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It’s time to redefine inflammation

Authors:

Abstract

Inflammation has been defined for many years as the response to tissue injury and infection. We are now forced to reconsider this definition by the avalanche of reports that molecules and cells associated with inflammation are activated or expressed in high concentration in a large variety of states in the absence of tissue injury or infection. Modest increases in concentration of C-reactive protein, a circulating marker of inflammation, have been reported to be associated with an astounding number of conditions and lifestyles felt to be associated with poor health; these conditions represent or reflect minor metabolic stresses. In recent years we have learned that inflammation is triggered by sentinel cells that monitor for tissue stress and malfunction-deviations from optimal homeostasis-and that molecules that participate in the inflammatory process play a role in restoring normal homeostasis. Accordingly, we suggest that inflammation be redefined as the innate immune response to potentially harmful stimuli such as pathogens, injury, and metabolic stress.-Antonelli, M., Kushner, I. It's time to redefine inflammation.
THE
JOURNAL REVIEW www.fasebj.org
Its time to redefine inflammation
Maria Antonelli and Irving Kushner
1
Division of Rheumatology, Case Western Reserve University at MetroHealth Medical Center, Cleveland, Ohio, USA
ABSTRACT: Inflammation has been defined for many years asthe response to tissue injury and infection. We are now
forced to reconsider this definition by the avalanche of reports that molecules and cells associated with inflam-
mation are activated or expressed in high concentration in a large variety of states in the absence of tissue injury or
infection. Modest increases in concentration of C-reactive protein, a circulating marker of inflammation, have been
reported to be associated with an astounding number of conditions and lifestyles felt to be associated with poor
health; these conditions represent or reflect minor metabolic stresses. In recent years we have learned that in-
flammation is triggered by sentinel cells that monitor for tissue stress and malfunctiondeviations from optimal
homeostasisand that molecules that participate in the inflammatory process play a role in restoring normal
homeostasis. Accordingly, we suggest that inflammation be redefined asthe innate immune response to potentially
harmful stimuli such as pathogens, injury, and metabolic stress.Antonelli, M., Kushner, I. Its time to redefine
inflammation. FASEB J. 31, 17871791 (2017). www.fasebj.org
KEY WORDS: C-reactive protein unfolded protein response homeostasis Claude Bernard innate immunity
It is becoming nearly impossible to pick up a medical or
scientific journal and not find a report that inflammation is
implicated in yet another pathologic process. Gerald
Weissmann, in an essay published in The FASEB Journal a
few years ago appropriately entitled Its complicated,
listed 12 conditions not accompanied by t he classic signs of
inflammation, for which inflammation has been held re-
sponsible (1), including atherosclerosis, obesity, depression,
Alzheimers disease, schizophrenia, and osteoporosis.
Among the conditions that can be added to this list are
asthma (2), insulin resistance (3), and type 2 diabetes (4).
Whatarewetomakeofthis?
Inflammation has always been a somewhat fuzzy,
loosely defined concept. As we suggested nearly 2 decades
ago, it is time to redefine the term inflammation(5). A
current textbook of pathology defines inflammation as a
responseto infections and damaged tissues that bring
cells and molecules of host defense from the circulation to
the sites where they are needed in order to eliminate the
offending agents(6). This definition defines inflammation
in terms of its stimulus and a limited view of its function.
Clearly, this definition is inadequate; many conditions
currently regarded as inflammatory, including those
mentioned in our first paragraph, occur without obvious
infection, damaged tissue, or an apparent offending
agent.The inflammation seen in acute gout is not trig-
gered by tissue injury or infection; nor are the auto-
inflammatory or autoimmune diseases.
We review the findings, as they have evolved through-
out history, which have led physicians to conclude that
inflammation is present; briefly survey some of the im-
mense variety of conditions that are currently felt to be
associated with inflammation; and discuss possible mech-
anisms that trigger inflammation in these conditions as
well as the presumed short and long term purposes of
the inflammatory process in different circumstances. We
conclude that there is a great variety of inflammatory
processes, if judged by stimuli, triggering mechanisms, and
functions. They differ enough that one might think it best if
they were regarded as separate entities, but it is probably
too late for that, in view of the ubiquitous use of the term
inflammationin recent years. Finally, we propose a def-
inition of inflammation, modified from that of Orozco et al.
(7), that reflects our current understanding.
HOW HAS INFLAMMATION BEEN RECOGNIZED
OVER TIME?
The term inflammation,derived from flame,owes its
name to the presence of warmth and redness, two of the
cardinal signs observed by Aulus Cornelius Celsus (ca.25
BC to ca. 50 AD)rubor (redness), tumor (swelling), calor
(warmth), and dolor (pain)in people with acute in-
flammation. Subsequently, varieties of what were called
inflammation began to be differentiated. We have long
been aware that inflammation did not always resolve, that
chronic inflammation might go on indefinitely, and that it
ABBREVIATIONS: CREBH, cyclic AMP response element-binding protein-
H; CRP, C-reactive protein; ER, endoplasmic reticulum; TLR, Toll-like
receptor; UPR, unfolded protein response
1
Correspondence: Division of Rheumatology, Case Western Reserve
University at MetroHealth Medical Center, 2500 MetroHealth
Dr., Cl ev el an d, Ohio, 44109 USA. E-mail: ixk2@case.edu
doi: 10.1096/fj.201601326R
0892-6638/17/0031-1787 © FASEB 1787
Vol.31, No.5 , pp:1787-1791, May, 2017The FASEB Journal. 174.100.218.47 to IP www.fasebj.orgDownloaded from
might take the form of persisting purulence, fibrosis, or
tissue destruction, as in abscesses or tuberculous cavities.
