2. Explain more details about chronic inflammation (with examples).Explain Causes of Chronic inflammation especially lifestyle, diet lack of exercise, obesity life-stress, genetic etc.…explain how lifestyles affect the cause of chronic inflammation.
3. Talk about Chronic inflammation associated diseases and treatments eg T2D. Atherosclerosis-cardiovascular, cancer.
Inflammation is referred to the localized physical condition where due to some physiological reactions, the body parts become reddened, hot, swollen and painful. Usually, these kinds of phenomenon results from the infection, external or internal injury (Aggarwal et al. 2012). The process is a part of complex biological response of body tissues towards the harmful stimuli including damaged cells, pathogens or irritants. Through these kinds of processes, the immune cells protect body system by involving different immune cells, blood vessels and molecular mediators. Through this process, the immune cells eliminate the initial causes of cell injury by clearing out the necrotic and damaged tissues from body and promote the tissue repairing system.
Its five basic signs, calor or heat, dolor or pain, rubor or redness, tumor or swelling and loss of function characterize the phenomenon, inflammation. It is the initial response of immune system and mediated by the immune cells, thus, it is classified under the innate immunity or cell mediated immunity in comparison to the adaptive immunity that is specific for each pathogen. There are mainly two types of inflammation which are acute and chronic inflammation (Cho and Yu 2012). Chronic inflammation is more severe form of inflammation than the acute one.
Acute infection is usually induced in the damaged tissues as a result of trauma, microbial invasion or noxious compounds. The acute inflammation is mediated by the immune cells and the secreted chemical mediators, which are known as cytokines and other molecules. In the case of acute inflammation, the anaphylatoxins are released at inflammation site, which are small inflammation-causing chemicals, these mediators promote the secretion of chemical mediators including histamine, prostaglandins or serotonin from the mast cells, thereby causing blood vessel expansion, making them more permeable (Daniluk 2012). In this way, the neutrophils are allowed to migrate into the affected tissue through diapedesis for clearing out the noxious substances in blood. The more blood cells accumulation causes redness and the destructive reactions cause heat. Most of bacterial or fungal infections cause acute inflammation. Lesions include pus, rash and abscess. For example, allergic anaphylaxis causes acute inflammation (Dietert and Luebke 2012).
In contrast to the acute inflammation, the chronic inflammation is seen as a response to some viral infections and hypersensitivity reactions. It is seen in some infections where the inflammation is persistent. In contrast to the neutrophils and chemical mediators released by mast cells, the primary immune cells are T lymphocytes and macrophages here. The cytokines secreted by these cells causes more long-term damage to the tissues (French 2011). In the case of chronic inflammation, the acute infection allows continuous tissue damage to cells leading to tissue fibrosis. Lesions include fibrosis, rash or granuloma. Example includes autoimmune condition such as rheumatoid arthritis.
2. Chronic inflammation
Chronic inflammation is usually the persistent and ongoing inflammation process after an acute inflammation. If the infection persists with more tissue destruction after the phase of acute inflammation, it can be said that chronic inflammation has taken place. In some cases, some pathogens directly provoke chronic inflammation in spite of initiating an acute inflammation first. Increased permeability of capillaries, increased blood flow and many other factors of acute inflammation continue with chronic stage (Lichti 2012). Neutrophils enter into the infected tissue and quickly recruit lymphocytes and macrophages through chemical mediators’ secretion. Macrophages initiate the phagocytosis process. Sometimes, they are not able to digest all the engulfed material and the pathogenic substances persist within macrophages while the macrophages are engulfing more, thereby continuing the symptoms of inflammation for longer period. In some cases, macrophages fuse and forms giant cells and these fused cells are found in the form of layers surrounding the damaged central core, which are known as granuloma. It is one of the significant features of tuberculosis (Ashton Acton 2012).
Causes of Chronic inflammation
There are a number of causes, which could cause chronic inflammation.
Sedentary lifestyle, stress and exhaustions are crucial cause of chronic inflammation. Consuming a huge number of antibiotics can cause inflammatory symptoms via cross-reaction. More exposure to toxin for example, farmers working with pesticides can cause chronic inflammation. Vitamin D is an important component of system modulation, lack of sun exposure lowers the immune system’s ability to work properly, enhancing chance of inflammation (Roy et al. 2012).
