Hyaluronan fragments produced during tissue injury: A signal amplifying the inflammatory response

Trimethylamine N-oxide (TMAO), a metabolite of gut microbiota, is involved in the regulation of lipid metabolism and inflammatory response; however, the role of TMAO in hyperlipidemia acute pancreatitis (HAP) is not clear. In this study, HAP mice were used as an animal model to explore the effects and possible mechanism of TMAO on HAP, which may provide new ideas for the treatment of HAP. Results found that the levels of triglycerides, total cholesterol, low-density lipoprotein cholesterol, nonestesterified fatty acid, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, α-amylase, TMAO, and flavin-containing monooxygenase 3 were significantly increased, the levels of high-density lipoprotein cholesterol and insulin were significantly decreased, and there was an obvious pancreatic injury and inflammatory response in the model group. The choline analogue 3,3-dimethyl-1-butanol (DMB) treatment reversed the changes of serum biochemical parameters, alleviated the pancreatic tissue injury, and reduced the levels of inflammatory cytokines. Further studies of toll-like receptor (TLR)/p-glycoprotein 65 (p65) pathway found that the expressions of TLR2, TLR4, and p-p65/p65 in the model group were significantly increased, which was more obvious after Escherichia coli (Migula) Castellani & Chalmers treatment, while activation of the TLR/p65 pathway was inhibited by DMB. The results indicated that TMAO promotes HAP by promoting inflammatory response through TLR/p65 signaling pathway, suggesting that TMAO may be a potential target of HAP.

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Sepsis Syndrome

The Brigham Intensive Review of Internal Medicine ◽

10.1093/med/9780199358274.003.0039 ◽

2014 ◽

pp. 395-402

Author(s):

Joshua A. Englert ◽

Rebecca Marlene Baron

Keyword(s):

Immune System ◽

Inflammatory Response ◽

Innate Immune System ◽

Tissue Injury ◽

Treatment Strategies ◽

Sepsis Syndrome ◽

Clinical Syndrome ◽

High Morbidity ◽

Early Management ◽

Inflammatory State

Sepsis is a clinical syndrome characterized by systemic inflammation leading to tissue injury that arises as a complication of an infection. According to current paradigms, sepsis arises as a result of the infection of a normally sterile body compartment. Infection leads to activation of the innate immune system to produce a systemic inflammatory response. This response is a necessary component of the body's defense against infection under normal conditions, but it is the lack of regulation of this response that is central to the pathogenesis of sepsis. As discussed in more detail below, this dysregulated inflammatory state can lead to tissue injury and dysfunction in organs not involved in the original infectious insult. Although sepsis remains a condition with exceedingly high morbidity and mortality, recent early management and treatment strategies have demonstrated exciting improvements in overall outcomes.

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Sepsis Syndrome

Mayo Clinic Infectious Diseases Board Review ◽

10.1093/med/9780199827626.003.0027 ◽

2012 ◽

pp. 274-279

Author(s):

Andrew D Badley

Keyword(s):

Systemic Inflammatory Response Syndrome ◽

Inflammatory Response ◽

Physical Examination ◽

Supportive Care ◽

Tissue Injury ◽

Tissue Perfusion ◽

Sepsis Syndrome ◽

Systemic Response ◽

Immune Mediated ◽

Patient’S History

Systemic inflammatory response syndrome (SIRS) is the specific host systemic response that may be elicited by various stimuli, including infection, burns, pancreatitis, ischemia, trauma, hemorrhage, immune-mediated tissue injury, and exogenous stimuli. 2. Sepsis is SIRS resulting from infection. Sepsis syndrome is sepsis with altered tissue perfusion of vital organs (resulting in oliguria, hypoxemia, elevated levels of lactate, or altered mentation or any combination of these conditions) When a patient has SIRS, the objective is to define its cause. If SIRS is caused by infection, appropriate antibiotics must be administered and supportive care guided by the patient's history and physical examination.