Thus, in a 1794 posthumous publication, A Treatise on the
Blood, Inflammation and Gunshot Wounds,thesurgeonJohn
Hunter (17281793) divided inflammation into 3 main
groups based on their gross appearance: adhesive, suppu-
rative, and ulcerative (8). Microscopy was introduced into
medicine in the middle of the 19th century, permitting
inflammation to be diagnosed histologically. It became
apparent that polymorphonuclear leukocytes were the
predominant cells involved in the early stages of acute in-
flammation, whereas cellular infiltrates largely consisted of
monocytes/macrophages and lymphocytes in chronic in-
flammation. A major change in our understanding of in-
flammation occurred during that era, when Rudolph
Virchow (18211902), the father of modern pathology, con-
cluded that there was not a single entity named in-
flammationbut rather that there were various inflammatory
processes. He differentiated 4 kinds of inflammation
exudative, infiltrative, parenchymatous, and proliferative
and stressed the importance of the inflammatory stimulus.
He unsuccessfully wrestled with the definition of in-
flammation throughout his life and even considered used a
different term, but apparently none came to mind (9).
Our understanding of the mechanisms that mediate in-
flammation has expanded and accelerated markedly since
then, most notably in the last half century, and the criteria
for concluding that inflammation is present have changed
accordingly. A large number of ancient innate immune
mechanismsthe pattern recognition molecules that signal
the need to initiate an inflammatory responsehave been
recognized. Some, such as Toll-like receptors (TLRs), rec-
ognize microorganisms (pathogen-associated molecular
patterns), and some recognize tissue injury (damage-
associated molecular patterns). Additionally, TLRs have
been found to play a role in other pathologic conditions such
as gout, in which TLR4 recognizes urate crystals. After en-
gagement of their ligands, an extraordinarily complex pro-
cess ensuesthe innate immune responseculminating in
the activation of many genes that encode the proteins that
mediate and regulate inflammation. An army of mediators
may participate, including multiple cytokines, histamine,
bradykinin, prostaglandins, leukotrienes, platelet-activating
factor, complement components, inflammasomes, and a
family of cell adhesionpromoting molecules. In addition,
circulating markers of inflammationacute phase proteins,
most notably C-reactive protein (CRP)are produced by
hepatocytes in response to circulating cytokines (10).
LOW-GRADE INFLAMMATION
As a result, we now regularly conclude that inflammation
is present when increased concentrations of the elements
of the innate immune response are found (i.e., extracellular
mediators, such as inflammatory cytokines, or activation
of intracellular mediators, such as the transcription factor
NF-kB). In addition, it is now commonly concluded that
inflammation is present when concentrations of the acute
phase protein CRP are elevated, even if only modestly.
Indeed, CRP elevation, variously defined (11), is today
regarded virtually as a synonym for inflammation. As a
result, a new, not quite official entity has arisen, variously
referred to as low-grade inflammation,”“subclinical in-
flammation,or microinflammation.Low-grade inflam-
mation is not a consequence of tissue injury or infection,
Celsuss classic signs of inflammation are not found, and
CRP levels are minimally elevated compared with those that
accompany acute inflammation after tissue injury or infec-
tion. Such modest CRP elevations (between 3 and 10 mg/L)
are found in about 30% of the American population (12).
What explains such a high prevalence of so-called low-
grade inflammation? Low-grade inflammation has been
reported to be associated with an astounding number of
conditions and lifestyles felt to be associated with poor
health; these conditions represent or reflect minor meta-
bolic stresses. The lengthy (partially cited here) list in-
cludes exposure to environmental irritants such as
cigarettes, secondhand smoke, sleep deprivation, low
levels of physical activity, atrial fibrillation, hypertension,
low birth weight, lumbar disc herniation, impaired cog-
nition, low grip strength, polycystic ovary syndrome,
living at high altitude (12, 13), prehypertension (14), ob-
structive sleep apnea (15), premenstrual symptoms (16), a
large variety of unhealthy diets (17), hypoxia (18), social
isolation (19, 20), being unmarried (21), and aging (22, 23).
QUALITY CONTROL IS ESSENTIAL TO
MAINTAIN HOMEOSTASIS
Human beings were not intelligently designed. Rather, we
were put together incrementally, building on preexisting
parts, by mutations, gene flow, genetic variation and re-
combination, in multiple steps, one might say haphaz-
ardly, over the course of millions of years. As the great
French biologist François Jacob pointed out, Nature is a
tinkerer and not an inventor: new sequences are adapted
from preexisting sequences rather than invented (24). As
one might expect in organisms that developed this way,
things do not always work smoothly. Very many quality
control mechanisms are required to prevent things from
going awry as a result of the minor perturbations, which
are part of daily life, that affect homeostasis. Thus, we have
a multitude of feedback loops, inhibitory molecules, the
unfolded protein response, heat shock proteins, etc.