There are a number of foods, which can cause inflammation. Sugar triggers a number of cytokines causing inflammation. Saturated fat is another food substance, which cause inflammation of adipose tissues. Thus, cheese, full-fat dairy products, grain-based desserts, red meat should be avoided in diet. Trans fat causes systematic inflammation. Gluten and casein are also causative agents of chronic inflammation. Thus, food substances containing these factors should be avoided from daily diet. Alcohol and smoking are also major causes of inflammation (Schillde 2013).
Lack of exercise
People having insomnia are prone to chronic inflammation due to over secretion of inflammation causing cytokines. Lack of sleep promotes inflammation. Individual experiencing autoimmune disease are seen to have less sleep which promote the situation with more pain. Exercise helps to active the immune system. Exercise causes healthy muscle contractions, which causes the secretion of cytokines like IL-6, IL-8 and IL-15, thereby contributing in anti-inflammatory actions (Wick and Grundtman 2012).
Obesity and depression
Macrophages infiltrate the adipose tissues and release another set of chemical mediators which further promote inflammation. It has been reported that the accumulation of macrophages also causes insulin resistance in obese people. In addition, evidence suggest that depression and stress has a significant link with chronic inflammation. At stressed condition, more cortisol hormones are produced which is also promoted to the cytokines released due to lack of sleep that is interconnected with stress. These are stimulators of chronic inflammation (Thilakarathna and Rupasinghe 2013).
Acute inflammation is followed by chronic inflammation signs through the signal transduction. JAK-STAT pathway has a major role in signal transduction. Mutation in these pathways can cause inflammation. Some autoimmune diseases are also caused by mutation in essential genes.
3. Chronic inflammation associated disease and treatments
Type 2 Diabetes
As described earlier, accumulation of macrophages at the site of inflammation has a major role in causing insulin resistance, which is the major cause of type 2 diabetes disease. Researchers found that accumulated macrophages secretes some immune mediators including TNF-alpha and other cytokines which are promoting the expression of some proteins which suppresses the insulin-signaling pathways, thereby making the system less responsive towards insulin and thereby loosing the control over glucose metabolism. It promotes the development of type 2 diabetes. FOXO 1 increase cytokine secretion, which has been shown to be more active during insulin resistance (Garc?a-Lafuente et al. 2009).
Avoiding sugar and saturated fat based food is the basic treatment of type two diabetes to reduce the chance of diabetes. Sulforaphane has been shown to have great response as an anti-inflammatory activity while acting against oxidative damage associated with inflammatory activities.
Atherosclerosis is a syndrome, which affects the blood vessels as a result of chronic inflammatory responses of WBCs present in the artery walls. The process is promoted by the LDLs as a result of failure of removing fats and cholesterol by the HDLs from macrophages. The result is formation of atherosclerotic lesion in artery, which is the cause of cardiovascular accident (Kawasaki et al. 2012). The retention of LDL particles promotes initial damage to vessel walls which promote inflammatory procedure. Macrophages further ingest oxidized LDLs and turn into foam cells which propagate the inflammatory process.
In the case of cardiovascular diseases, atherosclerosis is the major cause. High blood pressure, smoking, high cholesterol, all of these inflammatory phenomenon triggers cardiovascular diseases. The damage promotes inflammatory response and leads to the formation of plaque in artery. Two types of plaques are formed in the cardiovascular diseases as a result of inflammatory responses. Stable plaques in artery of heart cause chest pain and sudden rupture of plaque causes blood clot and myocardial infarction (Gentile et al. 2012).
Regular exercise and cessation of smoking are basic treatment. Combined treatment strategies are best for these cases. Lipoprotein transport behaviors have been shown successful results. Mediterranean diet can improve the symptoms. Medications for reducing high cholesterol can be a good treatment along with dietary improvement.
A number of inflammatory diseases increase the risk of cancer of an individual. For example, it has been found that chronic inflammatory bowel disease increases the risk of colon carcinoma. Bacterial, viral or parasitic infections or chemical irritants can cause chronic inflammation. Through the inclusion of proneoplastic mutation, apoptosis, adaptive responses the inflammatory mediators promote neoplasia (Guo et al. 2012). As much the inflammation persists, the risk of cancer increases. In this context, anti-inflammatory medications and healthy diet by avoiding inflammation-inductive foods can be helpful.
