SUMMARY

Mediators produced during inflammatory/immune responses dictate the type of response, as well as its magnitude (“quality and quantity”). The profile of cytokines and chemokines produced are responsible for the cell-to-cell communication that facilitates initial recognition of infection or damage. These signals, in turn, communicate with primary lymphoid tissues (the thymus and bone marrow) to mobilize inflammatory cells to the bloodstream. At the tissue site, chemokines and cytokines orchestrate leukocyte adhesion to vascular endothelium, extravasation, and localization of leukocytes at the site of inflammation. Recruitment of leukocyte populations into inflamed tissues is initiated by cytokine-induced expression of adhesion molecules on vascular endothelium. These adhesion molecules play an essential role in capturing and tethering circulating leukocytes from the bloodstream. Chemokines promote the tight adherence of leukocytes to activated endothelium, as well as direct the extravasation of cells into inflamed tissue. Cytokines and chemokines further coordinate the response of inflammatory effector cells as they arrive in inflamed tissues. The sequential activation and cellular recruitment cascades mediated by cytokines and chemokines are essential for successful resolution of infection or other tissue damage. However, overproduction or dysregulation of these inflammatory mediators can also lead to destructive, pathological consequences. This chapter will examine the role played by cytokines and chemokines in the initiation, amplification, and shaping of inflammatory responses.

The gastrointestinal (GI) tract is composed of a series of organs whose collective aim is to extract and absorb nutrients from food, and expel undigested matter as waste. As the lumen of the GI tract is essentially outside of the body, it is not surprising to find that the physical interface between “self” and the outside world is quite complex. The gut must be able to withstand fluctuations associated with changes in temperature, pH, and osmolarity, as well as overcome and respond to microbiota residence and the associated release of immunostimulatory molecules and detergent-like substances. As such, the mucosa has evolved to act as a first line of defense, its repertoire including (1) the spatial secretion of protective substances (acid, bicarbonate, and mucus); (2) the presence of tight junctions to limit the passive diffusion of harmful substances; (3) the mucosal microcirculation which enables rapid dilution/removal of noxious stimuli; and (4) the mucosal immune system where resident and blood-borne immunocytes and granulocytes are mobilized to initiate an appropriate inflammatory response. This so-called mucosal defense is supported by a catalogue of endogenous mediators; together these act to dampen the inflammatory response, which results from the aggressive accumulation of tissue-damaging metabolites.

The aim of this chapter is to review current knowledge regarding mediators involved in the pathogenesis of GI disease, with particular reference to nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy and colitis. We will address mediators that play a key role in the proresolution phase of inflammation, and discuss some of the new therapeutic approaches aimed at promoting mucosal healing and tissue homeostasis.

After tissue injury or exposure of the organ to a foreign body or infectious entity, a complex cascade of cellular and humoral events is initiated. These events, observed in virtually every organ system, including skin, muscle, meninges, dentition, bone, and visceral tissues, fall broadly under the rubric of “inflammation.” In general, this cascade serves to protect and maintain the functional integrity of the systems in the face of insult. The process activates the immune system and directs chemotactic agents, neutrophils, and mononuclear cells to migrate from the vascular bed to the injury site. The cardinal clinical signs of this process, rubor/calor (increased local blood flow) and tumor (swelling secondary to local plasma extravasation) are manifested to varying degrees in all of these tissues. The fourth cardinal sign, dolor (pain), typically accompanies such cascades. The biological processes whereby these inflammatory cascades serve to initiate and sustain a pain state are the focus of this commentary.

INFLAMMATORY PAIN PHENOTYPE

The acute application of a thermal or mechanical stimulus of such intensity as to potentially produce tissue injury will typically evoke a somatic escape response (e.g., a withdrawal of the stimulated limb) and an autonomic response (e.g., hypertension and tachycardia), a syndrome classically referred to by Sherrington as a nociceptive reflex [1]. These acute responses typically display four characteristics: (i) the magnitude of these responses varies directly with stimulus intensity; (ii) the latency varies inversely with stimulus intensity; (iii) the focus of the response is referred to as the specific site of stimulation (e.g., it is homotopic); and (iv) in the absence of tissue injury, removal of the acute stimulus results in a rapid attenuation of the sensation and the attendant behaviors.

