Journal of Pathology

Severe acute respiratory syndrome (SARS) is an acute infectious disease that spreads mainly via the respiratory route. A distinct coronavirus (SARS‐CoV) has been identified as the aetiological agent of SARS. Recently, a metallopeptidase named angiotensin‐converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS‐CoV. Although ACE2 mRNA is known to be present in virtually all organs, its protein expression is largely unknown. Since identifying the possible route of infection has major implications for understanding the pathogenesis and future treatment strategies for SARS, the present study investigated the localization of ACE2 protein in various human organs (oral and nasal mucosa, nasopharynx, lung, stomach, small intestine, colon, skin, lymph nodes, thymus, bone marrow, spleen, liver, kidney, and brain). The most remarkable finding was the surface expression of ACE2 protein on lung alveolar epithelial cells and enterocytes of the small intestine. Furthermore, ACE2 was present in arterial and venous endothelial cells and arterial smooth muscle cells in all organs studied. In conclusion, ACE2 is abundantly present in humans in the epithelia of the lung and small intestine, which might provide possible routes of entry for the SARS‐CoV. This epithelial expression, together with the presence of ACE2 in vascular endothelium, also provides a first step in understanding the pathogenesis of the main SARS disease manifestations. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Although current treatments for fibrotic diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis typically target the inflammatory response, there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen‐producing cell. Myofibroblasts are generated from a variety of sources including resident mesenchymal cells, epithelial and endothelial cells in processes termed epithelial/endothelial‐mesenchymal (EMT/EndMT) transition, as well as from circulating fibroblast‐like cells called fibrocytes that are derived from bone‐marrow stem cells. Myofibroblasts are activated by a variety of mechanisms, including paracrine signals derived from lymphocytes and macrophages, autocrine factors secreted by myofibroblasts, and pathogen‐associated molecular patterns (PAMPS) produced by pathogenic organisms that interact with pattern recognition receptors (i.e. TLRs) on fibroblasts. Cytokines (IL‐13, IL‐21, TGF‐β1), chemokines (MCP‐1, MIP‐1β), angiogenic factors (VEGF), growth factors (PDGF), peroxisome proliferator‐activated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin–angiotensin–aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being investigated as potential targets of antifibrotic drugs. This review explores our current understanding of the cellular and molecular mechanisms of fibrogenesis. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Autophagy is a self‐degradative process that is important for balancing sources of energy at critical times in development and in response to nutrient stress. Autophagy also plays a housekeeping role in removing misfolded or aggregated proteins, clearing damaged organelles, such as mitochondria, endoplasmic reticulum and peroxisomes, as well as eliminating intracellular pathogens. Thus, autophagy is generally thought of as a survival mechanism, although its deregulation has been linked to non‐apoptotic cell death. Autophagy can be either non‐selective or selective in the removal of specific organelles, ribosomes and protein aggregates, although the mechanisms regulating aspects of selective autophagy are not fully worked out. In addition to elimination of intracellular aggregates and damaged organelles, autophagy promotes cellular senescence and cell surface antigen presentation, protects against genome instability and prevents necrosis, giving it a key role in preventing diseases such as cancer, neurodegeneration, cardiomyopathy, diabetes, liver disease, autoimmune diseases and infections. This review summarizes the most up‐to‐date findings on how autophagy is executed and regulated at the molecular level and how its disruption can lead to disease. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Mononuclear phagocyte plasticity includes the expression of functions related to the resolution of inflammation, tissue repair and remodelling, particularly when these cells are set in an M2 or an M2‐like activation mode. Macrophages are credited with an essential role in remodelling during ontogenesis. In extraembryonic life, under homeostatic conditions, the macrophage trophic and remodelling functions are recapitulated in tissues such as bone, mammary gland, decidua and placenta. In pathology, macrophages are key components of tissue repair and remodelling that occur during wound healing, allergy, parasite infection and cancer. Interaction with cells bearing stem or progenitor cell properties is likely an important component of the role of macrophages in repair and remodelling. These properties of cells of the monocyte–macrophage lineage may represent a tool and a target for therapeutic exploitation.

