10
tribute to cellular proliferation and amplification of the inflammatory response Alarmins
and induce maturation of dendritic cells that process antigens. Fibroblasts HMGB1
ATP receptors
and endothelial cells also secrete ECM proteins, MMPs, and other ECM- S100 proteins
digesting enzymes. Initially, the response favors proteolytic activity to clear Heat shock proteins
damaged infrastructure. This is followed by a shift to increased production of IL-33
new ECM to allow tissue repair and wound healing. PROTEASES
Increased vascular permeability allows blood-borne proteins such as fibrino-
gen, fibronectin, and vitronectin to extravasate into the perivascular ECM. Matrix metalloproteinases TIMPs
 Collagenases
Interaction with preexisting ECM allows the assembly of new ligands for  Gelatinases
adhesion molecules (e.g., integrins α5β1 and αvβ3). A change in the profiles  Stromelysins
of adhesion molecules and ligands, in conjunction with release of chemoat-  Matrilysins
tractant molecules, contributes to leukocyte recruitment to sites of inflam- Serine proteases SERPINs, α2-macroglobulin
mation. Chemokines involved are IL-8 (for neutrophils), macrophage  Trypsin
chemoattractant protein-1 (MCP-1) for monocytes, RANTES (regulated on Chymotrypsin
activation, T-cell expressed and secreted) for monocytes and eosinophils, and Kallikrein
IL-16 (for CD4+ T cells). Plasmin
Chemokines have the capacity to recruit specific subsets of cells by binding Cysteine proteases
to G-protein coupled chemokine receptors.6 Directly targeting chemokines, ADAMTS family
such as CCL2, has met with limited success in clinical trials, perhaps because  Aggrecanases
the system is quite complex and highly redundant. Antibodies against CXCL10 SMALL MOLECULE MEDIATORS
on the other hand, have been successfully tested in early clinical trials for RA
and ulcerative colitis. Another approach could be to block chemokine recep- Prostaglandins (especially PGE2) Lipoxins
tors. However, neither CCR2 nor CCR5 antagonists were successful in RA Leukotrienes (especially LTB4) Cyclopentenone
clinical trials, possibly due to overlapping functions of multiple chemokines. C3a and C5a Antioxidants
An alternative approach might be to target intracellular mechanisms distal to Histamine
chemokine receptor ligation, such as the phosphoinositide-3 kinase (PI3K)
Bradykinin
system. PI3Kγ is mainly expressed in bone marrow–derived cells and is the
convergence point for multiple chemotactic factors. Reactive oxygen
Ligation of integrins on leukocytes prolongs their survival once they move Reactive nitrogen
into damaged tissue by preventing apoptosis. The central role of specific adhe- APOPTOSIS REGULATORS
sion molecule-ligand pairs has been confirmed in human diseases. For instance, Soluble Fas ligand Fas
α4β1 is key in recruiting lymphocytes to the central nervous system in multiple TRAIL
sclerosis, and blocking this interaction suppresses disease activity (Chapter Reactive oxygen
383). Eosinophils use the same adhesion receptors to migrate into the lung Reactive nitrogen
in allergen-induced asthma (Chapter 81). OTHER Phosphatases
Increased expression of intracellular adhesion molecule 1 (ICAM-1) and ADAMTS = a disintegrin and metalloproteinase family; ATP = adenosine triphosphate; CCL2 =
vascular cell adhesion molecule 1 (VCAM-1), as well as increased chemokine C-C motif chemokine ligand 2; CXCL10 = C-X-C motif chemokine 10; FGF = fibroblast growth
expression, is evident in other cell types, such as the airway epithelium after factor; IL = interleukin; LIF = leukemia inhibitory factor; MCP-1 = monocyte chemoattractant
allergen challenge in asthma. Rapid transient influx of neutrophils occurs in protein 1; R = receptor; Ra = receptor antagonist; RANTES = regulated on activation normal T cell
expressed and secreted; SERPINs = serine protease inhibitors; TGF = transforming growth factor;
allergic airway disease, along with activation of local T cells and mast cells. TIMPs = tissue inhibitors of metalloproteinase; TNF = tumor necrosis factor; TRAIL =
Neutrophils produce lipid mediators, reactive oxygen intermediates, and pro- TNF-related apoptosis-inducing ligand; VEGF = vascular endothelial growth factor; HMGB1= high
teases such as elastase, which may contribute to airflow obstruction, epithelial mobility-group box 1.
damage, and remodeling. Neutrophil elastase, together with chemokines released
by both recruited and allergen-activated T cells and mast cells, serves to recruit
eosinophils.