Claude Bernard, the founder of experimental medicine,
brilliantly perceived that our cells live in a fairly constant
internal environmentthe milieu int´
erieur (25). Late in his
life, he came up with this sweeping but valid statement: All
of the vital mechanisms, however varied they may be, have
always but one goal, to maintain the uniformity of life in the
internal environment.At first glance, it would seem that
inflammation is an exception to Bernards sweeping state-
ment because acute inflammation is accompanied by putting
aside the normal homeostatic settings and their replacement
by new set points, the acute phase response in the broad
sense. On reflection, all of the vital mechanismsdoes in-
deedincludeinflammation.Itisapparentthattheultimate
purpose of inflammation in response to tissue injury or in-
fection is to ultimately return tissues to their normal state,
including tissue repair and regeneration, which are the an-
atomic equivalent of metabolic homeostasis; cytokines ac-
tively participate in tissue repair (26).
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It is now clear that inflammation can also be induced by
tissue stress and malfunction in the absence of infection or
overt tissue damage (27). Low-grade inflammation occurs
when changes from the optimal internal environment lead
to stressed cells. Such deviations are recognized by macro-
phages, dendritic cells, and a variety of sentinel cells that
monitor tissue homeostasis. It has recently been found that
innate lymphoid cells also play a role in assuring tissue ho-
meostasis, although the mechanisms by which they recog-
nize metabolic or dietary stress and how they affect
homeostasis are poorly defined (28). Adjustments are then
made so that the normal homeostatic state is restored. We
now know that the inflammatory response in these instances
participates in the return to the optimal homeostatic state.
INFLAMMATION PARTICIPATES IN
RESTORING HOMEOSTASIS
The unfolded protein response (UPR), an essential adaptive
intracellular signaling pathway, is an instructive example of
the quality control mechanisms that respond to metabolic
stress in order to restore homeostasis (29). The endoplasmic
reticulum (ER) is the location in the cell where one third of
all newly synthesized proteins are folded, modified, sorted,
and transported to their ultimate location. Alterations in ER
homeostasis trigger UPR pathways with the goal of re-
storing homeostasis. Many metabolic stressors can create
ER stress, including glucose deprivation, perturbations of
intraluminal calcium levels, cytokines, altered cellular re-
dox state, hypoxia, toxins, viruses, increased protein traf-
ficking, and nutrient excess or deficiency (30). In response,
general protein translation is reduced and expression of
proteins that mark the targeted proteins for degradation is
increased. Once homeostasis is restored, global mRNA
translation resumes normally to allow cell survival.
Recent studies reveal connections between the UPR and
inflammation at multiple levels (31). The UPR results in
induction of many inflammation-associated genes, in-
cluding cytokines capable of acute-phase protein in-
duction. NF-kB, a master transcriptional regulator of
inflammation, can be activated by all 3 UPR pathways. ER
stress can activate the nod-like receptor family, pyrin
domain-containing-3 complex (NLRP3) (29). Obese adipose
tissue demonstrates up-regulation of inflammatory path-
ways leading to increased expression of TNF-aand IL-6 as
well as other mediators (32). Cyclic AMP response element-
binding protein-H (CREBH), a transcription factor similar
to activating transcription factor-6 (ATF-6; one of 3 sensors
lodged in the ER membrane that trigger the UPR), acts in an
especially liver-mediated acute phase response, resulting in
transcription of the acute-phase proteins CRP and hepcidin
(3335).Inaddition,inresponsetometabolicstress,CREBH
plays a key role in maintaining lipid homeostasis by regu-
lating expression of the genes involved in hepatic lipogen-
esis, fatty acid oxidation, and lipolysis (36). Finally, calcium
released from the ER augments the production of mito-
chondrial reactive oxygen species (37).
It should not surprise us that molecules that participate
in the inflammatory process play a role in restoring normal
homeostasis. As we stated in 1998: We often forget that
boundaries between various organ systems and between
categories of functional activity are merely man-made; an
attempt to impose conceptual order on biologic phenom-
ena. There is no a priori reason why nature should respect
these boundaries(5). As Okin and Medzhitov (38) point
out, Inflammatory mediatorsact on target tissues and
alter their functional states, promoting restoration of
tissue homeostasis.Inflammatory signals can mediate
numerous variables in homeostasis systems via cytokines,
chemokines, biogenic amines, and eicosanoids (39), thus
influencing metabolism. For example, the inflammatory
cytokines TNF-aand IL-1bactivate lipolysis and inhibit
gluconeogenesis; TNF-amakes fat, liver, and skeletal
muscle less sensitive to insulin; and TNF-aand IL-1b
suppress expression of GLUT2 and glucokinase in pan-
creatic bcells, thus making them less sensitive to blood
glucose levels (39).
THE INFLAMMATORY PROCESSES AND A
PROPOSED DEFINITION
Acute and low-grade inflammation differ both pheno-
typically and in being triggered by different mechanisms
(Table 1). Acute inflammation is accompanied by the
TABLE 1. Comparison of acute, low-grade, and autoinammatory inammation
Parameter Infection Tissue injury Low-grade inammation
Autoinammatory
diseases
Cause Pathogens Trauma, tissue infarction Metabolic malfunction Usually spontaneous
Mediators Molecules and cells of the
innate immune response
Molecules and cells of
the innate immune
response
Molecules and cells of the
innate immune response
Molecules and cells
of the innate
immune response
Classic signs
of inammation
+++ +++ None +++
CRP response +++ +++ + +++
Purpose Defense healing and repair Healing and repair Restoration of homeostasis None apparent
Triggering
mechanism
Pattern recognition
molecules, notably
for PAMPs and DAMPs
Pattern recognition
molecules, notably
for DAMPs
Sentinel cells that
monitor for tissue
stress, notably the UPR
Genetically based
dysregulation
DAMP, damage-associated molecular patterns; PAMP, pathogen-associated molecular pattern. Plus symbols indicate magnitude.