The role of macrophages in tumour growth and development is complex and multifaceted. Whilst there is limited evidence that tumour‐associated macrophages (TAMs) can be directly tumouricidal and stimulate the anti‐tumour activity of T cells, there is now contrasting evidence that tumour cells are able to block or evade the activity of TAMs at the tumour site. In some cases, tumour‐derived molecules even redirect TAM activities to promote tumour survival and growth. Indeed, evidence has emerged for a symbiotic relationship between tumour cells and TAMs, in which tumour cells attract TAMs and sustain their survival, with TAMs then responding to micro‐environmental factors in tumours such as hypoxia (low oxygen tension) by producing important mitogens as well as various growth factors and enzymes that stimulate tumour angiogenesis. This review presents evidence for the number and/or distribution of TAMs being linked to prognosis in different types of human malignancy. It also outlines the range of pro‐ and anti‐tumour functions performed by TAMs, and the novel therapies recently devised using TAMs to stimulate host immune responses or deliver therapeutic gene constructs to solid tumours. Copyright © 2002 John Wiley & Sons, Ltd.

TNF was originally described as a circulating factor that can cause necrosis of tumours, but has since been identified as a key regulator of the inflammatory response. This review describes the known signalling pathways and cell biological effects of TNF, and our understanding of the role of TNF in human disease. TNF interacts with two different receptors, designated TNFR1 and TNFR2, which are differentially expressed on cells and tissues and initiate both distinct and overlapping signal transduction pathways. These diverse signalling cascades lead to a range of cellular responses, which include cell death, survival, differentiation, proliferation and migration. Vascular endothelial cells respond to TNF by undergoing a number of pro‐inflammatory changes, which increase leukocyte adhesion, transendothelial migration and vascular leak and promote thrombosis. The central role of TNF in inflammation has been demonstrated by the ability of agents that block the action of TNF to treat a range of inflammatory conditions, including rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease and psoriasis. The increased incidence of infection in patients receiving anti‐TNF treatment has highlighted the physiological role of TNF in infectious diseases. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

In glucocorticoid‐treated rat thymocytes and the murine lymphoid cell lines L5178 and S49 the morphology of apoptosis is associated with chromatin cleavage. The cleavage is at internucleosomal sites, apparently through activation of an endogenous endonuclease. In variants of the cell lines selected for resistance to glucocorticoid, neither apoptosis nor chromatin cleavage were observed after steroid treatment, and steroid receptors were undetectable. In thymocytes, both the morphological changes of apoptosis and chromatin cleavage were inhibited by cycloheximide and actinomycin D. The calcium–magnesium ionophore A23187 induced apoptosis and chromatin cleavage in thymocytes, and these effects were also inhibited by cycloheximide. The data confirm that the condensed chromatin which characterizes apoptosis morphologically consists of endogenously digested chromatin fragments. They also provide support for the view that at least some cells enter apoptosis by a process dependent upon macromolecular synthesis.

The demonstration that fibroblastic cells acquire contractile features during the healing of an open wound, thus modulating into myofibroblasts, has open a new perspective in the understanding of mechanisms leading to wound closure and fibrocontractive diseases. Myofibroblasts synthesize extracellular matrix components such as collagen types I and III and during normal wound healing disappear by apoptosis when epithelialization occurs. The transition from fibroblasts to myofibroblasts is influenced by mechanical stress, TGF‐β and cellular fibronectin (ED‐A splice variant). These factors also play important roles in the development of fibrocontractive changes, such as those observed in liver cirrhosis, renal fibrosis, and stroma reaction to epithelial tumours. Copyright © 2003 John Wiley & Sons, Ltd.

Inflammatory response leading to organ dysfunction and failure continues to be the major problem after injury in many clinical conditions such as sepsis, severe burns, acute pancreatitis, haemorrhagic shock, and trauma. In general terms, systemic inflammatory response syndrome (SIRS) is an entirely normal response to injury. Systemic leukocyte activation, however, is a direct consequence of a SIRS and if excessive, can lead to distant organ damage and multiple organ dysfunction syndrome (MODS). When SIRS leads to MODS and organ failure, the mortality becomes high and can be more than 50%. Acute lung injury that clinically manifests as acute respiratory distress syndrome (ARDS) is a major component of MODS of various aetiologies. Inflammatory mediators play a key role in the pathogenesis of ARDS, which is the primary cause of death in these conditions. This review summarizes recent studies that demonstrate the critical role played by inflammatory mediators such as tumour necrosis factor (TNF)‐α, interleukin (IL)‐1β, IL‐6, platelet activating factor (PAF), IL‐10, granulocyte macrophage‐colony stimulating factor (GM‐CSF), C5a, intercellular adhesion molecule (ICAM)‐1, substance P, chemokines, VEGF, IGF‐I, KGF, reactive oxygen species (ROS), and reactive nitrogen species (RNS) in the pathogenesis of ARDS. It is reasonable to speculate that elucidation of the key mediators in ARDS coupled with the discovery of specific inhibitors would make it possible to develop clinically effective anti‐inflammatory therapy. Copyright © 2004 John Wiley & Sons, Ltd.