Steven L. Kunkel

CYTOKINES IN PROLIFERATIVE DIABETIC RETINOPATHY AND PROLIFERATIVE VITREORETINOPATHY

We determined whether interleukin-8, monocyte chemotactic protein-1, and macrophage-colony stimulating factor are present in the vitreous of patients with proliferative diabetic retinopathy (PDR) or proliferative vitreoretinopathy (PVR). The levels of these cytokines were measured by specific enzyme-linked immunoassays in vitreous from 30 patients with PDR, 13 patients with PVR, and 26 control individuals, including 10 cadaver eyes and 16 patients with idiopathic macular holes, idiopathic macular puckers, vitreous hemorrhages, or uncomplicated retinal detachments. Detectable levels of interleukin-8 were found in 90% of vitreous samples of patients with PDR, 85% with PVR, and 58% of control samples. IL-8 was significantly increased in PDR (mean +/- SEM; 25.0 +/- 5.3 ng/ml; p = 0.01), but not in PVR (11.9 +/- 3.9 ng/ml; p = 0.50) compared to control human vitreous (8.5 +/- 2.5 2.5 ng/ml). MCP-1 was detected in 90% of vitreous samples of patients with PDR, 92% with PVR, and 81% of control samples. MCP-1 was significantly increased in PDR (6.2 +/- 0.9 ng/ml, p = 0.001) and PVR (7.7 +/- 2.5 ng/ml, p = 0.001) over the levels in control vitreous (1.2 +/- 0.2 ng/ml). M-CSF was detected in 94% of vitreous samples of patients with PDR, 88% with PVR, and 92% from control vitreous. M-CSF was significantly elevated in PDR (32.3 +/- 8.3 ng/ml, p = 0.03), but not in PVR (23.6 +/- 12.8 ng/ml, p = 0.4) compared to control (10.7 +/- 3.5 ng/ml). Our results suggest that IL-8, MCP-1, and M-CSF participate in the pathogenesis of PDR and PVR.

C-X-C Chemokines and Lung Cancer Angiogenesis

Angiogenesis is an essential biologic event encountered in vertebrate animals (6,35,36,38,39,60,92). Embryonic development, the formation of inflammatory granulation tissue during wound healing, chronic inflammation, and the growth of malignant solid tumors represent physiologic and pathologic processes that are strictly dependent on neovascularization. The rate of normal capillary endothelial cell turnover in adults is typically measured in months or years (30,132). However, during wound repair and development of granulation tissue, resting endothelial cells become activated, leading to proteolytic degradation of their basement membrane and surrounding extracellular matrix, migration, proliferation, and establishment of newly functioning capillaries within a matter of days (60). An important feature of wound-associated angiogenesis is that it is locally controlled and transient. As rapidly as neovascularization occurs, these new vessels virtually disappear, returning the tissue vasculature to a homeostatic environment. This abrupt termination of angiogenesis in the context of the resolution of wound repair supports the notion of two possible mechanisms of control. First, there is probably a marked reduction in the synthesis and/or elaboration of angiogenic mediators. Second, a simultaneous increase occurs in the levels of factors that inhibit neovascularization (15). In contrast to the precise regulation of angiogenesis that accompanies wound repair, dysregulation of angiogenesis can lead to an imbalance in overexpression of angiogenic and underexpression of angiostatic factors that contributes to the pathogenesis of solid tumor growth. Thus, the complement of positive and negative regulators of angiogenesis may vary among different physiologic and pathologic settings. The recognition of this dual mechanism of control is critical in order to gain insight into this complex process and to understand its significance in regulating net angiogenesis.

