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Adenosine is an endogenously released purine nucleoside that signals via 4 widely expressed G protein-coupled receptors: A 1 , A 2A , A 2B , and A 3 . In the setting of inflammation, the generation and release of adenosine is greatly enhanced. Neutrophils play an important role in host defense against invading pathogens and are the cellular hallmark of acute inflammation. Neutrophils both release adenosine and can respond to it via expression of all 4 adenosine receptor subtypes. At low concentrations, adenosine can act via the A 1 and A 3 adenosine receptor subtypes to promote neutrophil chemotaxis and phagocytosis. At higher concentrations, adenosine acts at the lower-affinity A 2A and A 2B receptors to inhibit neutrophil trafficking and effector functions such as oxidative burst, inflammatory mediator production, and granule release. Modulation of neutrophil function by adenosine is relevant in a broad array of disease models, including ischemia reperfusion injury, sepsis, and noninfectious acute lung injury. This review will summarize relevant research in order to provide a framework for understanding how adenosine directly regulates various elements of neutrophil function.

Pulmonary infection due to

Clinical allergic airway disease is associated with persistent airway hyperreactivity and remodeling, but little is known about the mechanisms leading to these alterations. This paucity of information is related in part to the absence of chronic models of allergic airway disease. Herein we describe a model of persistent airway hyperreactivity, goblet cell hyperplasia, and subepithelial fibrosis that is initiated by the intratracheal introduction of Aspergillus fumigatus spores or conidia into the airways of mice previously sensitized to A. fumigatus. Similar persistent airway alterations were not observed in nonsensitized mice challenged with A. fumigatus conidia alone. A. fumigatus-sensitized mice exhibited significantly enhanced airway hyperresponsiveness to a methacholine challenge that was still present at 30 days after the conidia challenge. Eosinophils and lymphocytes were present in bronchoalveolar lavage (BAL) samples from A. fumigatus-sensitized mice at all times after conidia challenge. Compared with levels measured in A. fumigatus-sensitized mice immediately before conidia, significantly elevated interferon-␥ (IFN-␥) and transforming growth factor (TGF-␤) levels were present in whole lung homogenates up to 7 days after the conidia challenge. At day 30 after conidia challenge, significantly elevated levels of interleukin-4 (IL-4) and IL-13 were present in the A. fumigatussensitized mice. Histological analysis revealed profound goblet cell hyperplasia and airway fibrosis at days 30 after conidia, and the latter finding was confirmed by hydroxyproline measurements. Thus the

Pulmonary fibrosis is associated with a number of disorders that affect the lung. Although there are several cellular types that are involved in the pathogenesis pulmonary fibrosis, the resident lung fibroblast has been viewed traditionally as the primary cell involved in promoting the deposition of ECM that culminates in pulmonary fibrosis. However, recent findings demonstrate that a circulating cell (i.e., the fibrocyte) can contribute to the evolution of pulmonary fibrosis. Fibrocytes are bone marrow-derived mesenchymal progenitor cells that express a variety of cell-surface markers related to leukocytes, hematopoietic progenitor cells, and fibroblasts. Fibrocytes are unique in that they are capable of differentiating into fibroblasts and myofibroblasts, as well as adipocytes. In this review, we present data supporting the critical role these cells play in the pathogenesis of pulmonary fibrosis.

The understanding of the pathogenesis of pulmonary fibrosis continues to evolve. The initial hypothetical model suggested chronic inflammation as the cause of pulmonary fibrosis, whereas a subsequent hypothesis posited epithelial injury and impaired wound repair as the etiology of fibrosis without preceding inflammation. Over the past decade, several concepts have led to refinement of these hypotheses. These include the following: (1) the importance of the integrity of the alveolar-capillary barrier basement membrane (BM) to conserving the architecture of the injured lung; (2) conversely, that the failure of reepithelialization and reendothelialization of this BM results in pathologic fibrosis; (3) transforming growth factor-␤ is necessary but not sufficient to the pathologic fibrosis of the lungs; (4) the role of persistent antigens in the pathogenesis of usual interstitial pneumonia; and (5) the contribution of epithelial-to-mesenchymal transformation and bone marrow-derived progenitor cells in the pathogenesis of lung fibrosis. In this review, we will discuss these evolving conceptual mechanisms for the pathogenesis of pulmonary fibrosis relevant to idiopathic pulmonary fibrosis.(CHEST 2009; 136:1364 -1370)Abbreviations: BM ϭ basement membrane; ECM ϭ extracellular matrix; EMT ϭ epithelial to mesenchymal transition; IL ϭ interleukin; IPF ϭ idiopathic pulmonary fibrosis; TGF ϭ transforming growth factor; UIP ϭ usual interstitial pneumonia

Fibrotic interstitial lung diseases are characterized by progressive decline in lung function and premature death from respiratory failure. Fibrocytes are circulating bone marrow-derived progenitor cell that traffic to the lungs and contribute to fibrosis and may represent novel therapeutic targets in these diseases. We have previously found the recruitment of fibrocytes to the lung to be dependent on the chemokine ligand CXCL12. Given that the expression of the CXCL12 receptor, CXCR4, can be modulated pharmacologically in other cell types, we tested the hypotheses that the regulation of CXCR4 expression on fibrocytes mediates their influx to the lung in the context of pulmonary fibrosis and that pharmacologic inhibition of this process results in attenuated disease severity. CXCR4 was the predominant chemokine receptor on human fibrocytes, and its expression on fibrocytes was enhanced by hypoxia and by growth factors including platelet-derived growth factor. Both hypoxiainduced and growth factor-induced CXCR4 expressions were attenuated by specific inhibition of PI3 kinase and mTOR. Finally, in the mouse model of bleomycin-induced pulmonary fibrosis, treatment with the mTOR inhibitor rapamycin resulted in reduced numbers of CXCR4-expressing fibrocytes in the peripheral blood and lung as well as reduced lung collagen deposition. Taken together, these experiments support the notion that pharmacologic inhibition of the CXCR4/CXCL12 biological axis is achievable in human fibrocytes and reduces the magnitude of pulmonary fibrosis in an animal model. This approach may hold promise in human fibrotic lung diseases.

The tumor microenvironment is extremely complex that depends on tumor cell interaction with the responding host cells. Angiogenesis, or new blood vessel growth from preexisting vasculature, is a preeminent feature of successful tumor growth of all solid tumors. While a number of factors produced by both the tumor cells and host responding cells have been discovered that regulate angiogenesis, increasing evidence is growing to support the important role of CXC chemokines in this process. As a family of cytokines, the CXC chemokines are pleiotropic in their ability to regulate tumor-associated angiogenesis, as well as cancer cell metastases. In this chapter, we will discuss the disparate activity that CXC chemokines play in regulating cancer-associated angiogenesis and metastases.