scholarly journals Acetaminophen-Induced Rat Hepatotoxicity Based on M1/M2-Macrophage Polarization, in Possible Relation to Damage-Associated Molecular Patterns and Autophagy

2020 ◽  
Vol 21 (23) ◽  
pp. 8998
Author(s):  
Yuka Tsuji ◽  
Mizuki Kuramochi ◽  
Hossain M. Golbar ◽  
Takeshi Izawa ◽  
Mitsuru Kuwamura ◽  
...  
Keyword(s):  
Mhc Class Ii ◽  
Rat Model ◽  
Tissue Injury ◽  
Macrophage Polarization ◽  
Coagulation Necrosis ◽  
M2 Macrophage ◽  
Old Rats ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
M1 Type

Overdose of acetaminophen (APAP), an antipyretic drug, is an important cause of liver injury. However, the mechanism in the rat model remains undetermined. We analyzed APAP-induced hepatotoxicity using rats based on M1/M2-macrophage functions in relation to damage-associated molecular patterns (DAMPs) and autophagy. Liver samples from six-week-old rats injected with APAP (1000 mg/kg BW, ip, once) after 15 h fasting were collected at hour 10, and on days 1, 2, 3, and 5. Liver lesions consisting of coagulation necrosis and inflammation were seen in the affected centrilobular area on days 1 and 2, and then, recovered with reparative fibrosis by day 5. Liver exudative enzymes increased transiently on day 1. CD68+ M1-macrophages increased significantly on days 1 and 2 with increased mRNAs of M1-related cytokines such as IFN-g and TNF-α, whereas CD163+ M2-macrophages appeared later on days 2 and 3. Macrophages reacting to MHC class II and Iba1 showed M1-type polarization, and CD204+ macrophages tended to be polarized toward M2-type. At hour 10, interestingly, HMGB1 (representative DAMPs) and its related signals, TLR-9 and MyD88, as well as LC3B+ autophagosomes began to increase. Collectively, the pathogenesis of rat APAP hepatotoxicity, which is the first, detailed report for a rat model, might be influenced by macrophage functions of M1 type for tissue injury/inflammation and M2-type for anti-inflammatory/fibrosis; particularly, M1-type may function in relation to DAMPs and autophagy. Understanding the interplayed mechanisms would provide new insight into hepato-pathogenesis and contribute to the possible development of therapeutic strategies.

scholarly journals Association between early airway damage-associated molecular patterns and subsequent bacterial infection in patients with inhalational and burn injury

2015 ◽  
Vol 308 (9) ◽  
pp. L855-L860 ◽  
Author(s):  
Robert Maile ◽  
Samuel Jones ◽  
Yinghao Pan ◽  
Haibo Zhou ◽  
Ilona Jaspers ◽  
...  
Keyword(s):  
North Carolina ◽  
Bacterial Infection ◽  
Injury Severity ◽  
Burn Injury ◽  
Tissue Injury ◽  
Cell Damage ◽  
Inhalation Injury ◽  
High Mobility Group Protein ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Bacterial infection is a major cause of morbidity affecting outcome following burn and inhalation injury. While experimental burn and inhalation injury animal models have suggested that mediators of cell damage and inflammation increase the risk of infection, few studies have been done on humans. This is a prospective, observational study of patients admitted to the North Carolina Jaycee Burn Center at the University of North Carolina who were intubated and on mechanical ventilation for treatment of burn and inhalational injury. Subjects were enrolled over a 2-yr period and followed till discharge or death. Serial bronchial washings from clinically indicated bronchoscopies were collected and analyzed for markers of tissue injury and inflammation. These include damage-associated molecular patterns (DAMPs) such as hyaluronic acid (HA), double-stranded DNA (dsDNA), heat-shock protein 70 (HSP-70), and high-mobility group protein B-1 (HMGB-1). The study population was comprised of 72 patients who had bacterial cultures obtained for clinical indications. Elevated HA, dsDNA, and IL-10 levels in bronchial washings obtained early (the first 72 h after injury) were significantly associated with positive bacterial respiratory cultures obtained during the first 14 days postinjury. Independent of initial inhalation injury severity and extent of surface burn, elevated levels of HA dsDNA and IL-10 in the central airways obtained early after injury are associated with subsequent positive bacterial respiratory cultures in patients intubated after acute burn/inhalation injury.

scholarly journals Phenotype and function of macrophage polarization in monocrotaline-induced pulmonary arterial hypertension rat model