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213.e2 CHAPTER 42  Mechanisms of Inflammation and Tissue Repair
IL-1 and TNF comprise a small fraction of the acute cytokine response.
Many other factors also participate, including IL-6 and its related cytokines
(IL-11, osteopontin, and leukemia inhibitory factor), which can induce acute
phase reactants and bias an immune response toward a helper T type 1 (TH1)
or TH2 phenotype (Chapter 40). GM-CSF can regulate dendritic cell matura-
tion, increase expression of human leukocyte antigen (HLA-DR) on these
cells, and enhance antigen presentation. The TH1 lymphokine IFN-γ can also
induce expression of HLA-DR, increase expression of endothelial cell adhe-
sion molecules, and inhibit collagen production. IL-1, IL-6, and IL-23 can
coordinate differentiation toward TH17 cells, a phenotype that contributes to
autoimmunity due to production of IL-17A and perhaps IL-17F. The growth
factor TGF-β biases cells toward the regulatory T cell (Treg) phenotype,
which can suppress antigen-specific responses of other T cells. IL-6 and auto-
crine IL-21 promote differentiation of follicular helper T cells (TFH), which
secrete CXCL13, IL-21 and IL-4 and regulate germinal center formation and
function, providing specialized help to B cells. Cytokines also govern differ-
entiation of innate lymphoid cells (ILCs), which lack antigen receptors, are
enriched in epithelial and parenchymal tissues, and act as a local barrier against
infections and tumors and respond to tissue damage. ILCs can be classified
into four subsets, ILC1, ILC2, ILC3 and natural killer cells, that display cyto-
kine expression and immune functions similar to their homologous subsets
of CD4 (Th1, Th2, TH17) or CD8 T cells, respectively.
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Many cytokines activate cells by ligating their receptors and engaging the
Janus kinase (JAK) family of signaling molecules, including JAK1, JAK2, JAK3,
and Tyk2. These kinases phosphorylate the STAT proteins (signal transducer
and activator of transcription). The STATs serve as transcription factors that
initiate expression of other cytokines and mediators of inflammation. JAK
inhibition represents an alternative approach to abrogating the inflammatory
response. The JAK inhibitor tofacitinib rapidly lowers plasma CXCL10 levels
and decreases synovial phospho-STAT1 and phospho-STAT3 in RA. A1 
Cytokines play a key role in the establishment and perpetuation of immune-
mediated diseases. As noted above, autocrine and paracrine cytokine networks
play a critical role in the perpetuation of inflammation in RA (Chapter 248).
MCP-1 recruits and activates macrophages into atheromas containing oxLDLs
and foam cells. In allergic asthma (Chapter 81), IL-13 is emerging as a central
inflammatory cytokine. IL-13 functions through binding to cell surface IL-4
receptors, and IL-4R–deficient mice are relatively resistant to the development
of asthma.
The role of pro-inflammatory cytokines varies among different diseases, as
evidenced by varying benefit of individual cytokine inhibitors among different
diseases. For instance, IL-6 blockade is effective in RA, whereas IL-12/23
and IL-17A inhibition are very effective against psoriasis but not RA.
214 CHAPTER 42  Mechanisms of Inflammation and Tissue Repair
 