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classic signs of rubor, calor, tumor, dolor, and a substantial
acute phase protein response and has the immediate goal
of removing offending agents, removing necrotic tissue, and
restoring tissue integrity. Acute inflammation in response to
infection and tissue injury is triggered by pattern recogni-
tion molecules. In contrast, low-grade inflammation is not
accompanied by the classic signs of inflammation and
manifests a modest (at best) acute phase protein response.
Low-grade inflammation is triggered by sentinel cells that
monitor for tissue stress and malfunction, which are devia-
tions from the optimal homeostatic state. What do acute and
low-grade inflammation have in common? They share
many of the same effector molecules and cells and have the
same ultimate goal of restoring the normal, optimal ho-
meostatic state. We now know that acute gouty attacks are
triggered by binding of urate crystals to TLR4 (40). Yet an-
other species of inflammation, that seen in autoinflammatory
diseases, results from genetically based dysregulation of
suppressive components of the inflammatory response that
result in purposeless episodes of inflammation. Acute flares
of autoinflammatory diseases are usually not precipitated by
external stimuli. Autoimmune diseases may be regarded as a
variety of tissue injury in which the stimulus persists for
extended periods.
The boundary between normal adaptive homeostatic ad-
justments and inflammation is indistinct. It appears that there
is no sharp boundary between normal, quotidian adaptive,
homeostasis-restoring processes and inflammation. At what
pointdoweconcludethatitispathologicthat it is in-
flammationas we have understood it?
Inlightofthesesignificantdifferences, perhaps it would
be best if acute inflammation and low-grade inflammation
were regarded as separate entities. Indeed, the differences
between these entities are striking enough so that two lead-
ing investigators in the field have suggested a distinct no-
menclature for the latter state; both para-inflammationand
metaflammation(metabolically triggered inflammation)
have been proposed (30, 41). But it is probably too late; the
proverbial train seems to have already left the station. We
recognize that words have a range of meanings that change
with the times. In any case, if low-grade inflammationis to
be accepted as belonging in the inflammationcategory,
then a redefinition of inflammation is called for. We propose
a formulation modified from that used by Orozco et al.(7):
Inflammation is the innate immune response to harmful
stimuli such as pathogens, injury and metabolic stress.The
ultimate function of inflammation,inanycase,istorestore
the optimal homeostatic state, as, per Claude Bernard, is true
of all the bodys mechanisms.
ACKNOWLEDGMENTS
The authors thank David Samols, Nathan Berger, Stanley
Ballou, and Gary Kammer (Case Western Reserve University)
and John Volanakis (University of Alabama at Birmingham,
Birmingham, AL, USA) for helpful suggestions.
AUTHOR CONTRIBUTIONS
M. Antonelli and I. Kushner wrote and edited the
manuscript.
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Received for publication December 12, 2016.
Accepted for publication January 17, 2017.
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10.1096/fj.201601326RAccess the most recent version at doi:
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Maria Antonelli and Irving Kushner
It's time to redefine inflammation
References
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Vol.31, No.5 , pp:1787-1791, May, 2017The FASEB Journal. 174.100.218.47 to IP www.fasebj.orgDownloaded from
... Recent findings on inflammation show that particular pathologies are mediated by inflammatory responses defined as LGI or "chronic low-grade inflammation" [48][49][50][51][52]. Medzhitov [37] suggests that certain chronic pathologies, such as type 2 diabetes and cardiovascular diseases, and, in particular, atherosclerosis could not be caused by the well-known mechanism of inflammation. ...
... To confirm the role and characteristics of LGI, Antonelli et al. [52] specify that the dynamics of this type of inflammation differ from a normal inflammatory condition. In the latter, there is a high concentration of the elements of the innate immune response (inflammatory cytokines), associated with high levels of C-reactive protein (CRP) (Figure 2A). ...
... According to a recent study [52], when changes in the internal environment lead to cellular stress (metabolic stress, injury, and pathogens), LGI manifests itself as an innate immune response. ...
Article
Over the years, several authors have discussed the possibility of considering somatic dysfunction (SD) as a “nosological element” detectable on palpation. There are many aspects to consider regarding the etiology and diagnosis of SD, and the literature on osteopathic issues provides details on physiological signs that characterize it, including tissue texture changes. Recent knowledge suggests that how tissue and, in particular, connective tissue, responds to osteopathic treatment may depend on the modulation of the inflammation degree. Low-grade inflammation (LGI) may act on the extracellular matrix (ECM) and on cellular elements; and these mechanisms may be mediated by biological water. With its molecules organized in structures called exclusion zones (EZ), water could explain the functioning of both healthy and injured tissues, and how they can respond to osteopathic treatment with possible EZ normalization as a result. The relationship between inflammation and DS and the mechanisms involved are described by several authors; however, this review suggests a new model relating to the characteristics of DS and to its clinical implications by linking to LGI. Tissue alterations detectable by osteopathic palpation would be mediated by body fluids and in particular by biological water which has well-defined biophysical characteristics. Research in this area is certainly still to be explored, but our suggestion seems plausible to explain many dynamics related to osteopathic treatment. We believe that this could open up a fascinating scenario of therapeutic possibilities and knowledge in the future.