The Function of Chemokines in Health and Disease

The cascade of events that dictate the normal physiologic processes leading to the initiation, maintenance, and final resolution of inflammation is the result of the host responding to a variety of direct or indirect stimuli. Although these stimuli may represent either infectious agents (viruses, bacteria, and protozoans) or noninfectious processes (trauma, autoimmune disorders, and ischemia/reperfusion injury), they all result in the activation and directed migration of leukocytes into an area of tissue injury. Our current understanding of inflammation suggests that the recruitment of leukocytes from the lumen of a vessel into a localized area of injury depends on an interrelated network of events, which must occur with some fidelity in order for the cells to arrive successfully at a site of inflammation. Although many of the steps involved in leukocyte activation and elicitation have been identified, a complete understanding of these processes, including the subsequent tissue injury, are not entirely known.

The Role of Chemokines in Linking Innate and Adaptive Immunity

Of the myriad of immune defense systems that exist in nature, the mammalian defense system is clearly the most sophisticated and successful. This immune sophistication arises from the fact that immune events in mammals involve a progression of detailed events leading to exquisite specificity toward a bacterial, viral, or fungal byproduct, or a nonself protein. On its simplest level, the immune response in mammals is divided into two major components: the nonspecific innate and the adaptive or acquired immune systems (1). When examined phylogenetically, the innate immune system appears to be more ancient than its acquired counterpart, and, historically, it was thought that the innate response was nonselectively directed toward microorganisms. However, the distinctions between the innate and acquired immune responses are now widely viewed as somewhat artificial, as it has been shown that both arms of the immune response share several common features including amazing degrees of specificity for pathogens and foreign antigens (2). Indeed, there is increasing evidence that the induction of different types of effector adaptive responses is directed by the innate immune system after its highly selective recognition of particular groups of pathogens through pattern recognition molecules (i.e., the Toll-like receptor family) and the elaboration of soluble protein signals that activate the relevant lymphoid cell population.

The Role of CC Chemokines in Th1- and Th2-Type Pulmonary Inflammation Models

Elucidation of the factors involved in the initiation and persistence of inflammatory diseases within the interstitial space of the lung has garnered great research interest over the past two decades. Interstitial lung diseases are defined as pulmonary inflammatory disorders that lead to excessive tissue injury and progressive fibrosis. Idiopathic fibrosis and end-stage sarcoidosis are two clinically predominant examples (1). Whereas the list of inflammatory mediators present in interstitial lung diseases has grown immensely to include cytokines, growth factors, prostanoids, eicosanoids, and free radicals (2) little is presently known about the manner in which these factors initiate and sustain these complex diseases. An inflammatory response to infection or injury within the lung is typically characterized by the de novo generation of inflammatory mediators by tissue resident immune (i.e., alveolar macrophages and mast cells) and nonimmune (i.e., epithelial) cells. These mediators modulate the function of these cells and also promote the infiltration of lymphocytes and phagocytes, and the concerted efforts of all of these cells facilitate the destruction and/or clearance of the inflammatory stimulus. Once this aim has been achieved, the last stage of the inflammatory response involves the restoration of the tissue to its original state. Clearly, the recruitment and tissue-reparative stages must be closely regulated in the lung because excessive tissue injury or overexuberant tissue healing can significantly disrupt the pulmonary architecture and even lead to respiratory failure (3). In prolonged inflammatory diseases of the lung, clinical and laboratory evidence suggest that the inability of the lung to contain the inflammatory process and/or repair itself correctly is related to the persistence of one or several inflammatory signals (4).

Cytokines and Lung Injury

Pulmonary inflammation represents a consequence of local tissue responses to a variety of direct or indirect stimuli. Many clinical entities, including trauma, infection, ischemia-reperfusion injury, as well as the syndrome of acute respiratory distress in adults (ARDS), are characterized by varying degrees of pulmonary insult and the resulting impairment of normal gas exchange. These inflammatory responses involve coordinated interactions between immune and non-immune cells and are specifically initiated, maintained and finally resolved. A variety of mediators are involved in the coordination of these activities and include lipids, such as prostaglandins; a group of small peptides, including bradykinin; and numerous polypeptides, of which a group has been classified as cytokines.