Inflammation in the lung is common in both physiologic responses as well as many respiratory illnesses. In particular, chronic inflammation is associated with a variety of prevalent disorders, including asthma, chronic obstructive pulmonary disease, bronchiectasis, and interstitial lung diseases [1 – 3]. For purposes of host defense, an overexuberant inflammatory response can also lead to respiratory disorders. For example, inhalation of pathogens, toxins, or specific allergens initiates an acute inflammatory response that characterizes acute exacerbations of bronchiectasis, COPD, and asthma [1, 4]. Perhaps the most extensively investigated example of acute inflammation and its spontaneous resolution is pneumonia. In this chapter, a common clinical presentation of pneumonia is provided with examples of its radiographic appearance and histology during both the initiation and resolution phases of the illness.

Bea Coffin is a 56-year-old woman who presents with a new cough and dyspnea. She has felt ill for about 3 days. Her cough is productive of blood-tinged green phlegm. She has also had fevers, chills, and sweats that are getting worse. The symptoms began with the sudden onset of right sided chest pain that makes it difficult to take a deep breath. She has tried acetaminophen and an expectorant, but these interventions have not been successful in controlling her symptoms. She is a lifelong nonsmoker and has no significant past medical history.

PSORIASIS

Psoriasis is a common, chronic inflammatory skin disease with an overall prevalence of 2%–3% of the world population with a higher prevalence in the United States and Canada (4.6% and 4.7%, respectively) compared to a lower prevalence of 0.4–0.7% in Africans, African Americans, and Asians [1].

Psoriasis can appear at any age but there is a tendency toward a peak at ages 20–30 years and then again at ages 50–60 years. It has a chronic relapsing and remitting nature in response to a variety of stressors. It is rarely life threatening but is associated with a high degree of morbidity. Psoriasis can be limited to skin but can also be associated with debilitating arthritis in 5%–30% of sufferers. Its burden on health care economy is on par with cardiovascular disease, diabetes, and depression.

Its aetiology is multifactorial, combining genetics, immunity, and environmental triggers. There is a 2–3-fold increase in risk of developing psoriasis in monozygotic versus dizygotic twins, and results of WGAS (whole genome wide association scans) show that psoriasis is a complex genetic disease [2]. At least 19 gene loci have been implicated but replication of a single locus has been provided for only a few of these. One of these regions lies on a 210-kb stretch of DNA on the short arm of chromosome 6 (termed PSORS1) which includes genes coding for HLA-Cw6, a potential immunological candidate gene, and corneodesmosin, a potential epidermal structure related candidate gene [3].

INTRODUCTION

Named after their affinity for alkaline stains and possessed of numerous potent inflammatory substances, basophils are the rarest of the granulocytes, typically constituting 0.5%–1.5% of peripheral blood leukocytes. Studied both for their suspected effector roles in parasitic and allergic diseases and for their similarity to mast cells, these peripheral blood cells are increasingly hypothesized to have important immunoregulatory functions. This chapter focuses primarily on the human basophil, but makes reference to the basophils of other species to point out phenotypic differences from human basophils, to describe phenomena that have been elucidated best in nonhuman basophils, and to describe murine and other mammalian models of disease in which the role of the basophil has been explored.

IDENTIFICATION

Historical Discovery

Paul Ehrlich, the German Nobel prize winner who made foundational contributions to immunology, is credited with the first description of the human basophil in 1879 in a paper in which he also proposed the name Mastzellen for connective tissue cells that also took up aniline dyes in their numerous cytoplasmic granules. Because of their infrequency among peripheral blood leukocytes, basophils were given scant attention until their functional similarity to mast cells in terms of IgE-mediated histamine release was appreciated more than eight decades later.

