The 18 glycosyl hydrolase family of chitinases is an ancient gene family that is widely expressed from prokaryotes to eukaryotes. In mammals, despite the absence of endogenous chitin, a number of chitinases and chitinase-like proteins (C/CLPs) have been identified. However, their roles have only recently begun to be elucidated. Acidic mammalian chitinase (AMCase) inhibits chitin-induced innate inflammation; augments chitin-free, allergen-induced Th2 inflammation; and mediates effector functions of IL-13. The CLPs BRP-39/YKL-40 (also termed chitinase 3-like 1) inhibit oxidant-induced lung injury, augments adaptive Th2 immunity, regulates apoptosis, stimulates alternative macrophage activation, and contributes to fibrosis and wound healing. In accord with these findings, levels of YKL-40 in the lung and serum are increased in asthma and other inflammatory and remodeling disorders and often correlate with disease severity. Our understanding of the roles of C/CLPs in inflammation, tissue remodeling, and tissue injury in health and disease is reviewed below.

Cigarette smoke exposure is the major cause of chronic obstructive pulmonary disease (COPD). However, only a minority of smokers develop significant COPD, and patients with asthma or asthma-like airway hyperresponsiveness or eosinophilia experience accelerated loss of lung function after cigarette smoke exposure. Pulmonary inflammation is a characteristic feature of lungs from patients with COPD. Surprisingly, the mediators of this inflammation and their contributions to the pathogenesis and varied natural history of COPD are not well defined. Here we show that IL-13, a critical cytokine in asthma, causes emphysema with enhanced lung volumes and compliance, mucus metaplasia, and inflammation, when inducibly overexpressed in the adult murine lung. MMP-2, -9, -12, -13, and -14 and cathepsins B, S, L, H, and K were induced by IL-13 in this setting. In addition, treatment with MMP or cysteine proteinase antagonists significantly decreased the emphysema and inflammation, but not the mucus in these animals. These studies demonstrate that IL-13 is a potent stimulator of MMP and cathepsin-based proteolytic pathways in the lung. They also demonstrate that IL-13 causes emphysema via a MMP-and cathepsin-dependent mechanism(s) and highlight common mechanisms that may underlie COPD and asthma. in proteases and/or reduction in pulmonary antiproteases (1). Inflammation, characterized by increased numbers of macrophages, lymphocytes, neutrophils, and/or eosinophils is a characteristic feature of lungs from patients with COPD (1,(14)(15)(16)(17)(18)(19). However, the nature of the mediators involved in this inflammation and the ability of these mediators to generate the emphysema and mucus changes, protease/antiprotease alterations, and varied natural history of COPD have not been investigated.Because Th2-dominated inflammation underlies the pathogenesis of asthma and generates AHR and eosinophilia (20-22), we hypothesized that Th2 cytokines can also activate proteolytic pathways that could contribute to the pathogenesis of COPD. To test this hypothesis, we used an inducible overexpression transgenic modeling system to target IL-13, a Th2 cytokine that is strongly implicated in the pathogenesis of asthma and causes AHR and eosinophilia (20,23), to the adult murine lung. These studies demonstrate that IL-13 causes a phenotype that mirrors human COPD including emphysema with enhanced lung volumes and pulmonary compliance; mucus metaplasia; and macrophage-, lymphocyte-, and eosinophil-rich inflammation. They also define the MMP and cathepsin abnormalities that generate the emphysema and demonstrate the efficacy of proteolytic blockade in ameliorating this response. MethodsTransgenic mice. These experiments were undertaken with CC10-rtTA-IL-13 mice in which the Clara cell 10-kDa (CC10) protein promoter and two transgenic constructs target IL-13 to the murine lung in an externally regulatable fashion. The CC10-rtTA transgenic system and the constructs that were used have been described previously by our laboratory (24). Construct 1,...