2021 ◽  
Author(s):  
Yong Fan ◽  
Yanjie Hao ◽  
Dai Gao ◽  
Lan Gao ◽  
Guangtao Li ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Lung Tissue ◽  
Rat Model ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
M1 Macrophages ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by vascular remodeling and chronic inflammation. Macrophages are the key orchestrators of inflammatory and repair responses, and have been demonstrated to be vital in the pathogenesis of PAH. However, specific phenotype of macrophage polarization (M1 & M2 macrophage) in the development of PAH and the underlying mechanisms how they work are still largely unclear. A rat model of monocrotaline (MCT) induced PAH was used. Hemodynamic analysis and histopathological experiments were conducted at day 3, 7, 14, 21 and 28, respectively. In PAH rat lung tissue, confocal microscopic images showed that CD68+NOS2+ M1-like macrophages were remarkably infiltrated on early stage, but dramatically decreased in mid-late stage. Meanwhile, CD68+CD206+ M2-like macrophages in lung tissue accumulated gradually since day 7 to day 28, and the relative ratio of M2/M1 macrophage increased over time. Results detected by western blot and immunohistochemistry were consistent. Further vitro functional studies revealed the possible mechanism involved in this pathophysiological process. By using Transwell co-culture system, it was found that M1 macrophages induced endothelial cell apoptosis, while M2 macrophages significantly promoted proliferation of both endothelial cell and smooth muscle cell. These data preliminarily demonstrated a temporal dynamic change of macrophage M1/M2 polarization status in the development of experimental PAH. M1 macrophages participated in the initial stage of inflammation by accelerating apoptosis of endothelial cell, while M2 macrophages predominated in the reparative stage of inflammation and the followed stage of aberrant tissue remodeling.

scholarly journals Roles of Macrophage Polarization and Macrophage-Derived miRNAs in Pulmonary Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Amit Kishore ◽  
Martin Petrek
Keyword(s):  
Pulmonary Fibrosis ◽  
Tissue Injury ◽  
Macrophage Polarization ◽  
Future Perspective ◽  
Current Evidence ◽  
M2 Macrophage ◽  
Cellular Mirnas ◽  
Exosomal Mirnas ◽  
Macrophage Populations ◽  
And Function

This mini-review summarizes the current evidence for the role of macrophage activation and polarization in inflammation and immune response pertinent to interstitial lung disease, specifically pulmonary fibrosis. In the fibrosing lung, the production and function of inflammatory and fibrogenic mediators involved in the disease development have been reported to be regulated by the effects of polarized M1/M2 macrophage populations. The M1 and M2 macrophage phenotypes were suggested to correspond with the pro-inflammatory and pro-fibrogenic signatures, respectively. These responses towards tissue injury followed by the development and progression of lung fibrosis are further regulated by macrophage-derived microRNAs (miRNAs). Besides cellular miRNAs, extracellular exosomal-miRNAs derived from M2 macrophages have also been proposed to promote the progression of pulmonary fibrosis. In a future perspective, harnessing the noncoding miRNAs with a key role in the macrophage polarization is, therefore, suggested as a promising therapeutic strategy for this debilitating disease.

scholarly journals Tissue damage drives co-localization of NF-κB, Smad3, and Nrf2 to direct Rev-erb sensitive wound repair in mouse macrophages

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Dawn Z Eichenfield ◽  
Ty Dale Troutman ◽  
Verena M Link ◽  
Michael T Lam ◽  
Han Cho ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Tissue Damage ◽  
Wound Repair ◽  
Macrophage Polarization ◽  
Expression Of Genes ◽  
Mouse Macrophages ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Although macrophages can be polarized to distinct phenotypes in vitro with individual ligands, in vivo they encounter multiple signals that control their varied functions in homeostasis, immunity, and disease. Here, we identify roles of Rev-erb nuclear receptors in regulating responses of mouse macrophages to complex tissue damage signals and wound repair. Rather than reinforcing a specific program of macrophage polarization, Rev-erbs repress subsets of genes that are activated by TLR ligands, IL4, TGFβ, and damage-associated molecular patterns (DAMPS). Unexpectedly, a complex damage signal promotes co-localization of NF-κB, Smad3, and Nrf2 at Rev-erb-sensitive enhancers and drives expression of genes characteristic of multiple polarization states in the same cells. Rev-erb-sensitive enhancers thereby integrate multiple damage-activated signaling pathways to promote a wound repair phenotype.