... Therefore, inflammation is a protective process which occur in response to injury. In general, inflammation is not a disease but a symptom of a disease resulting from an inflammatory mediator's activity (Antonelli and Kushner, 2017;Chen et al. 2018;Bennett et al. 2018). Several diseases begin with inflammatory response at the initial stage and these include; syphilis, tuberculosis, leprosy, scleroma, cancer etc (Antonelli and Kushner, 2017;Chen et al. 2018;Bennett et al. 2018). ...
... In general, inflammation is not a disease but a symptom of a disease resulting from an inflammatory mediator's activity (Antonelli and Kushner, 2017;Chen et al. 2018;Bennett et al. 2018). Several diseases begin with inflammatory response at the initial stage and these include; syphilis, tuberculosis, leprosy, scleroma, cancer etc (Antonelli and Kushner, 2017;Chen et al. 2018;Bennett et al. 2018). There are a number of agents that trigger inflammation such as bacteria, viruses, change in temperature, injury, drugs, immunological disorders and metabolic disorders (Chen et al. 2018;Bennett et al. 2018). ...
... There are a number of agents that trigger inflammation such as bacteria, viruses, change in temperature, injury, drugs, immunological disorders and metabolic disorders (Chen et al. 2018;Bennett et al. 2018). After cell injury, the brain usually responds to cell damage by directing the release of a number of local inflammatory mediators such as interleukin-1β (IL-1β), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), bradykinin, prostaglandins, leukotrienes, platelet-activating factor, which eventually cause inflammation (Antonelli and Kushner, 2017;Chen et al. 2018;Bennett et al. 2018). In the presence of inflammatory stimulus, phospholipase A2 converts phospholipid to arachidonic acid which is subsequently converted to endoperoxides in the presence of cyclooxiginase enzymes. ...
... While much factual knowledge was accrued regarding clinical (bedside), histological, and molecular components of the inflammatory response, there remains no established unifying concept relating these components. No concise definition of inflammation has been established (Kushner, 1998;Groopman, 2015;Antonelli and Kushner, 2017). In addition to uncovering what regularities lie at the heart of inflammation, there is need to unify notions of local and systemic inflammation so they can be understood as manifestations of a single process. ...
... Confusion about inflammation has been noted and reviewed by Groopman (2015), in the FASEB Journal by Weissmann (2010) and later by Antonelli and Kushner (2017). There seems to be little agreement on what comprises inflammation other than association with innate immune antimicrobial activity, where innate immunity refers to host antipathogen function that does not require prior exposure to pathogen. ...
Article
Full-text available
Sepsis is infection sufficient to cause illness in the infected host, and more severe forms of sepsis can result in organ malfunction or death. Severe forms of Coronavirus disease-2019 (COVID-19), or disease following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are examples of sepsis. Following infection, sepsis is thought to result from excessive inflammation generated in the infected host, also referred to as a cytokine storm. Sepsis can result in organ malfunction or death. Since COVID-19 is an example of sepsis, the hyperinflammation concept has influenced scientific investigation and treatment approaches to COVID-19. However, decades of laboratory study and more than 100 clinical trials designed to quell inflammation have failed to reduce sepsis mortality. We examine theoretical support underlying widespread belief that hyperinflammation or cytokine storm causes sepsis. Our analysis shows substantial weakness of the hyperinflammation approach to sepsis that includes conceptual confusion and failure to establish a cause-and-effect relationship between hyperinflammation and sepsis. We conclude that anti-inflammation approaches to sepsis therapy have little chance of future success. Therefore, anti-inflammation approaches to treat COVID-19 are likewise at high risk for failure. We find persistence of the cytokine storm concept in sepsis perplexing. Although treatment approaches based on the hyperinflammation concept of pathogenesis have failed, the concept has shown remarkable resilience and appears to be unfalsifiable. An approach to understanding this resilience is to consider the hyperinflammation or cytokine storm concept an example of a scientific paradigm. Thomas Kuhn developed the idea that paradigms generate rules of investigation that both shape and restrict scientific progress. Intrinsic features of scientific paradigms include resistance to falsification in the face of contradictory data and inability of experimentation to generate alternatives to a failing paradigm. We call for rejection of the concept that hyperinflammation or cytokine storm causes sepsis. Using the hyperinflammation or cytokine storm paradigm to guide COVID-19 treatments is likewise unlikely to provide progress. Resources should be redirected to more promising avenues of investigation and treatment.
... Obesity, aging, tobacco use, physical inactivity, and unhealthy diets are considered the main risk factors for LGCI. These physiologic, environmental, and/or behavioral stimuli modify the cellular homeostasis, leading to cell stress and to the production of cytokines (3,4,7). ...
Article
Full-text available
Low-grade chronic inflammation (LGCI) is a common feature of non-communicable diseases. Cytokines play a crucial role in LGCI. This study aimed to assess how LGCI risk factors [e.g., age, body mass index (BMI), smoke, physical activity, and diet] may impact on specific cytokine levels in a healthy population. In total, 150 healthy volunteers were recruited and subjected to questionnaires about the last 7-day lifestyle, including smoking habit, physical activity, and food frequency. A panel of circulating cytokines, chemokines, and growth factors was analyzed by multiplex ELISA. BMI showed the heaviest impact on the correlation between LGCI-related risk factors and cytokines and was significantly associated with CRP levels. Aging was characterized by an increase in IL-1b, eotaxin, MCP-1, and MIP-1α. Smoking was related to higher levels of IL-1b and CCL5/RANTES, while physical activity was related to MIP-1α. Within the different eating habits, CRP levels were modulated by eggs, red meat, shelled fruits, and greens consumption; however, these associations were not confirmed in a multivariate model after adjusting for BMI. Nevertheless, red meat consumption was associated with an inflammatory pattern, characterized by an increase in IL-6 and IL-8. IL-8 levels were also increased with the frequent intake of sweets, while a higher intake of shelled fruits correlated with lower levels of IL-6. Moreover, IL-6 and IL-8 formed a cluster that also included IL-1b and TNF-α. In conclusion, age, BMI, smoke, physical activity, and dietary habits are associated with specific cytokines that may represent potential markers for LGCI.