  CELLULAR METABOLISM TABLE 42-1 COMMON MATRIX METALLOPROTEINASES AND

Many signalling pathways activated during inflammation alter cellular metabo- THEIR SUBSTRATES
lism to support growth and survival.10 Activated cells respond to stress and
MMP FAMILY MATRIX SUBSTRATES OTHER SUBSTRATES
inflammation by increasing glucose uptake and glycolysis. This allows for
increased cellular proliferation by augmenting ATP generation and providing Collagenases Collagen I, II, III, VII, and X Pro-MMP-1, -2, -8, -9, and -13
substrates for macromolecule synthesis. Increased flux through multiple meta- Aggrecan Pro-TNF
bolic pathways has been reported in immune cells and the blood of patients Entactin α1-Proteinase inhibitors
with a variety of inflammatory conditions such as SLE, RA, ankylosing spon- Gelatin
dylitis, and gout. Tenascin
Gelatinases Aggrecan Pro-MMP-1, -2, and -13
EPIGENETIC REGULATION OF INFLAMMATION Denatured collagen Pro-TNF
Elastin Pro-IL-1β
 

Epigenetic regulation of gene expression, such as through DNA methylation

Fibronectin Latent TGF-β
or histone modification, can profoundly alter cell function.11,12 For example, Laminin
the balance of Th1 and Th2 cells by altered DNA methylation contributes to Vitronectin
risk for diseases like asthma. Aberrant DNA methylation and cell imprinting
Matrilysins Proteoglycans Pro-MMP-2 and -7
has also been observed in peripheral blood cells of patients with SLE and Denatured collagens Pro-TNF
synovial cells in RA. The genes and pathways that are modified by these epi- Entactin Membrane-bound Fas ligand (FasL)
genetic marks often involve immune pathways, such as cytokine receptor Fibrin, fibrinogen
interactions, cell adhesion, and cell migration. The disease-specific signatures Fibronectin Plasminogen
that regulate the behavior of innate and adaptive immune cells can potentially Gelatin β4 Integrins
be used to identify novel therapeutic targets and provide deeper understanding Laminin
of disease pathogenesis. Tenascin
Vitronectin
  Mechanisms of Tissue Damage in Inflammation Stromelysins Proteoglycans Pro-MMP-1, -3, -7, -8, -9, -10, and
-13
  REACTIVE OXYGEN AND NITROGEN Aggrecan
Macrophages, neutrophils, and other phagocytes generate toxic reactive oxygen Collagen III, IV, V, IX, X, Pro-TNF
intermediates (ROIs) and reactive nitrogen intermediates (RNIs) that directly and XI
kill pathogens. ROIs and RNIs also serve as signal transduction molecules Pro-IL-1β
that regulate inflammatory gene expression. Entactin Plasminogen
These molecules can also have deleterious effects on normal tissue by dam- Fibrin, fibrinogen α1-Proteinase inhibitors
aging DNA, oxidizing membrane lipids, and nitrosylating proteins. Release of Fibronectin
reactive intermediates can be initiated by microbial products, inflammatory Gelatin
Laminin
cytokines, and the engagement of Fc receptors by IgG. These events cause Tenascin
translocation of several cytosolic proteins, including Rac2 and Rho-family Vitronectin
guanosine triphosphatase (GTPase), to the membrane-bound complex carrying IL = interleukin; MMP = matrix metalloproteinase; TGF = transforming growth factor; TNF =
cytochrome c, with subsequent activation of reduced nicotinamide adenine tumor necrosis factor.
dinucleotide phosphate (NADPH) oxidase. The reaction catalyzed by NADPH
oxidase leads to superoxide production, which, in turn, increases hydrogen
peroxide, hydroxyl radicals and anions, hypochlorous acid, and chloramines.
ROIs can contribute directly to the initiation of chronic disease. Lipid oxi-
dation produces aldehydes that substitute lysine residues in apolipoprotein   Tissue Repair and Resolution of Inflammation
B-100. This altered moiety either binds to TLR2 to induce cytokine pro- Inflammation is a normal physiologic response, but can cause serious host
duction or is internalized by macrophages, leading to production of foam injury if it persists. Mechanisms are required to reestablish homeostasis once
cells and fatty streaks, the primary lesions of atherosclerosis. Subsequently, this response is initiated. Suppression of acute inflammation by removal or
altered epitopes in damaged host proteins can be presented to T cells to ini- deactivation of mediators and effector cells permits the host to repair damaged
tiate an adaptive immune response that amplifies the inflammatory vascular tissues through elaboration of appropriate growth factors and cytokines (Fig.
lesion. 42-1). As in the generation of an inflammatory response, components of reso-
Nitric oxide synthases (NOS) convert l-arginine and molecular oxygen to lution include a cellular response (apoptosis and necrosis), formation of soluble
l-citrulline and nitric oxide (NO). There are three NOS isoforms: neuronal mediators (such as anti-inflammatory cytokines and antioxidants), and pro-
NOS (ncNOS or NOS1) and endothelial cell NOS (ecNOS or NOS3) are duction of direct effectors (such as protease inhibitors).
constitutively expressed, whereas macrophage NOS (macNOS, iNOS, or
NOS2) is induced by pro-inflammatory cytokines, viral products, microbes,   DELETION OF INFLAMMATORY CELLS
and low oxygen tension and low environmental pH. Cells can be removed from an inflammatory site by several mechanisms. First,
cell influx can be decreased by suppressing chemotactic factor production
  PROTEASES AND MATRIX DAMAGE and vascular adhesion molecule expression. Second, cells, especially lympho-
Production of enzymes that degrade the extracelluar matrix (ECM) regulate cytes, can be released from the tissue and return to circulation through lym-
tissue turnover in inflammation. Matrix reconfiguration remodels damaged phatics. Third, stressed cells can undergo necrosis with the release of their
tissue, releases matrix-bound growth factors and cytokines, prepares tissue contents into the local environment. A fourth mechanism, known as autophagy,
for ingrowth of new blood vessels, and alters the local milieu to permit adher- can lead to digestion of internal organelles and ultimately cell death.
ence and retention of newly recruited cells. Perhaps the most critical and effective method for clearing cells from an
The MMPs are a family of more than 20 extracellular endopeptidases that inflammatory site is programmed cell death, or apoptosis. PMN phagocytes
participate in degradation and remodeling of the ECM (Table 42-1). They have a very short tissue half-life, and persistence or release of their contents into
are produced as pro-enzymes and require limited proteolysis or partial dena- the microenvironment after death can be deleterious. Other cells, including T
turation to expose the catalytic site. They are dependent on metal ions (zinc/ lymphocytes, undergo postactivation apoptosis to prevent an overwhelming
metzincin superfamily) for their ability to degrade ECM proteins. MMPs also persistent host response. Defective apoptosis or even persistence of apop-
cleave cell surface molecules and other pericellular nonmatrix proteins, thereby totic cells that escape clearance may contribute to chronic inflammatory and
regulating cell behavior. MMPs can alter cell growth by digesting matrix pro- autoimmune diseases.
teins associated with growth factors such as FGF and TGF-β. Matrix proteolysis Cell commitment to apoptosis is initiated by a number of factors, including
releases growth factors, making them available to cell surface receptors. MMPs ROIs in the cellular microenvironment and signaling through death receptor
also directly cleave and activate growth factors and affect cell migration by pathways (e.g., FasL/Fas and TNF-related apoptosis-inducing ligand [TRAIL]).
altering cell-matrix or cell-cell receptor sites. The former can damage DNA; if excessive, repair by tightly regulated mismatch