4. Components of chronic inflammation
There are different chemical and biological mediators of chronic inflammation, which are important components of chronic inflammation. Cytokines are the most important agents having significant role in inflammation. The cytokines, which promote inflammation, are known as the pro-inflammatory cytokines, which involve IL-6, IL-8, IL-15, TNF-alpha. The chemical mediators of inflammation include histamine, postraglandin, bradykinin and serotonin. Histamine is one of the initial chemical mediators released from mast cells which attracts macrophages at the site of inflammation (Mathur and Pedersen 2009).
Neutrophils are most abundant granulocytes having a major role in inflammation process. These are the first leukocytes, which are recruited to the site of inflammation. They are able to eliminate the pathogens through phagocytosis. These cells have high capacity of infiltrating in the damaged tissues. These cells have a significant role in the chronic inflammation of joint. The granules in neutrophils secrete anti-microbial substances including toxic oxygen metabolites. And drive inflammation through antigen presentation and cytokine secretion. These are found in rheumatoid joints in large amount (Guo et al. 2012).
Monocytes are one of the important white blood cells. Monocytes migrate in different tissues while differentiating into macrophages. In inflammation, the macrophages has three major roles, phagocytosis of pathogenic substances, antigen presentation to the T lymphocytes and immunomodulation by producing and secreting different cytokines and growth factors. The chemical mediators secreted by the neutrophils make the macrophages active and these macrophages can infiltrate tissues easily. Activated macrophages can destroy the pathogens by phagocytosis more vigorously (Sica and Mantovani 2012).
Mechanism of macrophage activation or polarization
M1, M2 and M3 polarization
Macrophages play an essential role in regulation of the process of healing of wound and regeneration of tissue by changing their state of polarization in response to the stimulus of local microenvironment. The native roles of macrophages that are polarized includes the needs of tissue remodeling and biomaterials, yet directing the response of polarization has been mainly not present as a probable strategy to use in regenerative medicine up till now (Herder et al. 2015). The macrophages that are derived from the precursors of monocyte go through specific differentiation depending on the environment of local tissues. They give response to the environmental signals within then tissues such as the activated lymphocytes, microbial products and damaged cells to distinguish into functional phenotypes. The phenotype of M1 macrophage is differentiated by the production of elevated levels of pro-inflammatory cytokines, capacity to mediate resistance against pathogens, high production of reactive intermediates of oxygen and nitrogen, strong microbial properties and promotion of responses of Th1. On the contrary, the M2 macrophages are differentiated by their involvement in the process of remodeling of tissue, parasite control, and regulation of immune system. Kappa (NF-KB) is a nuclear factor, which acts as a signaling molecule in the M1, M2 and M3 Polarization (Herder et al. 2015).
5. THP-1 cell model
This model encompasses human leukemia monocytic cell line that has been widely utilized to study the mechanisms, functions, pathways of signaling and transport of drugs and nutrients involved with macrophages/monocytes. This model encompassing the cell line has become widespread for estimating the modulation of the activities of macrophages and monocytes (Qin, Z., 2012). THP-1 is a human monocytic cell line, which is derived from the patient suffering from acute monocytic leukemia. This cell line is utilized for the testing the cell lines of leukemia immunocytochemical analysis of protein-protein interaction and immunohistochemistry. These cells have C3b and Fc receptors and they are devoid of cytoplasmic and surface immunoglobulins. They are responsible for the production of IL-1 and stain positive for alpha-napthyl butyrate esterase. They exhibit increased production of carbondioxide during phagocytosis and can be distinguished into cells, which are like macrophage (Chanput et al. 2014).
Strengths and Limitation
In the present settings of research, THP-1 model is extensively used for the investigation of regulation and function of macrophages and monocytes in the cardiovascular system. In the studies, associated with the interaction between a variety of vascular cells and THP-1 cells, THP-1 cells offer several exceptional values like a model for investigating the mechanisms of the different stages of atherogenesis (Chanput et al. 2014). A few studies that are associated with the transcriptome, histone modification of THP-1 cells and microRNA profile, a number of molecules have been identified which may play crucial roles in regulating the macrophages and monocytes under pathological and physiological conditions. The limitation of this model is that there are noteworthy differences between the primary monocytes-macrophages and THP-1 cells and it is necessary to identify the differences between them. Moreover, both of them have diverse pathophysiological processes in programmed cell death or apoptosis (Qin, Z., 2012).