... The term "inflammation," derived from "flame," owes its name to the presence of warmth and redness [154] . Inflammation is a complex biological response to tissue injury or pathogens and protects body against microorganism or tissue damage [155] . ...
Article
Pyrazolone is a well-known influential synthon for the synthesis of many molecules which hold remarkable potential in the advancement of functional materials, coordination chemistry, and pharmaceutical chemistry. Taking the advantage of diversity as well as multiple active sites of starting materials, a number of effective methods for synthesizing different pyrazolone compounds have been effectively established over the last few years. The chemistry of pyrazolone derivatives have attracted interests due to their diverse pharmacological functions such as analgesic, anti-inflammatory, anti-cancer, antibacterial, antifungal, anti-oxidant, anti-diabetic, anti-viral, anti-proliferative and many other biological activities. This review article provides an overview of this field, with the aim of highlighting the remarkable achievements that have been made with the multiple reaction sites of different pyrazolone synthons and the synthetic strategies for existing and novel pyrazolone derivatives. In addition, chemical synthetic schemes, important mechanisms, structure activity relationships (SAR) and promising biological investigations relating to the corresponding products are also discussed.
... As L. luisieri and L. pedunculata are used in traditional medicine to treat several conditions that share an inflammatory component, the present study aimed to validate the anti-inflammatory potential of these species considering their high chemical variability [7,8], which can affect oil quality and compromise both safety and bioactivity profiles. Inflammation is considered an important mechanism that maintains homeostasis, regardless of whether the insult is exogenous, as in the case of infections, or endogenous, as occurs, for instance, in metabolic disorders [34]. During this process, the first line of defense is provided by macrophages, which in the presence of a Toll-like receptor agonist such as microbial LPS, produce several pro-inflammatory mediators, including NO, COX-2, prostaglandins and cytokines, such as IL-1β [35]. ...
Article
Full-text available
Portuguese lavenders remain undervalued in global markets due to the lack of high-quality end-products and scarcity of scientific-based studies validating their bioactive potential. Moreover, chemical variability is frequent in these species, and can compromise both safety and efficacy. In the present study, the anti-inflammatory potential of L. luisieri and L. pedunculata, two highly prevalent species in Portugal, was assessed and correlated with their chemical variability. Representative samples with distinct chemical profiles were selected to assess the anti-inflammatory effect on LPS-stimulated macrophages. L. luisieri essential oil with low quantities of necrodane derivatives was the most potent at inhibiting NO production. Interestingly, the essential oil was more effective than its main compounds (1,8-cineole and fenchone), assessed alone or in combination. Our results also demonstrated a significant effect of the oil on the expression of the inflammatory proteins (iNOS and pro-IL-1β) and on the NF-κB pathway. Overall, this study highlights the impact of chemical variability on oils’ efficacy by showing distinct effects among the chemotypes. We also identify L. luisieri essential oil, which has low quantities of necrodane derivatives, as the most promising in mitigation of the inflammatory response, thus corroborating its traditional uses and paving the way for the development of herbal medicinal products.
... We report a significant inverse relationship between O3I and NLR. By excluding individuals with CRP >3 mg/L, we could examine the O3I-NLR relationship in individuals without any evidence of tissue injury, infection, or systemic acute inflammation [57,58], i.e. a cohort suitable for deriving O3I standards on which Dietary Reference Intakes (DRIs) could be developed for planning and assessing EPA+DHA intakes of healthy people. NLR values measured in this cohort ( Table 1) were similar to those measured in healthy adults globally [8,24,[59][60][61][62][63]. ...
Article
The neutrophil-lymphocyte ratio (NLR) is a biomarker of systemic inflammation and measures innate-adaptive immune system balance. The omega-3-index (O3I) measures the amount of EPA+DHA in blood. Both a low O3I and an elevated NLR are associated with increased risk for chronic disease and mortality, including cardiovascular diseases and cancer. Hypothesizing that low O3I may partly contribute to systemic chronic inflammation, we asked if a relationship existed between O3I and NLR in healthy adults (≥18y, n=28,871, 51% female) without inflammation [C-reactive protein (CRP) <3mg/mL)] who underwent a routine clinical assessment. NLR was inversely associated with O3I before (p<0.0001) and after adjusting for age, sex, BMI, and CRP (p<0.0001). Pearson correlations of other variables with NLR were r=0.06 (CRP), r=0.14 (age), and r=0.01(BMI). In this healthy population, an O3I <6.6% was associated with increasing NLR whereas NLR remained relatively constant (low) when O3I >6.6%, suggestive of a quiescent, balanced immune system.
... In most laboratories in Europe, for routine detection of CRP, the cut-off defining an abnormal level is set at 5 or 10 mg/L. However, for estimation of CVD risk, a 'high-sensitivity' CRP assay is usually applied [13,14]. At Linköping University Hospital (Sweden), the lower limit of quantification for this high-sensitivity CRP assay is 0.15 mg/L. ...