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 CHAPTER 42  Mechanisms of Inflammation and Tissue Repair
ECM degradation is usually initiated by collagenases, which cleave native
collagen. Denatured collagen is recognized and further degraded by gelatinases
and stromelysins. Unlike collagenases, stromelysins demonstrate broad sub-
strate specificity and act on many ECM proteins, such as proteoglycans, fibro-
nectin, laminin, and cartilage proteins. Stromelysins amplify the remodeling
process by activating collagenase through limited proteolysis.
MMP expression can be induced by many pro-inflammatory cytokines,
including TNF, IL-1, IL-17A, and IL-18, largely through the transcription
factor activator protein-1 (AP-1). AP-1 is a dimer that includes members of
the Jun and Fos families. Cytokines regulate MMP expression by activating
MAPKs, especially c-Jun amino terminal kinase ( JNK), which phosphorylates
214.e1
c-Jun and markedly enhances MMP production. NF-κB and NF-κB-like
binding sites also contribute to protease transcription.
Other proteases remodel the ECM, including serine and cysteine proteases.
High levels of active serine proteases, such as trypsin, chymotrypsin, and
elastase, are released by infiltrating PMNs at sites of inflammation and can
directly digest the ECM or activate the pro-enzyme forms of secreted MMPs.
The ADAM (a disintegrin and metalloproteinase) family can cleave the extra-
cellular domain of cytokine receptors. These ECM proteases include two
members of the aggrecanase family. Antibodies directed against aggrecanase
2 (ADAMTS5) are being explored for osteoarthritis because they decrease
cartilage destruction in mouse models of the disease.