Advantage and disadvantage of THP-1 cells over other cell models
THP-1 cell line has some technical advantages in comparison to the other cell line models. For example, the genetic background of THP-1 cell line is homogenous leading to the minimization of the degree of variability in the phenotype of the cell. Another advantage is that the genetic modification of these cell lines by small interfering RNAs for the regulation of specific proteins is comparatively uncomplicated. The most regularly utilized read-out systems for reactions of THP-1 cells involves production of significant cytokines or transcription of the cytokines are significant and depends on the experimental designs, which are specific in nature (Chanput et al. 2015).
6. Methods of regulating chronic inflammation
Chronic inflammation is usually results from the infection, which can be bacterial, viral, parasitic or fungal. Thus, the primary way to control chronic or persistent inflammation is to take precaution against infection by infection prevention methods. The primary prevention method is having a healthy diet by avoiding substances that induce inflammation. Therefore, getting control is very important (Kawasaki et al. 2012). Red meat should be avoided highly as it causes inflammation. Fries, which are rich in gluten, should be avoided as it causes chronic inflammation. Bad fat or Trans fat also have pro-inflammatory activities, refines carbohydrates, acid forming food can cause inflammation, which should be avoided. Today, most of the natural vegetables are grown by applying harmful pesticides, which are major causes of inflammation. Thus, vegetables should be washed before consumption very carefully. Candida is a major opportunistic pathogen, which causes inflammation through infection of gut. Thus, keeping a healthy gut is very important to control chronic inflammation (Chanput et al. 2015).
7. Bioactive Molecules
Flavonoids and plant derived molecules
Flavonoids encompass a group of phytochemicals, which have exhibited several effects of health and have been studied comprehensively (Vezza et al., 2016). They are secondary metabolites in plants and belong to the category of polyphenols. Among the six common classes of food flavonoids, the ubiquitous distribution of flavonols has been observed in different plant foods while noticeable quantities of isoflavones have been discovered in the foods that are obtained from leguminous plants (George et al. 2016). Flavonoids have exhibited promising health enhancing effects in human cell cultures, experimental human and animal clinical studies. They have exhibited hypocholesterolemic, anti-inflammatory and antioxidant effects together with the ability to adapt cell signaling as well as gene expression associated with the development of diseases (Haid et al. 2012).
Sources and mode of action
The sources of Flavonoids are fruits, vegetables and spices. They are rich in the fruits that grow on trees. Citrus fruits such as lemons, oranges and grapes contain a high amount of falavonoids (Paul Dzoyem et al. 2013). Beans such as kidney bean are high in flavonoids. Their best property is to protect the body against reactive oxygen species. They have discovered to possess antimicrobial, antiviral, anti-inflammatory and antihepatotoxic activities. They also possess biochemical effects that lead to the inhibition of a variety of enzymes such as phosphodiesterase, xanthine oxidase, aldol reductase, cycloxygenase and lipoxygenase. They also have a role in the regulation of a number of hormones such as androgens, thyroid hormone and estrogens. They also show anti-inflammatory activities in exudative as well as proliferative phases of inflammation (George et al. 2016).
Anti-inflammation properties of flavonoids
The anti-inflammation properties of flavonoids in cellular models engages the inhibition of the activities and synthesis of a number of pro-inflammatory mediators like adhesion molecules, cytokines, c-reactive protein and eicosanoids (Haid et al. 2012). The studies on humans which aims to investigate the effects of flavoniods on the inflammatory markers are inadequate and are primarily focused on the sources of food that are rich in flavonoids but not on the molecules that are pure. Several of the studies lack evaluation of absorption of flavonoids or fail to relate the effect off inflammation with an alteration in the circulating levels of flavonoids (Paul Dzoyem et al. 2013).
In this literature review, recent literatures have been reviewed regarding the chronic inflammation. Chronic inflammation is one of the basic steps that progress towards severe human diseases, while increasing the risk of fatal consequences including cardiovascular accident or cancer. In this literature review, the basic concept related to the chronic inflammation and how chronic inflammation is related to the severe diseases has been discussed. Recent research has been found direct relation between chronic inflammation prevention and consumption of dietary flavonoids. From different recent studies, it has been analyzed that flavonoids have anti-inflammatory activities, which could have major impact upon treatment and prevention of chronic inflammation. Thus, flavonoids can be used as prophylactic agents. The role of flavonoids has been discussed here. Further studies should focus on in-depth analysis of the natural product to establish its use in treating chronic inflammation related diseases.
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