scholarly journals NLRP3 Inflammasome Inhibitors in Cardiovascular Diseases

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 976
Author(s):  
Eleonora Mezzaroma ◽  
Antonio Abbate ◽  
Stefano Toldo
Keyword(s):  
Cardiovascular Diseases ◽  
Inflammatory Response ◽  
Nlrp3 Inflammasome ◽  
Tissue Injury ◽  
Scientific Evidence ◽  
Rapid Induction ◽  
Pyrin Domain ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Inflammasome Inhibitors

Virtually all types of cardiovascular diseases are associated with pathological activation of the innate immune system. The NACHT, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome is a protein complex that functions as a platform for rapid induction of the inflammatory response to infection or sterile injury. NLRP3 is an intracellular sensor that is sensitive to danger signals, such as ischemia and extracellular or intracellular alarmins during tissue injury. The NLRP3 inflammasome is regulated by the presence of damage-associated molecular patterns and initiates or amplifies inflammatory response through the production of interleukin-1β (IL-1β) and/or IL-18. NLRP3 activation regulates cell survival through the activity of caspase-1 and gasdermin-D. The development of NLRP3 inflammasome inhibitors has opened the possibility to targeting the deleterious effects of NLRP3. Here, we examine the scientific evidence supporting a role for NLRP3 and the effects of inhibitors in cardiovascular diseases.

scholarly journals Colchicine-Containing Nanoparticles Attenuates Acute Myocardial Infarction Injury by Inhibiting Inflammation

2021 ◽  
Author(s):  
Li Wang ◽  
Yun-fan Peng ◽  
Li-jun Song ◽  
Da-sheng Xia ◽  
Chao Li ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Calcium Carbonate ◽  
Rat Model ◽  
Myocardial Infarct ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Myocardial Infarct Size ◽  
Anti Inflammatory

Abstract Purpose Anti-inflammatory therapy is important for reducing myocardial injury after acute myocardial infarction (MI). New anti-inflammatory drugs and their mechanism are necessary to be explored to improve the clinical efficacy. We aimed to improve the efficacy of colchicine on attenuating MI injury by nano-drug delivery systems, and to investigate the mechanism of anti-inflammatory. Methods Colchicine-containing delivery system based on calcium carbonate nanoparticles (ColCaNPs) was synthesized. The protection against MI by ColCaNPs was evaluated using an in vivo rat model established by ligating the left anterior descending coronary artery. Macrophage polarization and the levels of inflammatory cytokines were determined using immunohistochemistry, western blot and ELISA analysis. Results ColCaNPs treatment showed about a 45% reduction in myocardial infarct size and attenuating myocardial fibrosis compared with groups without drug intervention after MI. Furthmore, ColCaNPs significantly decreased the levels of CRP, TNF-α and IL-1β in serum and the expression of proinflammatory cytokine in myocardial tissues after MI (p < 0.05). We also found that ColCaNPs notably restrained pyroptosis, and inhibited inflammatory response by modulating on M1/M2 macrophage polarization and suppressing TLR4/NFκB/NLRP3 signal pathway. Conculsion Colchicine-containing nanoparticles can protect against MI injury in a clinically relevant rat model by reducing inflammation. In addition, calcium carbonate nanoparticles can increase the cardioprotective effects of colchicine.

scholarly journals Damage-associated molecular patterns in resuscitated hemorrhagic shock are mitigated by peritoneal fluid administration