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 CHAPTER 42  Mechanisms of Inflammation and Tissue Repair
Re-establishing homeostasis after inflammation
Inflammatory cell Anti-inflammatory
deletion mediators
Decreased Lymphocyte Anti- Cytokine
immune cell return to Necrosis inflammatory decoy
influx circulation cytokines receptors
Cytokine
Autophagy Apoptosis Prostaglandins
antagonists
FIGURE 42-1.  Mechanisms that resolve inflammation and lead to repair of the extracellular matrix. MMPs = matrix metalloproteinases.
repair mechanisms is terminated, and programmed cell death can be initiated
by genes such as the p53 tumor suppressor. The burden of mutations induced
by ROIs or RNIs in chronic inflammation can potentially accumulate over
time and lead to amino acid substitutions in regulatory proteins. Ultimately,
as has been observed in ulcerative colitis, neoplastic disease can ensue.
Although some immune cells are deleted during the resolution phase, other
cell lineages expand. Mesenchymal cells, especially fibroblasts, proliferate and
produce new matrix that can contract to form a fibrotic scar. Locally produced
growth factors such as PDGF induce DNA synthesis of these stromal cells
through activation of PI3Ks. TGF-β also stimulates fibroblast proliferation
and converts cell phenotype to matrix formation rather than destruction by
increasing collagen production and suppressing MMP expression. In addition,
mesenchymal stem cells that reside in the tissue or migrate from the peripheral
blood can differentiate into the appropriate organ-specific lineage. The plu-
ripotent cells, in the presence of the appropriate milieu, can become adipocytes,
chondrocytes, bone cells, or other terminally differentiated stromal cells.
  SOLUBLE MEDIATORS
  Anti-Inflammatory Cytokines
A variety of anti-inflammatory cytokines are released by resident and infiltrat-
ing cells. TGF-β and IL-10 are produced by macrophages, interstitial fibroblasts,
or T cells. T-cell cytokines, including IL-4, IL-10, and IL-13, suppress MMP
expression by cells stimulated by IL-1 or TNF. In addition to increasing fibro-
blast proliferation, TGF-β suppresses collagenase production, increases collagen
deposition, and decreases MMP activity by inducing production of tissue
inhibitors of metalloproteinases (TIMPs). The repair phase is abnormal in
diseases in which tissue fibrosis represents a major pathologic manifestation.
For example, scleroderma (Chapter 251) is marked by diffuse fibrosis and is
accompanied by high levels of TGF-β and increased production of ECM.
Cytokine decoy receptors also downregulate the inflammatory response.
Receptors can be shed from the cell surface after proteolytic cleavage and
absorb cytokines, preventing them from ligating functional receptors on cell
membranes. These cytokine inhibitors can be released as a coordinated attempt
to prevent unregulated inflammation, as in septic shock (Chapter 100), in
which endotoxin induces production of soluble receptors. Other cytokine-
binding proteins are produced as counter-regulatory mechanisms, including
IL-18-binding protein (IL-18BP), an Ig superfamily-related receptor that
captures IL-18. In bone remodeling, interactions of receptor activator of NF-κB
(RANK) with RANK ligand are required for osteoclast-mediated resorption.
The competitive antagonist osteoprotegerin is a member of the TNF receptor
family that binds to RANK ligand and inhibits osteoclast activation.
  Deactivation of Signaling Pathways
The signaling pathways that initiate an inflammatory response have intracellular
mechanisms to assure that the process is self-limited. Many kinases, such as
growth factor receptors and MAPKs, require post-translational modification
through phosphorylation to increase enzyme activity. A system of phospha-
tases that remove these phosphates can return the kinase to its resting form.
Multiple phosphatases, including PTP1B, suppress growth factor signaling
by dephosphorylating cell surface kinases that act as growth factor recep-
tors. Several phosphatases inhibit signaling by dephosphorylation of MAPKs.
DUSP1 dephosphorylates p38 MAPK as well as other MAPKs. DUSP1 expres-
sion is increased by p38 MAPK; thus, the very process of activating the cell
through p38 is responsible for its own counter-regulatory mechanism. NF-κB
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215
Cell Inhibitors of direct
Tissue repair
deactivation effectors
Phosphatase Mesenchymal
Collagen ↑ New matrix
inhibitory Antioxidants cell
MMPs ↓ formation
activity proliferation
Other
Protease Pluripotent cell Fibrotic scar
signaling
inhibitors differentiation formation
inhibitors
activation is typically initiated by phosphorylation of IkB, which targets it
for proteolysis.13 IkB expression later increases dramatically and stops the
signaling through this pathway. JAK-STAT signaling is inhibited by suppres-
