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Inflammatory responses and inflammation-associated diseases in organs
Linlin Chen,#1 Huidan Deng,#1 Hengmin Cui,1,2 Jing Fang,1,2 Zhicai Zuo,1,2 Junliang Deng,1,2 Yinglun Li,1,2 Xun Wang,1,2 and Ling Zhao1,2
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Abstract
Inflammation is a biological response of the immune system that can be triggered by a variety of factors, including pathogens, damaged cells and toxic compounds. These factors may induce acute and/or chronic inflammatory responses in the heart, pancreas, liver, kidney, lung, brain, intestinal tract and reproductive system, potentially leading to tissue damage or disease. Both infectious and non-infectious agents and cell damage activate inflammatory cells and trigger inflammatory signaling pathways, most commonly the NF-κB, MAPK, and JAK-STAT pathways. Here, we review inflammatory responses within organs, focusing on the etiology of inflammation, inflammatory response mechanisms, resolution of inflammation, and organ-specific inflammatory responses.
Keywords: inflammation, inflammatory signaling pathways, chemokines, cytokines, organ diseases
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INTRODUCTION
Inflammation is the immune system's response to harmful stimuli, such as pathogens, damaged cells, toxic compounds, or irradiation [1], and acts by removing injurious stimuli and initiating the healing process [2]. Inflammation is therefore a defense mechanism that is vital to health [3]. Usually, during acute inflammatory responses, cellular and molecular events and interactions efficiently minimize impending injury or infection. This mitigation process contributes to restoration of tissue homeostasis and resolution of the acute inflammation. However, uncontrolled acute inflammation may become chronic, contributing to a variety of chronic inflammatory diseases [4].
At the tissue level, inflammation is characterized by redness, swelling, heat, pain, and loss of tissue function, which result from local immune, vascular and inflammatory cell responses to infection or injury [5]. Important microcirculatory events that occur during the inflammatory process include vascular permeability changes, leukocyte recruitment and accumulation, and inflammatory mediator release [2, 6].
Various pathogenic factors, such as infection, tissue injury, or cardiac infarction, can induce inflammation by causing tissue damage. The etiologies of inflammation can be infectious or non-infectious (Table (Table1).1). In response to tissue injury, the body initiates a chemical signaling cascade that stimulates responses aimed at healing affected tissues. These signals activate leukocyte chemotaxis from the general circulation to sites of damage. These activated leukocytes produce cytokines that induce inflammatory responses [7].
Table 1
Etiology of inflammation
Non-infectious factors Infectious factors
Physical: burn, frostbite, physical injury, foreign bodies, trauma, lionizing radiation
Chemical: glucose, fatty acids, toxins, alcohol, chemical irritants (including fluoride, nickel and other trace elements)
Biological: damaged cells
Psychological: excitement Bacteria viruses other microorganisms
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INFLAMMATORY RESPONSE MECHANISMS
The inflammatory response is the coordinate activation of signaling pathways that regulate inflammatory mediator levels in resident tissue cells and inflammatory cells recruited from the blood [8]. Inflammation is a common pathogenesis of many chronic diseases, including cardiovascular and bowel diseases, diabetes, arthritis, and cancer [9]. Although inflammatory response processes depend on the precise nature of the initial stimulus and its location in the body, they all share a common mechanism, which can be summarized as follows: 1) cell surface pattern receptors recognize detrimental stimuli; 2) inflammatory pathways are activated; 3) inflammatory markers are released; and 4) inflammatory cells are recruited.
Pattern recognition receptor activation
Microbial structures known as pathogen-associated molecular patterns (PAMPs) can trigger the inflammatory response through activation of germline-encoded pattern-recognition receptors (PRRs) expressed in both immune and nonimmune cells [10, 11]. Some PRRs also recognize various endogenous signals activated during tissue or cell damage and are known as danger-associated molecular patterns (DAMPS) [11]. DAMPs are host biomolecules that can initiate and perpetuate a non-infectious inflammatory response [12]. Disrupted cells can also recruit innate inflammatory cells in the absence of pathogens by releasing DAMPs [13].
Classes of PRR families include the Toll-like receptors (TLRs), C-type lectin receptors (CLRs), retinoic acid-inducible gene (RIG)-I-like receptors (RLRs), and NOD-like receptors (NLRs) [5]. TLRs are a family of highly conserved, mammalian PRRs that participate in the activation of the inflammatory response [14]. More than ten members of the TLR family have been identified, and TLRs are the most well-studied of the known PRRs [15]. Transmission of PAMPs and DAMPs is mediated by myeloid differentiation factor-88 (MyD88) along with TLRs. Signaling through TLRs activates an intracellular signaling cascade [16, 17] that leads to nuclear translocation of transcription factors, such as activator protein-1 (AP-1) and NF-κB or interferon regulatory factor 3 (IRF3) (Figure (Figure1).1). DAMPs and PAMPs share receptors, such as TLR4, suggesting similarities between infectious and noninfectious inflammatory responses [18, 19].
RESOLUTION OF INFLAMMATION
To prevent progression from acute inflammation to persistent, chronic inflammation, the inflammatory response must be suppressed to prevent additional tissue damage. Inflammation resolution is a well-managed process involving the spatially- and temporally-controlled production of mediators, during which chemokine gradients are diluted over time. Circulating white blood cells eventually no longer sense these gradients and are not recruited to sites of injury. Dysregulation of this process can lead to uncontrolled chronic inflammation [78]. Inflammation resolution processes that rectify tissue homeostasis include reduction or cessation of tissue infiltration by neutrophils and apoptosis of spent neutrophils, counter-regulation of chemokines and cytokines, macrophage transformation from classically to alternatively activated cells, and initiation of healing [79, 80].
Chronic inflammation occurs when acute inflammatory mechanisms fail to eliminate tissue injury [81], and may lead to a host of diseases, such as cardiovascular diseases, atherosclerosis, type 2 diabetes, rheumatoid arthritis, and cancers [82]. Understanding the common mechanisms that orchestrate dysfunction in the various organ systems will allow for development and production of improved targeted therapies.
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ORGAN-SPECIFIC INFLAMMATORY RESPONSES
Inflammation has long been recognized as a major cause of disease. It is estimated that some 15% of human cancers are associated with chronic infection and inflammation [83]. Acute and chronic inflammation-mediated tissue injury is observed in many organ systems, including the heart, pancreas, liver, kidney, lung, brain, intestinal tract, and reproductive system.
Lung
Lung inflammatory diseases involve complex interactions among and between structural and immune cells [139]. Lung inflammation results predominantly from tissue exposure to bacterial and viral pathogens, and/or environmental pollutants. Excessive acute inflammation and subsequent lung injury can cause pulmonary fibrosis and impair gas exchange. Unresolved lung injury and chronic inflammation are frequently observed in acute respiratory distress syndrome, cystic fibrosis, chronic obstructive pulmonary disease (COPD), and asthma [140–142]. Approximately 90% of COPD cases are associated with cigarette smoking-induced inflammation in small airways and lung parenchyma [143]. Cigarette smoking is a major risk factor for COPD, which involves both systemic and pulmonary inflammation. Long-term smoking can cause macrophage, neutrophil, and activated T lymphocyte infiltration into airways, and promote production of chemokines, oxygen radicals, proteases, and cytokines, including that of TNF-α, IL-6 and IL-8, in the lung [144].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805548/