SUMMARYMembers of the 18 glycosyl hydrolase (GH 18) gene family have been conserved over species and time and are dysregulated in inflammatory, infectious, remodeling, and neoplastic disorders. This is particularly striking for the prototypic chitinase-like protein chitinase 3-like 1 (Chi3l1), which plays a critical role in antipathogen responses where it augments bacterial killing while stimulating disease tolerance by controlling cell death, inflammation, and remodeling. However, receptors that mediate the effects of GH 18 moieties have not been defined. Here, we demonstrate that Chi3l1 binds to interleukin-13 receptor α2 (IL-13Rα2) and that Chi3l1, IL-13Rα2, and IL-13 are in a multimeric complex. We also demonstrate that Chi3l1 activates macrophage mitogen-activated protein kinase, protein kinase B/AKT, and Wnt/β-catenin signaling and regulates oxidant injury, apoptosis, pyroptosis, inflammasome activation, antibacterial responses, melanoma metastasis, and TGF-β1 production via IL-13Rα2-dependent mechanisms. Thus, IL-13Rα2 is a GH 18 receptor that plays a critical role in Chi3l1 effector responses.

Abstract-This paper presents applications of entropic spanning graphs to imaging and feature clustering applications. Entropic spanning graphs span a set of feature vectors in such a way that the normalized spanning length of the graph converges to the entropy of the feature distribution as the number of random feature vectors increases. This property makes these graphs naturally suited to applications where entropy and information divergence are used as discriminants including: texture classification; feature clustering; image indexing; and image registration. Among other areas, these problems arise in geographical information systems, digital libraries, medical information processing, video indexing, multi-sensor fusion, and content-based retrieval.

IL-13 stimulates inflammatory and remodeling responses and contributes to the pathogenesis of human airways disorders. To further understand the cellular and molecular events that mediate these responses, we characterized the effects of IL-13 on monocyte chemotactic proteins (MCPs) and compared the tissue effects of transgenic IL-13 in mice with wild-type (+/+) and null (−/−) CCR2 loci. Transgenic IL-13 was a potent stimulator of MCP-1, -2, -3, and -5. This stimulation was not specific for MCPs because macrophage-inflammatory protein (MIP)-1α, MIP-1β, MIP-2, MIP-3α, thymus- and activation-regulated chemokine, thymus-expressed chemokine, eotaxin, eotaxin 2, macrophage-derived chemokines, and C10 were also induced. The ability of IL-13 to increase lung size, alveolar size, and lung compliance, to stimulate pulmonary inflammation, hyaluronic acid accumulation, and tissue fibrosis, and to cause respiratory failure and death were markedly decreased, whereas mucus metaplasia was not altered in CCR2−/− mice. CCR2 deficiency did not decrease the basal or IL-13-stimulated expression of target matrix metalloproteinases or cathepsins but did increase the levels of mRNA encoding α1-antitrypsin, tissue inhibitor of metalloproteinase-1, -2, and -4, and secretory leukocyte proteinase inhibitor. In addition, the levels of bioactive and total TGF-β1 were decreased in lavage fluids from IL-13 transgenic mice with −/− CCR2 loci. These studies demonstrate that IL-13 is a potent stimulator of MCPs and other CC chemokines and document the importance of MCP-CCR2 signaling in the pathogenesis of the IL-13-induced pulmonary phenotype.

