Biggest Causes Of Inflammation In The Body – Sepsis is one of the leading causes of death worldwide, and no treatment other than intensive care is yet available. The patient’s outcome is determined by the complex interaction between the body’s pro- and anti-inflammatory responses, that is, the homeostatic balance that must be achieved between these two competing events for the patient to heal. Early attempts at drug development focused mainly on controlling inflammation, but failed to produce any concrete results. This is despite the fact that most deaths occur during the immune paralysis phase of this biphasic disease. Recently, the focus has been shifting towards understanding immune paralysis (induced by apoptosis and anti-inflammatory cytokines) in order to develop therapeutic drugs. In this review, we put forward an argument for a proper understanding of the molecular basis of inflammation as well as apoptosis in order to develop an effective treatment.

The first medical records record infectious diseases in humans as early as B.C. It has been documented as far back as 1000 BC, yet pathogenic infection remains a leading cause of disease and death (Ruffer and Ferguson, 1911; Cossart, 2014). The infection that causes sepsis remains one of the biggest health problems worldwide. Although the absolute global burden of the disease is difficult to discern, it is estimated that thirty million people are affected each year (Reinhart et al., 2013). The disease predominantly affects low- to middle-income countries and is responsible for an estimated six million deaths (Fleischmann et al., 2016). Additionally, one million newborn deaths each year are caused by maternal/newborn sepsis (Vogel, 2017). In the United States alone, costs associated with this disease can exceed $16 billion, as most patients admitted to the intensive care unit require mechanical ventilation to survive ( Angus et al., 2001 ).

Biggest Causes Of Inflammation In The Body

Biggest Causes Of Inflammation In The Body

Despite the heavy cost of sepsis, the etiology of the disease remains mysterious. In the past, the primary source of infection was believed to originate solely from the gut microbiota ( Friedman et al., 1998 ). However, later studies found that Pseudomonas sp. This infection, which colonizes and causes infection in the upper respiratory tract, is the infection most commonly associated with sepsis (Rangel-Frausto, 1999; Mayr et al., 2014). We now know that sepsis is a highly heterogeneous disease, both in terms of its cause and course. Before the 90s, gram-negative organisms were seen in the blood of the majority of septic patients who applied to the clinic (Polat et al., 2017). This has led some scientists to establish diagnostic criteria for sepsis syndrome; argued that specific medical symptoms and the known cause of infection are central to diagnosis (Bone et al., 1989). Over the following decade, it became apparent that although gram-negative bacteria were still common in septic patients, the gram-positive microbiota was becoming more prominent in patient sera (Friedman et al., 1998). In fact, today almost the same number of gram-negative and gram-positive bacteria are associated with the disease (Vincent and Abraham, 2006). However, the causative agent is not always bacteria, as parasites and fungi can also cause sepsis (Hubner et al., 2013; Florescu and Kalil, 2014; Liang, 2016). Additionally, an infectious pathogen cannot be detected in approximately one-third of patients (Bone et al., 1989; Liang, 2016). This includes trauma patients who often show clinical signs of sepsis but do not have bacteria in their blood (Goris et al., 1985). These inconsistencies forced physicians to change the diagnostic criteria for sepsis at the Consensus Conference in Chicago in 1992 (Bone et al., 1992). These new criteria suggested that infection did not have to be limited to bacteria, and systemic inflammatory response syndrome (SIRS) became the new age term to describe the disease (Bone et al., 1992).

Inflammation: Causes, Symptoms And Treatment

Although diagnostic criteria are regularly updated (one aspect of sepsis that has caught researchers’ attention and remained constant) has been the presence of inflammation during the disease. The inflammatory nature of sepsis was investigated as far back as 1960; here the first clinical trial to attenuate the inflammatory response was initiated (Bennett et al., 1962). These studies led to the use of corticosteroids; however, no therapeutic benefit was noted (Bennett et al., 1962). Drug trials targeting the inflammatory phase of sepsis would continue into the 2000s without any tangible benefit in terms of patient survival (Polat et al., 2017). A recent shift in paradigm would lead researchers to believe that inflammation is actually necessary to fight disease-associated infection ( Ding et al., 2018 ). However, these descriptions are relatively new and treatments for the disease are still being investigated.

