The inflammatory response is central to effectively dealing with invasive infectious
agents (bacteria, viruses, and protozoa) as well as in the setting of tissue and organ
“sterile” injury (eg, ischemia-reperfusion injury, hemorrhagic shock, nonpenetrating
trauma, and so forth) and in repair of damaged tissues. With infectious agents, activation
of the acute inflammatory response occurs via the innate immune system, featuring
local buildup of neutrophils (polymorphonuclear leukocytes [PMNs]) from the bone marrow
and blood, as well as accumulation of blood mononuclear cells, which migrate into
extravascular sites and mature into tissue macrophages. The emergence of new technologies
for more than the past many decades has propelled research into the inflammatory response
along many new directions. These new technologies include mass spectroscopy and related
technologies, cloning and expression of peptides, new methods to rapidly purify peptides,
proteins and lipids, and breakthrough technologies for sequencing of proteins, DNA,
and RNA as well as their “editing.” The appearance of molecular biology along with
the ability to clone and express purified peptides has allowed access to products
that are homogenous and not contaminated with substances that could cause experimental
artifacts. In the current issue, there is a wide range of mechanisms that can be linked
to inflammatory injury. The heme oxygenase pathway generates carbon monoxide, which
together with nitric oxide has been used in humans to suppress lung inflammatory responses.
1
Products of tryptophan metabolism may amplify inflammatory responses.
2
Various anti-inflammatory strategies have been used to treat chronic obstructive
pulmonary disease and asthmatic conditions.
3
Several years ago, it was discovered that C-C chemokine receptor type 5 (CCR5) and
C-X-C chemokine receptor type 4 (CXCR4) play key roles in entry of human immunodeficiency
virus (HIV) into CD4+ T cells.
4
,
5
Part of this discovery process was related to mutations occurring in CCR5 of humans,
which impaired entry of HIV into T cells. Numerous synthetic inhibitors of CCR5 have
been developed, which impair HIV entry into T cells, and some have been approved by
the Food and Drug Administration (FDA) for clinical application. On the basis of this
type of strategy, chemokine receptor antagonists may find application in the area
of inflammatory diseases, such as inflammatory bowel disease, for which there is a
dearth of clinically effective anti-inflammatory drugs. The “metabolic syndrome” can
be manipulated by targeting the inflammatory system, including the NLR family, pyrin
domain containing 3 (NLRP3) inflammasome.
6
Even in sickle cell disease, inflammatory targets have been suggested.
7
Anti-inflammatory interventions after immune reconstitution in humans after bone
marrow transplantation may provide clinically desirable outcomes.
8
It is also clear that in acute lung injury both in mice and in humans, new targets
(histones) have been suggested.
9
Similar strategies may be used in type I diabetes,
10
chronic renal disease,
11
graft-vs-host disease,
12
and in acute ischemic injury involving the heart.
13
Another poorly understood condition is nonalcoholic fatty liver disease, which may
be emerging to be the most prevalent liver disease, with increased risk of liver-related
and cardiovascular-related mortality.
14
As this disease progresses, inflammation and fibrotic changes in liver appear and
engagement of toll-like receptors may be linked to cytokine production by hepatocytes.
Obviously, much more information is needed before a rational therapeutic approach
can be considered. There are many new review articles describing numerous inhibitors
and neutralizing monoclonal antibodies (mAbs) that block complement activation products, cytokines, or chemokines, to treat
various inflammatory conditions.
15
,
16
,
17
,
18
The relationship between obesity, insulin-resistance, and pancreatic β cell dysfunction
suggests a linkage between cytokine release from adipocytes and residential macrophages
and signaling pathways activated by the cytokines, which all result in eventual apoptosis
of pancreatic β cells and onset of type 2 diabetes.
19
Assuming these pathways cause the diabetic condition, it may be possible to intervene
early on with targeted anti-inflammatory interventions.To read this article in full you will need to make a payment
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Article info
Publication history
Published online: August 13, 2015
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© 2016 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