sor of cytokine stimulation (SOCS) proteins as well as by phosphatases that
dephosphorylate JAK or STAT proteins.
  Anti-Inflammatory Prostanoids and Cyclooxygenase
COX2 induced by pro-inflammatory mediators appears early and contributes
to inflammatory responses. However, late COX2 expression suggests that it
also functions to resolve inflammation. This regulation might occur through
formation of the cyclopentenone prostaglandins (CyPG). These prostanoids
can serve as ligands for peroxisome proliferator-activated receptors (PPARs)14
(Chapter 216). There are three main classes of PPAR receptors—PPARα,
PPARβ/δ, and PPARγ—all of which bind to DNA as heterodimers in associa-
tion with the retinoid X receptor. Activation of PPARγ by CyPG is associated
with the suppression of activator protein 1 (AP-1) and STAT transcriptional
pathways in macrophages. A variety of natural and synthetic PPAR agonists
have demonstrated efficacy in models of ischemia-reperfusion injury, arthritis,
and inflammatory airway disease.
  INHIBITORS OF DIRECT EFFECTORS
  Antioxidants
Antioxidant enzymes such as catalase and superoxide dismutase inactivate
toxic intermediates. Catalase is a peroxisomal enzyme that catalyzes the con-
version of hydrogen peroxide to water and oxygen. Superoxide dismutases
(SOD) catalyze the dismutation of superoxide to hydrogen peroxide, which
is then removed by catalase or glutathione peroxidase. Glutathione peroxidases
and glutathione reductase are additional mechanisms for maintaining redox
balance and removal of toxic metabolites. Insufficient production of intracel-
lular antioxidants such as glutathione can suppress lymphocyte responses and
could account for defective T-cell receptor signaling and blunted immunity
in T cells derived from RA synovium (Chapter 248).
  Protease Inhibitors
Protease inhibitors (Table 42-2) regulate the function of endogenous proteases
and reduce the likelihood of collateral damage to tissues, and are classified as
active site inhibitors and α2-macroglobulin (α2M).15 The family of serine
protease inhibitors (SERPINs) are the most abundant members of the former
class of protease inhibitors and play a major role in regulation of blood clot
resolution and inflammation, as indicated by many of their names: antithrombin
III, plasminogen activator inhibitors 1 and 2, α2-antiplasmin, α1-antitrypsin,
and kallistatin. The latter acts by covalently linking the protease to the α2M
chain and thereby blocking access to substrates. α2M binds to all classes of
proteases and, after forming a covalent bond, conveys them to cells through
receptor-mediated endocytosis with subsequent enzymatic inactivation.
The tissue inhibitor of metalloproteinases (TIMP) family blocks the func-
tion of most MMPs. TIMPs bind to activated MMPs and irreversibly block
their catalytic sites. Examples of disease states with an unfavorable balance
between TIMPs and MMPs include loss of cartilage in arthritis and regulation
of tumor metastasis. TIMP-MMP imbalance in destructive forms of arthritis
appears to be caused by the limited production capacity for protease inhibi-
tors, which is overwhelmed by the prodigious expression of MMPs. Whereas
IL-1 and TNF induce MMPs, IL-6 and TGF-β suppress production of MMPs
and increase levels of TIMPs. Therefore, the cytokine profile has a profound
 CHAPTER 42  Mechanisms of Inflammation and Tissue Repair
Removal of apoptotic bodies is rapid and can be accomplished by macro-
phages, fibroblasts, epithelial and endothelial cells, muscle cells, and dendritic
cells. The surface receptors used in recognition and engulfment of apoptotic
cells include integrins (e.g., αvβ3), lectins, scavenger receptors, adenosine
triphosphate (ATP)-binding cassette transporter 1, LPS receptor, CD14, and
complement receptors CR3 and CR4. Some of these receptors can be used
in pro-inflammatory and apoptotic pathways, the divergence of which may
be based on differing ligands and accessory molecules. Apoptotic cells display
a series of membrane-associated molecular patterns that interact with recep-
tors on phagocytes. A general feature of apoptotic cells is loss of phospholipid
asymmetry, with external presentation of phosphatidylserine.
215.e1
Interactions of free radicals with surrounding molecules can generate sec-
ondary radical species in a self-propagating chain reaction. Chain-breaking
antioxidants are small molecules that can receive or donate an electron and
thereby form a stable byproduct with a radical. These antioxidant molecules
are categorized as either aqueous phase (vitamin C, albumin, reduced gluta-
thione) or lipid phase (vitamin E, ubiquinol-10, carotenoids, and flavonoids).
Transition metal-binding proteins (ceruloplasmin, ferritin, transferrin, and
lactoferrin) can serve as antioxidants by sequestering cationic iron and copper
and thereby inhibiting propagation of hydroxyl radicals.