Development

Like other leukocytes, basophils derive from totipotent hematopoietic stem cells, and are believed to arise from the common myeloid precursor by means of the common granulocyte precursor.

The acute inflammatory response is the body's first system of alarm signals that are directed toward containment and elimination of microbial invaders. Uncontrolled inflammation has emerged as a pathophysiologic basis to many of the widely occurring diseases in the general population that were not initially known to be linked to events in the inflammatory response. These include cardiovascular diseases and neurodegenerative diseases (including Alzheimer's disease), and it has now become apparent that inflammation is an important component of cancer progression and the persistence of neuropathic pain. These are diseases that cross many disciplines. To better manage treatment, diagnosis, and prevention of diseases, multidisciplinary research efforts are under way in both academic and industry settings. Since knowledge of the acute inflammatory response in itself spans many disciplines, the editors' mission is to provide in this text an introduction to the cell types, chemical mediators, and general mechanisms that are involved in this primordial first response of the host to invasion. It is also now clear that the termination or the resolution of the acute inflammatory response is an active process, which is pivotal and is the outcome of the acute response. As an endogenous programmed response, the terrain of resolution holds many new possibilities for treatment and prevention of uncontrolled inflammation in a wide range of diseases.

INTRODUCTION

Macrophages are a major leukocyte involved in orchestrating inflammatory responses. Their name is derived from the Greek term “big eaters” (makros, large; and phagein, eat). This gives some insight into the primary function of this cell in clearance of invading pathogens, cell debris, and apoptotic cells by a process of engulfment and digestion called “phagocytosis.” However, the role of the macrophage goes beyond that of what its name suggests. They are endowed with the ability to rapidly react to and secrete a plethora of biological agents and mediators that can influence the initiation, progression, and resolution of an inflammatory response and coordinate processes to establish acquired immunity against specific pathogens. This chapter is an overview of the basics of macrophage biology and function, with particular insights into the involvement of macrophages in disease pathogenesis as well as pharmacological modulation of macrophage responses as targets for treatment of disease.

IDENTIFICATION

Historical Discovery

Elie Metchnikoff first used the term “macrophage” to describe large mononuclear phagocytic cells he observed in tissues over 100 years ago. Macrophages are now recognized as the major phagocytic cell type with diverse characteristics and localities around the body where they are important for both innate and acquired immune responses as well as maintenance of tissue homeostasis and regulation of various processes subsidiary to the immune defense such as hematopoiesis.

INTRODUCTION

Polymorphonuclear neutrophil leukocytes (PMN) are “professional” phagocytic cells of the innate immune system that act as the first line of defense against invading pathogens, principally bacteria and fungi but also viruses. Because of their powerful micro bicidal equipment, they have a major role in inflammatory responses other than anti-infectious defenses. In fact, after agonist challenge, neutrophils have the capacity to generate reactive oxygen species (ROS) and release lytic enzymes with potent antimicrobial activity, which are all essential for pathogen killing. Conversely, PMN-derived ROS and proteases may also damage the surrounding tissues if released in an uncontrolled manner, as observed in inflammatory diseases dominated by neutrophils. Nevertheless, it is now clear that the role of neutrophils goes far beyond phagocytosis and pathogen killing, as uncovered in the past two decades (Figure 4B.1). For instance, it has been documented that neutrophils have the capacity to migrate toward the lymph nodes and to express major histocompatibility complex class II (MHC II) molecules, once appropriately activated. An additional and fascinating aspect that has gradually come to light is the ability of neutrophils to newly express a number of genes, whose products lie at the core of inflammatory and immune responses. Not only neutrophils synthesize numerous proteins involved in their effector functions, including some complement components and Fc receptors, but they also produce a variety of cytokines and chemokines.