Sepsis is basically an inflammatory disease mediated by the host’s immune response. The innate immune response is facilitated by activation of pattern recognition receptors (PRR) during early sepsis. The receptor response is highly dynamic and can be elicited by both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), such as mitochondria released from injured tissues (Mogensen, 2009; Hauser and Otterbein, 2018). At the organismal level, surface receptors of complement, epithelial, endothelial, and disseminated immune surveillance cells promote such responses ( Takeuchi and Akira, 2010 ). The intracellular signaling process is quite complex; It involves complementary and/or redundant roles for numerous signaling pathways, ultimately leading to the expression of genes involved in adaptive immunity and inflammation. However, dysregulated hyperinflammation can lead to many symptoms, including disseminated intravascular coagulation (DIC) seen in the early stage of sepsis and subsequent multiple organ dysfunction syndrome (MODS), inflammation-coagulation due to abnormal platelet activation, peripheral vasodilation leading to low blood pressure. . blood pressure and renal failure leading to hypoperfusion of the kidney ( Dhooria et al., 2016 ; Wang et al., 2018 ). Therefore, sepsis is a multifaceted disease that manifests in many forms, including endocrine dysfunction, coagulopathy, polyneuropathy, complement activation, and polyneuropathy, all resulting from dysregulated inflammation (Figure 1).

Figure 1. Sepsis is a multifaceted disease. There are numerous disorders involving many different organs in sepsis, ranging from altered coagulation to immunosuppression, inflammation and multiple organ failure.

Inflammation is an important step in alerting the immune system to the presence of infection so that host white blood cells can quickly locate and fight the pathogen (Weighardt et al., 2000). This response is typically tightly controlled; Once the infection resolves, inflammation subsides and the host’s white blood cells subsequently return to basal levels. When homeostasis is achieved, excessive inflammation and immune cell activity are avoided and the immune system can prepare itself to respond effectively to future infection (Newton and Dixit, 2012). During sepsis, the stimulus recognized by the immune system is much greater than during normal infections, from PAMP-like endotoxins and viruses to DAMPs during severe trauma ( Hotchkiss et al., 2016 ). The immediate result is a cytokine storm that occurs due to overstimulation of large numbers of white blood cells that recognize these factors. This dysregulation in response causes numerous symptoms that make sepsis distinctly different from normal infections, regardless of severity (Martin, 2012). When the immune system functions normally, it can fight off most infections, and an unnoticeable amount of inflammation occurs before pathogens are cleared from the host. The ability to resolve most infections so quickly, with little harm to the host, is due to the tight regulation of cytokines. Cytokines are essential in the process of initiating and enhancing the innate immune response as well as the adaptive immune response ( Banyer et al., 2000 ). However, high levels of inflammatory cytokines may coexist with significant innate immune suppression, leading to nosocomial infections ( Hall et al., 2013 ).

Inflammatory Skin Conditions: Eczema, Seborrheic Dermatitis, And Psoriasis

In addition to many different antigenic components resulting from bacteria, viruses and fungi, tissue trauma is also known as the causative agents of sepsis. Common pathogens repeatedly isolated from septic patients include the gram-positive Staphylococcus aureus and Streptococcus pneumoniae and the gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa (Martin et al., 2003). PAMPs, such as LPS, are recognized by toll-like receptors (TLRs) expressed on antigen-presenting cells (APCs), such as macrophages and dendritic cells ( Poltorak et al., 1998 ). APCs express a diversity of these TLRs containing leucine-rich repeats that act to sense these antigens and elicit responses against them ( Kawai and Akira, 2010 ). Upon contact of receptors with cognate ligands, proinflammatory intermediates are activated; some of these are phosphorylation-activated mitogen-activated protein kinases (MAPKs), signal transducers and activators of transcription (STAT), Janus kinases (JAK), and nuclear. factor κ (kappa)—light chain enhancer of activated B cells (NF-κB)—translocates to the nucleus. As a result, gene expression is initiated to promote inflammatory cytokine and chemokine production (Johnston et al., 1995). This finely tuned process depends on the repertoire of PAMPs, DAMPs, and induced signaling pathways to determine the intensity and pathway of the response in an effort to reestablish host homeostasis. In the septic response, excessive inflammation due to dysregulated intrinsic mechanisms is associated with pathology ( Surbatovic et al., 2013 ).

The transcription complex NF-κB is triggered in response to numerous extracellular inflammatory stimuli ( Sen and Baltimore, 1986 ; Pahl, 1999 ). Activation of NF-κB by post-translational mechanisms induces the expression of early activation genes, including IL-1/12/18 and type-1 IFNs, to name a few ( Naumann and Scheidereit, 1994 ). These inflammatory cytokines exacerbate the inflammatory response by initiating the synthesis of other cytokines and chemokines such as IL-6/8, IFN-γ, and CXC-chemokine ligands. Stimulation of PRRs leading to the inflammatory cascade results in stimulation of adaptive immune components.

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