Article
Full-text available
C-reactive protein (CRP) is well-known as a sensitive albeit unspecific biomarker of inflammation. In most rheumatic conditions, the level of this evolutionarily highly conserved pattern recognition molecule conveys reliable information regarding the degree of ongoing inflammation, driven mainly by interleukin-6. However, the underlying causes of increased CRP levels are numerous, including both infections and malignancies. In addition, low to moderate increases in CRP predict subsequent cardiovascular events, often occurring years later, in patients with angina and in healthy individuals. However, autoimmune diseases characterized by the Type I interferon gene signature (e.g., systemic lupus erythematosus, primary Sjögren’s syndrome and inflammatory myopathies) represent exceptions to the general rule that the concentrations of CRP correlate with the extent and severity of inflammation. In fact, adequate levels of CRP can be beneficial in autoimmune conditions, in that they contribute to efficient clearance of cell remnants and immune complexes through complement activation/modulation, opsonization and phagocytosis. Furthermore, emerging data indicate that CRP constitutes an autoantigen in systemic lupus erythematosus. At the same time, the increased risks of cardiovascular and cerebrovascular diseases in patients diagnosed with systemic lupus erythematosus and rheumatoid arthritis are well-established, with significant impacts on quality of life, accrual of organ damage, and premature mortality. This review describes CRP-mediated biological effects and the regulation of CRP release in relation to aspects of cardiovascular disease and mechanisms of autoimmunity, with particular focus on systemic lupus erythematosus.
... A controversy exists about inflammation definition (Netea et al., 2017). One of the latest definitions was about the "innate immune response to potentially harmful stimuli such as pathogens, injury, and metabolic stress" (Antonelli & Kushner, 2017). Several cytokines including (but not limited) leptin, interleukin 6 (IL-6), TNF-α, adipsin, resistin and angiotensinogen/protein activator inhibitor 1 (PAI-1) and adiponectin are recognized as mediators of inflammation (Rodríguez-Pérez et al., 2019). ...
Chapter
Moringa oleifera (MO) Lam is an useful tree that have been traditionally employed for nutritional, medicinal and industrial purposes. Apart from its high-quality nutritional value, it is rich in bioactive compounds such as phenolic compounds, stilbenes, curcuminoids, lignans, glucosinolates, carotenoids, tocopherols and phytosterols, among others coming from different MO parts, for example, leaves, seeds, roots, flowers barks, or pods. Indeed, its composition in bioactive compounds confers its medicinal properties and makes this tree a high valuable crop for commercial and pharmacological uses. This book chapter encompasses a full-composition of all MO parts in bioactive compounds and summarizes the most recent evidence of the antioxidative and antiinflammatory activities of MO in vivo.
Article
Background and aim Raloxifene treatment has been reported to be associated with cardiovascular benefits if prescribed to women during the postmenopausal period. However, a final conclusion regarding this hypothesis has not yet been achieved. We conducted a systematic review and meta-analysis to evaluate the effect of raloxifene on the endothelial function and inflammation in postmenopausal women. Methods We systematically searched the following 4 databases from inception to 23 January 2021 without any language restrictions: Web of Science, PubMed/Medline, Embase and Scopus. The eligible randomized controlled trials (RCTs) reporting the effects of raloxifene on the flow-mediated dilatation (FMD), C-reactive protein (CRP), carotid intima-media thickness (CIMT), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and E-selectin levels, were included in the final meta-analysis. Results A total of 16 RCTs were included in the final analysis. Raloxifene administration had no significant effect on ICAM-1 and E-selectin levels. However, we observed a decrease of the CIMT (WMD: −0.071 mm, 95% CI: −0.09 to −0.04, P = 0.000), CRP (WMD: −0.342 mg/L, 95% CI: −0.591, −0.094, p = 0.007), and VCAM-1 (WMD: −197.90 mg/L, 95% CI: −269.58 to −126.23, P = 0.000) levels in the intervention versus control groups following the prescription of this pharmacological agent. Moreover, raloxifene treatment resulted in a significant elevation of the FMD (WMD: 1.64%, 95% CI: 0.46 to 2.81, P = 0.006), particularly if the intervention was equal to or exceeded 12 weeks. Conclusion Raloxifene might emerge as a potential therapeutic option in the management of endothelial dysfunction and inflammation in postmenopausal women.
Article
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Deposition of crystallized monosodium urate (MSU) in joints as a result of hyperuricemia is a central risk factor for gout. However other factors must exist that control the progression from hyperuricaemia to gout. A previous genetic association study has implicated the toll-like receptor 4 (TLR4) which activates the NLRP3 inflammasome via the nuclear factor-κB signaling pathway upon stimulation by MSU crystals. The T-allele of single nucleotide polymorphism rs2149356 in TLR4 is a risk factor associated with gout in a Chinese study. Our aim was to replicate this observation in participants of European and New Zealand Polynesian (Māori and Pacific) ancestry. A total of 2250 clinically-ascertained prevalent gout cases and 13925 controls were used. Non-clinically-ascertained incident gout cases and controls from the Health Professional Follow-up (HPFS) and Nurses Health Studies (NHS) were also used. Genotypes were derived from genome-wide genotype data or directly obtained using Taqman. Logistic regression analysis was done including age, sex, diuretic exposure and ancestry as covariates as appropriate. The T-allele increased the risk of gout in the clinically-ascertained European samples (OR = 1.12, P = 0.012) and decreased the risk of gout in Polynesians (OR = 0.80, P = 0.011). There was no evidence for association in the HPFS or NHS sample sets. In conclusion TLR4 SNP rs2143956 associates with gout risk in prevalent clinically-ascertained gout in Europeans, in a direction consistent with previously published results in Han Chinese. However, with an opposite direction of association in Polynesians and no evidence for association in a non-clinically-ascertained incident gout cohort this variant should be analysed in other international gout genetic data sets to determine if there is genuine evidence for association.