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Repair and recovery mechanisms following critical illness

10.1093/med/9780199600830.003.0309 ◽

2016 ◽

Author(s):

Geoffrey Bellingan ◽

Brijesh V. Patel

Keyword(s):

Critical Illness ◽

Inflammatory Response ◽

Inflammatory Responses ◽

Tissue Injury ◽

Structure And Function ◽

Tissue Structure ◽

Inflammatory Activation ◽

Recovery Mechanisms ◽

And Function

Inflammation is the beneficial host response to foreign challenge or tissue injury that ultimately leads to the restoration of tissue structure and function. Critical illness is associated with an overwhelming and prolonged inflammatory activation. Resolution of the inflammatory response is an active process that requires removal of the inciting stimuli, cessation of the pro-inflammatory response, a timely coordinated removal of tissue leukocyte infiltration, a conversion from ‘toxic’ to reparative tissue environment, and restoration of normal tissue structure and function. Mortality may result from deficits in these resolution mechanisms. Improved delivery of critical care through prevention of harm and removal of stimuli has already delivered significant mortality benefits. Most critically-ill patients present with uncontrolled inflammation, hence anti-inflammatory strategies ameliorating this response are likely to be too late and thus futile. Rather, strategies augmenting endogenous pathways involved in the control and appropriate curtailment of such inflammatory responses may promote resolution, repair, and catabasis. Recent evidence showing that inflammation does not simply ‘fizzle out’, but its resolution involves an active and coordinated series of events. Dysfunction of these resolution checkpoints alters the normal inflammatory pathway, and is implicated in the induction and maintenance of states such as ARDS and sepsis. Improved understanding of resolution biology should provide translational pathways to not only improve survival, but also to prevent long-term morbidity resulting from tissue damage.

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Proinflammatory Responses of Heme in Alveolar Macrophages: Repercussion in Lung Hemorrhagic Episodes

Mediators of Inflammation ◽

10.1155/2013/946878 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 9

Author(s):

Rafael L. Simões ◽

Maria Augusta Arruda ◽

Cláudio Canetti ◽

Carlos H. Serezani ◽

Iolanda M. Fierro ◽

...

Keyword(s):

Inflammatory Response ◽

Alveolar Macrophages ◽

Nuclear Translocation ◽

Tissue Injury ◽

Proinflammatory Responses ◽

Proinflammatory Molecule ◽

Free Heme ◽

Inflammatory Processes ◽

Lung Hemorrhage ◽

And Function

Clinical and experimental observations have supported the notion that free heme released during hemorrhagic and hemolytic episodes may have a major role in lung inflammation. With alveolar macrophages (AM) being the main line of defense in lung environments, the influence of free heme on AM activity and function was investigated. We observed that heme in a concentration range found during hemolytic episodes (3–30 μM) elicits AM to present a proinflammatory profile, stimulating reactive oxygen species (ROS) and nitric oxide (NO) generation and inducing IL-1β, IL-6, and IL-10 secretion. ROS production is NADPH oxidase-dependent, being inhibited by DPI and apocynin, and involves p47 subunit phosphorylation. Furthermore, heme induces NF-κB nuclear translocation, iNOS, and also HO-1 expression. Moreover, AM stimulated with free heme show enhanced phagocytic and bactericidal activities. Taken together, the data support a dual role for heme in the inflammatory response associated with lung hemorrhage, acting as a proinflammatory molecule that can either act as both an adjuvant of the innate immunity and as an amplifier of the inflammatory response, leading tissue injury. The understanding of heme effects on pulmonary inflammatory processes can lead to the development of new strategies to ameliorate tissue damage associated with hemorrhagic episodes.

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Angiotensin-Converting Enzyme 2 as a Possible Correlation between COVID-19 and Periodontal Disease

Applied Sciences ◽

10.3390/app10186224 ◽

2020 ◽

Vol 10 (18) ◽

pp. 6224 ◽

Cited By ~ 1

Author(s):

Leonardo Mancini ◽

Vincenzo Quinzi ◽

Stefano Mummolo ◽

Giuseppe Marzo ◽

Enrico Marchetti

Keyword(s):

Angiotensin Ii ◽

Inflammatory Response ◽

Angiotensin Converting Enzyme ◽

Transforming Growth Factor ◽

Tissue Injury ◽

Interleukin 2 ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Cell Functions