At least two distinct mechanisms contribute to natural IL-1 inhibition. An

IL-1 decoy receptor (type II IL-1R) has membrane and soluble forms that
neutralize IL-1 activity. A natural IL-1 antagonist, IL-1Ra, can also bind to
functional IL-1 receptors and compete with IL-1α or IL-1β. IL-1Ra does
not transduce a signal to the cell and blocks ambient IL-1 functions. The
balance of IL-1 and IL-1Ra production depends on many influences. For
instance, monocytes produce more IL-1, whereas mature macrophages produce
IL-1Ra.

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 TABLE 42-2 COMMON PROTEASE INHIBITORS
AND THEIR TARGETS
INHIBITOR CLASS TARGET PROTEASE MECHANISM
α2-macroglobulin Pan-protease inhibitor Covalently traps protease
in irreversible,
quasi-active state;
small-molecule but not
protein substrates can
be hydrolyzed
SERPINs Serine proteases Covalently bind protease
(e.g. anti-thrombin III, (e.g. thrombin, and irreversibly distort
α1-proteinase inhibitors, plasminogen activator, active site
plasminogen activator trypsin, granzymes)
inhibitors, α2-antiplasmin,
α1-antitrypsin, kallistatin,
PI9)
TIMPs Metalloproteases Block access to protease
TIMP-1, -2, -4 MMPs active site and
TIMP-3 MMPs, ADAM and coordinate catalytic
ADAMTS proteases metal ion
Cystatins Cysteine proteases Block access to protease
(e.g. calpain) active site
XIAP Caspases Blocks substrate entry into
caspase-3 and caspase-7
active sites; sequesters
caspase-9 in
monomeric state
MMP = matrix metalloproteinase; PI9 = protease inhibitor 9; TGF = transforming growth factor;
SERPINs = serine protease inhibitors; XIAP = X-linked inhibitor of apoptosis protein.

influence on the status of remodeling. When pro-inflammatory cytokines

predominate, the balance favors matrix destruction; in the presence of pro-
inflammatory cytokine inhibitors and growth factors, matrix protein production
increases, and MMPs are inhibited by TIMPs.

  Grade A References

A1. Boyle DL, Soma K, Hodge J, et al. The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT
signalling in rheumatoid arthritis. Ann Rheum Dis. 2015;74:1311-1316.

GENERAL REFERENCES
For the General References and other additional features, please visit Expert Consult
at https://expertconsult.inkling.com.

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 CHAPTER 42  Mechanisms of Inflammation and Tissue Repair
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