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It is unclear whether obstructive sleep apnea (OSA) is independently associated with increased levels of the acute-phase reactant C-reactive protein (CRP). The purpose of this study was to evaluate the relationship between OSA and high-sensitivity CRP (hs-CRP) levels according to the presence or absence of metabolic syndrome (MetS). This study recruited 245 male bus drivers from one transportation company in Taiwan. Each participant was evaluated by a polysomnography (PSG) test, blood lipids examination, and hs-CRP. Severity of OSA was categorized according to the apnea-hypopnea index (AHI). Subjects were categorized into severe OSA group (n = 44; 17.9 %), moderate and mild OSA group (n = 117; 47.8 %), and non-OSA group (n = 84; 34.3 %). AHI had a significant association with hs-CRP (β = 0.125, p = 0.009) adjusting for age, smoking, drinking, and MetS status. Hs-CRP was elevated with severe OSA (β = 0.533, p = 0.005) even adjusting for BMI and MetS. Moreover, there was an independent effect for adjusted odds ratios (AORs) between the stratification of the severity for OSA and MetS. Elevated hs-CRP level is associated with severe OSA, independent of known confounders. The effect of OSA in CRP is independent of MetS was identified.
Article
Background: About 80% of women experience premenstrual symptoms (PMSx), and about 50% of women seek medical care for them, posing a large medical care burden. However, despite women's use of anti-inflammatory agents for relief from these symptoms, and the fact that anti-inflammatory agents provide relief from some PMSx, the relationship of inflammation to PMSx has not been well investigated. Methods: We, therefore, undertook the present cross-sectional analyses using baseline data from the longitudinal Study of Women's Health Across the Nation (SWAN), a racially/ethnically diverse cohort of midlife women (n = 2939), to determine if a biomarker of inflammation, high-sensitivity C-reactive protein (hs-CRP), was associated with PMSx. We performed factor analyses with Varimax rotations to determine five groupings of eight symptoms to develop a parsimonious set of outcome variables. We conducted backward stepwise multiple logistic regression models for each grouping, eliminating non-significant (p > 0.05) covariates. Results: Having an hs-CRP level >3 mg/L was significantly positively associated with premenstrual mood symptoms (adjusted odds ratio [aOR] = 1.27, 95% confidence interval [95% CI] 1.02-1.58), abdominal cramps/back pain (aOR = 1.40, 95% CI 1.09-1.80), appetite cravings/weight gain/bloating (aOR = 1.41, 95% CI 1.04-1.89), and breast pain (aOR = 1.26, 95% CI 1.02-1.55). Elevated hs-CRP level was not associated with premenstrual headaches or reporting three or more PMSx. Conclusions: The significant relationships of specific groups of PMSx with elevated hs-CRP levels have potential clinical implications for treatment and possibly for prevention by advising women about the factors associated with inflammation and the potential for treatment with anti-inflammatory agents.
Article
Inflammation underlies many chronic and degenerative diseases, but it also mitigates infections, clears damaged cells and initiates tissue repair. Many of the mechanisms that link inflammation to damage repair and regeneration in mammals are conserved in lower organisms, indicating that it is an evolutionarily important process. Recent insights have shed light on the cellular and molecular processes through which conventional inflammatory cytokines and Wnt factors control mammalian tissue repair and regeneration. This is particularly important for regeneration in the gastrointestinal system, especially for intestine and liver tissues in which aberrant and deregulated repair results in severe pathologies.
Article
In eukaryotic cells, the endoplasmic reticulum is essential for the folding and trafficking of proteins that enter the secretory pathway. Environmental insults or increased protein synthesis often lead to protein misfolding in the organelle, the accumulation of misfolded or unfolded proteins - known as endoplasmic reticulum stress - and the activation of the adaptive unfolded protein response to restore homeostasis. If protein misfolding is not resolved, cells die. Endoplasmic reticulum stress and activation of the unfolded protein response help to determine cell fate and function. Furthermore, endoplasmic reticulum stress contributes to the aetiology of many human diseases.
Article
Even though several studies have implicated the role of inflammation in the pathogenesis of hypertension and other cardiovascular disease, there are only limited studies about inflammatory markers in prehypertension. The objective of the present article was to review the role of markers like C-reactive protein, interleukin-6, tumor necrosis factor-α and sialic acid in prehypertension. An extensive literature search was made in Pubmed (http://www.ncbi.nlm.nih.gov/pubmed/) using phrases such as prehypertension, inflammation, C-reactive protein, cardiovascular disease, cytokines and sialic acid. Several investigators have reported increased inflammatory markers like C-reactive protein, interleukin-6, tumor necrosis factor-α and sialic acid in prehypertension indicating the role of inflammation in the pathogenesis of prehypertension and its complications. Elevated inflammatory markers may enhance the risk for cardiovascular disease in subjects with prehypertension.