SARS-CoV-2 propagation in the world has led to rapid growth and an acceleration in the discoveries and publications of various interests. The main focus of a consistent number of studies has been the role of angiotensin-converting enzyme 2 (ACE2) in binding the virus and its role in expression of the inflammatory response after transmission. ACE2 is an enzyme involved in the renin–angiotensin system (RAS), whose key role is to regulate and counter angiotensin-converting enzyme (ACE), reducing the amount of angiotensin II and increasing angiotensin 1–7 (Ang1–7), making it a promising drug target for treating cardiovascular diseases. The classical RAS axis, formed by ACE, angiotensin II (Ang II), and angiotensin receptor type 1 (AT1), activates several cell functions and molecular signalling pathways related to tissue injury and inflammation. In contrast, the RAS axis composed of ACE2, Ang1–7, and Mas receptor (MasR) exerts the opposite effect concerning the inflammatory response and tissue fibrosis. Recent studies have shown the presence of the RAS system in periodontal sites where osteoblasts, fibroblasts, and osteoclasts are involved in bone remodelling, suggesting that the role of ACE2 might have a fundamental function in the under- or overexpression of cytokines such as interleukin-6 (IL-6), interleukin-7 (IL-7), tumour necrosis factor alpha (TNF-α), interleukin-2 (IL-2), interleukin-1 beta (IL-1β), monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta (TGF-β), associated with a periodontal disorder, mainly during coinfection with SARS-CoV-2, where ACE2 is underexpressed and cannot form the ACE2–Ang1–7–MasR axis. This renders the patient unresponsive to an inflammatory process, facilitating periodontal loss.

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Inflammation: a role for NR4A orphan nuclear receptors?

Biochemical Society Transactions ◽

10.1042/bst0390688 ◽

2011 ◽

Vol 39 (2) ◽

pp. 688-693 ◽

Cited By ~ 109

Author(s):

Jason P. McMorrow ◽

Evelyn P. Murphy

Keyword(s):

Inflammatory Response ◽

Nuclear Receptors ◽

Acute Phase ◽

Immune Cells ◽

Inflammatory Responses ◽

Acute Phase Proteins ◽

Tissue Injury ◽

Chronic Phase ◽

Psoriatic Skin ◽

Orphan Nuclear Receptors

Inflammation is paradoxical; it is essential for protection following biological, chemical or physical stimuli, but inappropriate or misdirected inflammation is responsible for tissue injury in a variety of inflammatory diseases. The polarization of immune cells is critical in controlling the stages of inflammatory response. The acute phase of inflammation is characterized by a T-lymphocyte:Th2 cytokine profile and involves a co-ordinated migration of immune cells to the site of injury where production of cytokines and acute-phase proteins brings about healing. However, persistent inflammation can result in inappropriate and prolonged T-lymphocyte:Th1 cytokine-mediated action and reaction of self-molecules, leading to a chronic phase in diseases such as RA (rheumatoid arthritis), Ps (psoriasis) and atherosclerosis. The inflammatory response is also controlled by activated macrophage cells, with classically activated (M1) cells producing a wide variety of pro-inflammatory mediators, while alternatively activated (M2) macrophages participate in anti-inflammatory response. Members of the NR4A subfamily (NR4A1/NUR77, NR4A2/NURR1 and NR4A3/NOR1) of orphan NRs (nuclear receptors) have emerged as key transcriptional regulators of cytokine and growth factor action in diseases affecting our aging population. As ligand-independent and constitutively active receptors, the activity of these transcription factors is tightly controlled at the level of expression, post-translational modification and subcellular localization. NR4A subfamily members are aberrantly expressed in inflamed human synovial tissue, psoriatic skin, atherosclerotic lesions, lung and colorectal cancer cells. Significantly, prolonged or inappropriate inflammatory responses contribute to the pathogenesis of these diseases. In activated cells, NR4A receptors are rapidly and potently induced, suggesting that these receptors may act as important transcriptional mediators of inflammatory signals. NR4A receptors may contribute to the cellular processes that control inflammation, playing a critical part in the contribution of chronic inflammation or they may have a protective role, where they may mediate pro-resolution responses. Here, we will review the contribution of the NR4A orphan NRs to integration of cytokine signalling in inflammatory disorders.