2018 ◽  
Vol 315 (3) ◽  
pp. L339-L347
Author(s):  
Paul J. Matheson ◽  
Mark A. Eid ◽  
Matthew A. Wilson ◽  
Victoria S. Graham ◽  
Samuel A. Matheson ◽  
...  
Keyword(s):  
Blood Flow ◽  
Hemorrhagic Shock ◽  
Tissue Injury ◽  
High Mobility ◽  
Primary Response ◽  
Sprague Dawley ◽  
Shed Blood ◽  
Lung Blood Flow ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Conventional resuscitation (CR) of hemorrhagic shock (HS), a significant cause of trauma mortality, is intravenous blood and fluids. CR restores central hemodynamics, but vital organ flow can drop, causing hypoperfusion, hypoxia, damage-associated molecular patterns (DAMPs), and remote organ dysfunction (i.e., lung). CR plus direct peritoneal resuscitation (DPR) prevents intestinal and hepatic hypoperfusion. We hypothesized that DPR prevents lung injury in HS/CR by altering DAMPs. Anesthetized male Sprague-Dawley rats were randomized to groups ( n = 8/group) in one of two sets: 1) sham (no HS, CR, or DPR), 2) HS/CR (HS = 40% mean arterial pressure (MAP) for 60 min, CR = shed blood + 2 volumes normal saline), or 3) HS/CR + DPR. The first set underwent whole lung blood flow by colorimetric microspheres. The second set underwent tissue collection for Luminex, ELISAs, and histopathology. Lipopolysaccharide (LPS) and DAMPs were measured in serum and/or lung, including cytokines, hyaluronic acid (HA), high-mobility group box 1 (HMGB1), Toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 protein (MYD88), and TIR-domain-containing adapter-inducing interferon-β (TRIF). Statistics were by ANOVA and Tukey-Kramer test with a priori P < 0.05. HS/CR increased serum LPS, HA, HMGB1, and some cytokines [interleukin (IL)-1α, IL-1β, IL-6, and interferon-γ]. Lung TLR4 and MYD88 were increased but not TRIF compared with Shams. HS/CR + DPR decreased LPS, HA, cytokines, HMGB1, TLR4, and MYD88 levels but did not alter TRIF compared with HS/CR. The data suggest that gut-derived DAMPs can be modulated by adjunctive DPR to prevent activation of lung TLR-4-mediated processes. Also, DPR improved lung blood flow and reduced lung tissue injury. Adjunctive DPR in HS/CR potentially improves morbidity and mortality by downregulating the systemic DAMP response.

scholarly journals Toll-Like Receptors in Hepatic Ischemia/Reperfusion and Transplantation

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
John Evankovich ◽  
Timothy Billiar ◽  
Allan Tsung
Keyword(s):  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Innate Immune ◽  
Toll Like Receptors ◽  
Hepatic Ischemia ◽  
Danger Signals ◽  
The Family ◽  
Hepatic Ischemia Reperfusion ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

The family of Toll-like receptors (TLRs) function as pattern-recognition receptors (PRRs) that respond to a myriad of highly conserved ligands. These substrates include pathogen-associated molecular patterns (PAMPs) for the recognition of invading pathogens, as well as damage-associated molecular patterns (DAMPs) for the recognition of endogenous tissue injury. While the functions of TLRs are diverse, they have received much attention for their roles in ischemia/reperfusion (I/R) injury of the liver and other organs. The TLRs play central roles in sensing tissue damage and activating the innate immune system following I/R. Engagement of TLRs by endogenous DAMPs activates proinflammatory signaling pathways leading to the production of cytokines, chemokines and further release of endogenous danger signals. This paper focuses on the most recent findings regarding TLR family members in hepatic I/R injury and transplantation.

Inflammatory outcomes of apoptosis, necrosis and necroptosis

2014 ◽  
Vol 395 (10) ◽  
pp. 1163-1171 ◽  
Author(s):  
Pavel Davidovich ◽  
Conor J. Kearney ◽  
Seamus J. Martin
Keyword(s):  
Cell Death ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Necrotic Cell Death ◽  
Caspase Activation ◽  
Microbial Infection ◽  
Necrotic Cell ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Pro Inflammatory Cytokines

Abstract Microbial infection and tissue injury are well established as the two major drivers of inflammation. However, although it is widely accepted that necrotic cell death can trigger or potentiate inflammation, precisely how this is achieved still remains relatively obscure. Certain molecules, which have been dubbed ‘damage-associated molecular patterns’ (DAMPs) or alarmins, are thought to promote inflammation upon release from necrotic cells. However, the precise nature and relative potency of DAMPs, compared to conventional pro-inflammatory cytokines or pathogen-associated molecular patterns (PAMPs), remains unclear. How different modes of cell death impact on the immune system also requires further clarification. Apoptosis has long been regarded as a non-inflammatory or even anti-inflammatory mode of cell death, but recent studies suggest that this is not always the case. Necroptosis is a programmed form of necrosis that is engaged under certain conditions when caspase activation is blocked. Necroptosis is also regarded as a highly pro-inflammatory mode of cell death but there has been little explicit examination of this issue. Here we discuss the inflammatory implications of necrosis, necroptosis and apoptosis and some of the unresolved questions concerning how dead cells influence inflammatory responses.

Sign in / Sign up

Export Citation Format

Share Document