Cytokines and chemokines are peptide mediators that regulate a broad range of processes involved in the pathogenesis of inflammatory diseases and cancer. It is well established that an imbalance cytokine or chemokine activities can favor chronic inflammation leading to organ failure. Chemokines and cytokines are also implicated in malignant disease with links to tumor progression, angiogenesis, and invasion. Biological therapies targeting cytokines and chemokines have already improved outcomes of inflammatory disease and clinical trials are ongoing in cancer patients. Targeting tumor necrosis factor (TNF)-α represents a major success story for this approach. Anti-TNF-α was the first antibody against an inflammatory cytokine demonstrated to be efficacious in human disease and it showed over the years to be effective in a range of inflammatory diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and more recently, cancer.

CANCER AND INFLAMMATION

The cells and mediators of inflammation also form a major part of the tumor microenvironment. In some cancers, inflammatory conditions precede development of malignancy; in others, oncogenic changes drive a tumor-promoting inflammatory milieu. Whatever its origin, this “smoldering” inflammation aids proliferation and survival of malignant cells, angiogenesis, and metastasis; subverts adaptive immunity, and alters response to hormones and chemotherapeutic agents [1, 2]. The cytokine (Figure 19.1) and chemokine network (Figure 19.2) is of great importance in the processes of cancer-related inflammation regulating both host and malignant cells in the tumor microenvironment [3].

SUMMARY

It is without doubt that resolution of acute inflammation is under strict checkpoint control by endogenous proresolution factors. It is these factors and mechanisms inherent in resolution that are crucial in preventing excessive tissue injury, autoimmunity, and chronic inflammation. In this chapter, resolution and the factors that control it are detailed to underline its importance in human pathology and highlight new and more effective treatment modalities with fewer side effects for chronic inflammatory diseases.

INFLAMMATION IN HEALTH AND DISEASE

Inflammation is a beneficial host response to foreign challenge or tissue injury that leads ultimately to the restoration of tissue structure and function. It is a reaction of the microcirculation that is characterized by the movement of serum proteins and leukocytes from the blood to the extravascular tissue. This movement is regulated by the sequential release of vasoactive and chemotactic mediators, which contribute to the cardinal signs of inflammation – heat, redness, swelling, pain, and loss of tissue function (Figure 2.1A). Local vasodilation increases regional blood flow to the inflamed area and, together with an increase in microvascular permeability, results in the loss of fluid and plasma proteins into the tissues. Concomitantly, there is an upregulation of adhesion molecule expression on endothelial cells and the release of chemotactic factors from the inflamed site, which facilitate the adherence of circulating cells to the vascular endothelium and their migration into the affected area.

INTRODUCTION

In the human kidney, some 1 million glomeruli filter 180 liters of plasma daily, allowing passage of low-molecular-weight products while restricting the passage of albumin and larger macromolecules. The resulting urine is extensively modified in the renal tubular system, with changes to both composition and volume necessary to maintain extracellular volume and homeostasis. As a consequence of this, immune complexes formed in the circulation are delivered at a high rate to the intraglomerular capillary bed and trapping occurs primarily in the mesangium and or on the subendothelial surface of the capillary wall. In contrast to in vitro models, which are somewhat limited to assessing isolated cell, antibody, and antigen function, or indeed, human biopsy specimens which give a snapshot at a particular clinical stage, in vivo animal models can outline how structure and function changes with initiation, progression, and potential regression within affected organs and the various cellular and humoral factors involved in disease progression. The nephron is the functioning unit of the kidney and the glomerulus is a branching network of capillaries responsible for plasma filtration and the initial step in urine formation. This chapter will review the use of experimental animal models in delineating the pathogenesis of glomerulonephritis (GN). GN at its basic definition is the term used to describe an inflammatory process involving the glomeruli characterized morphologically by an influx of leucocytes and cellular proliferation often accompanied by glomerular capillary wall abnormalities.