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Complement factor 3 deficiency attenuates hemorrhagic shock-related hepatic injury and systemic inflammatory response syndrome

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00282.2010 ◽

2010 ◽

Vol 299 (5) ◽

pp. R1175-R1182 ◽

Cited By ~ 19

Author(s):

Changchun Cai ◽

Roop Gill ◽

Hyun-Ae Eum ◽

Zongxian Cao ◽

Patricia A. Loughran ◽

...

Keyword(s):

Inflammatory Response ◽

Hemorrhagic Shock ◽

Complement Activation ◽

Tissue Injury ◽

Soft Tissue Injury ◽

High Mobility ◽

Organ Damage ◽

Heme Oxygenase 1 ◽

Complement Factor ◽

Wild Type

Although complement activation is known to occur in the setting of severe hemorrhagic shock and tissue trauma (HS/T), the extent to which complement drives the initial inflammatory response and end-organ damage is uncertain. In this study, complement factor 3-deficient (C3−/−) mice and wild-type control mice were subjected to 1.5-h hemorrhagic shock, bilateral femur fracture, and soft tissue injury, followed by 4.5-h resuscitation (HS/T). C57BL/6 mice were also given 15 U of cobra venom factor (CVF) or phosphate-buffered saline injected intraperitoneally, followed by HS/T 24 h later. The results showed that HS/T resulted in C3 consumption in wild-type mice and C3 deposition in injured livers. C3−/− mice had significantly lower serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and circulating DNA levels, together with much lower circulating interleukin (IL)-6, IL-10, and high-mobility group box 1 (HMGB1) levels. Temporary C3 depletion by CVF preconditioning also led to reduced transaminases and a blunted cytokine release. C3−/− mice displayed well-preserved hepatic structure. C3−/− mice subjected to HS/T had higher levels of heme oxygenase-1, which has been associated with tissue protection in HS models. Our data indicate that complement activation contributes to inflammatory pathways and liver damage in HS/T. This suggests that targeting complement activation in the setting of severe injury could be useful.

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Leishmanial lipid suppresses the bacterial endotoxin-induced inflammatory response with attenuation of tissue injury in sepsis

Journal of Leukocyte Biology ◽

10.1189/jlb.3a1113-582r ◽

2014 ◽

Vol 96 (2) ◽

pp. 325-336 ◽

Cited By ~ 9

Author(s):

N. Chatterjee ◽

S. Das ◽

D. Bose ◽

S. Banerjee ◽

T. Jha ◽

...

Keyword(s):

Inflammatory Response ◽

Tissue Injury ◽

Bacterial Endotoxin

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Osthole Protects against Acute Lung Injury by Suppressing NF-κB-Dependent Inflammation

Mediators of Inflammation ◽

10.1155/2018/4934592 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 9

Author(s):

Yiyi Jin ◽

Jianchang Qian ◽

Xin Ju ◽

Xiaodong Bao ◽

Li Li ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Response ◽

Nuclear Translocation ◽

Tissue Injury ◽

Kidney Injury ◽

Peritoneal Macrophages ◽

Anti Inflammatory

Inflammation is a key factor in the pathogenesis of ALI. Therefore, suppression of inflammatory response could be a potential strategy to treat LPS-induced lung injury. Osthole, a natural coumarin extract, has been reported to protect against acute kidney injury through an anti-inflammatory mechanism, but its effect on ALI is poorly understood. In this study, we investigated whether osthole ameliorates inflammatory sepsis-related ALI. Results from in vitro studies indicated that osthole treatment inhibited the LPS-induced inflammatory response in mouse peritoneal macrophages through blocking the nuclear translocation of NF-κB. Consistently, the in vivo studies indicated that osthole significantly prolonged the survival of septic mice which was accompanied by inflammation suppression. In the ALI mouse model, osthole effectively inhibited the development of lung tissue injury, leukocytic recruitment, and cytokine productions, which was associated with inhibition of NF-κB nuclear translocation. These findings provide evidence that osthole was a potent inhibitor of NF-κB and inflammatory injury and suggest that it could be a promising anti-inflammatory agent for therapy of septic shock and acute lung injury.

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