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IntroductionTissue remodeling responses are prominent features of inflammatory disorders of the airway and parenchyma of the lung. These responses are readily apparent in chronic obstructive pulmonary disease (COPD), asthma, and interstitial lung diseases: in which remodeling causes the alveolar septal destruction and changes in compliance that are characteristic of pulmonary emphysema (1), the subepithelial fibrosis, mucus metaplasia, and other structural alterations seen in asthmatic airway remodeling (2), and the pulmonary fibrosis that characterizes the interstitial disorders (3). Elevated levels of matrix metalloproteinases (MMPs) have been noted in patients with these disorders (4-12). In addition, studies from our laboratories and others demonstrated that MMP-12 plays an essential role in the pathogenesis of cigarette smoke-induced emphysema in mice (13) and that pretreatment with broad-spectrum MMP antagonists decreases the inflammation and airway hyperresponsiveness in murine models of asthma and the fibrosis in murine models of interstitial lung disorders (14,15). Surprisingly, little else is known about the roles that individual MMPs play in the pathogenesis of these important pulmonary disorders.IL-13 is a pleiotropic 12-kDa product of a gene on chromosome 5 at q31 that is produced in large quantities by Th2 cells and in lesser quantities by Th1 cells. IL-13 potently stimulates eosinophilic and lymphocytic inflammation and alveolar remodeling in the lung, effects that depend on the induction of various matrix metalloproteinases (MMPs).Here, we compared the remodeling and inflammatory effects of an IL-13 transgene in lungs of wild-type, MMP-9-deficient, or MMP-12-deficient mice. IL-13-induced alveolar enlargement, lung enlargement, compliance alterations, and respiratory failure and death were markedly decreased in the absence of MMP-9 or MMP-12. Moreover, IL-13 potently induced MMPs-2, -12, -13, and -14 in the absence of MMP-9, while induction of MMPs-2, -9, -13, and -14 by IL-13 was diminished in the absence of MMP-12. A deficiency in MMP-9 did not alter eosinophil, macrophage, or lymphocyte recovery, but increased the recovery of total leukocytes and neutrophils in bronchoalveolar lavage (BAL) fluids from IL-13 transgenic mice. In contrast, a deficiency in MMP-12 decreased the recovery of leukocytes, eosinophils, and macrophages, but not lymphocytes or neutrophils. These studies demonstrate that IL-13 acts via MMPs-9 and -12 to induce alveolar remodeling, respiratory failure, and death and that IL-13 induction of MMPs-2, -9, -13, and -14 is mediated at least partially by an MMP-12-dependent pathway. The also demonstrate that MMPs-9 and -12 play different roles in the generation of IL-13-induced inflammation, with MMP-9 inhibiting neutrophil accumulation and MMP-12 contributing to the accumulation of eosinophils and macrophages.

Asthma is a disease whose ability to cause episodic symptomatology has been appreciated since antiquity. Although the fine points of the definition can be debated, it is reasonable to think of asthma as a pulmonary disorder characterized by the generalized reversible obstruction of airflow and to define reversibility as a greater than 12% increase in the patient's forced expiratory volume in 1 second (FEV 1 ) that occurs either spontaneously or with therapy. Airway hyperresponsiveness, an exaggerated bronchospastic response to nonspecific agents such as methacholine and histamine or specific antigens, is the physiologic cornerstone of this disorder. A diagnosis of asthma is established based on a history of recurrent wheeze, cough, or shortness of breath, reversible airway obstruction demonstrated by pulmonary-function testing, and, in cases where questions exist, a methacholine challenge demonstrating airway hyperresponsiveness. It has long been assumed that patients with asthma experience intermittent attacks and have relatively normal lung function during intervening periods. More recent studies have demonstrated that asthma can cause progressive lung impairment and, in some patients, eventuate in partially reversible or irreversible airway obstruction.Any discussion of asthma must take into account the recent increase in its prevalence. Since approximately 1980, the frequency of this disorder has almost doubled. As a result of this "epidemic," asthma now affects approximately 8-10% of the population in the US, is the leading cause of hospitalization among children less than 15 years of age, and costs society billions of dollars annually. This increase in prevalence is not simply due to diagnostic transference or increased diagnostic awareness, since asthma mortality rates have also increased during this interval.An aerosol antigen challenge of an appropriately sensitized asthmatic patient can induce two types of airway responses. The early response is an acute bronchospastic event that occurs 15-30 minutes after exposure and resolves over time. The late-phase response peaks 4-6 hours after exposure and can cause prolonged symptomatology. Over the years, a variety of concepts of pathogenesis have been put forth in an attempt to explain one or both of these responses (Table 1). Early investigators postulated that there was an intrinsic airway smooth muscle abnormality at the root of the asthmatic diathesis. However, many studies with airway myocytes in culture have not corroborated this contention. This was followed by the contention that asthma is an autonomic dysfunction syndrome characterized by excess cholinergic and/or tachykinin pathway activity. This was never proven or disproven. Instead, IgE-mediated mast cell and/or basophil degranulation with the release of leukotrienes, histamine, prostaglandins, tryptase, cytokines (such as IL-4 and IL-5), and other mediators was appreciated to be a key event in the acute response. The prominent eosinophil-, macrophage-, and lymphocyte-rich inflammatory response i...