Host defense against viruses probably depends on targeted death of infected host cells and then clearance of cellular corpses by macrophages. For this process to be effective, the macrophage must presumably avoid its own virus-induced death. Here we identify one such mechanism. We show that mice lacking the chemokine Ccl5 are immune compromised to the point of delayed viral clearance, excessive airway inflammation and respiratory death after mouse parainfluenza or human influenza virus infection. Virus-inducible levels of Ccl5 are required to prevent apoptosis of virus-infected mouse macrophages in vivo and mouse and human macrophages ex vivo. The protective effect of Ccl5 requires activation of the Ccr5 chemokine receptor and consequent bilateral activation of G(alphai)-PI3K-AKT and G(alphai)-MEK-ERK signaling pathways. The antiapoptotic action of chemokine signaling may therefore allow scavengers to finally stop the host cell-to-cell infectious process.

Human airway epithelial cells appear specially programmed for expression of immune response genes implicated in immunity and inflammation. To better determine how this epithelial system operates in vivo, we analyzed its behavior in mouse models that allow for in vitro versus in vivo comparison and genetic modification. Initial comparisons indicated that tumor necrosis factor α induction of epithelial intercellular adhesion molecule 1 required sequential induction of interleukin (IL)-12 (p70) and interferon γ, and unexpectedly localized IL-12 production to airway epithelial cells. Epithelial IL-12 was also inducible during paramyxoviral bronchitis, but in this case, initial IL-12 p70 expression was followed by 75-fold greater expression of IL-12 p40 (as monomer and homodimer). Induction of IL-12 p40 was even further increased in IL-12 p35-deficient mice, and in this case, was associated with increased mortality and epithelial macrophage accumulation. The results placed epithelial cell overgeneration of IL-12 p40 as a key intermediate for virus-inducible inflammation and a candidate for epithelial immune response genes that are abnormally programmed in inflammatory disease. This possibility was further supported when we observed IL-12 p40 overexpression selectively in airway epithelial cells in subjects with asthma and concomitant increases in airway levels of IL-12 p40 (as homodimer) and airway macrophages. Taken together, these results suggest a novel role for epithelial-derived IL-12 p40 in modifying the level of airway inflammation during mucosal defense and disease.

Paramyxoviral infections cause most of the acute lower respiratory tract illness in infants and young children and predispose to the development of chronic wheezing, but the relationship between these short-and long-term viral effects are uncertain. Here we show that a single paramyxoviral infection of mice (C57BL6/J strain) not only produces acute bronchiolitis, but also triggers a chronic response with airway hyperreactivity and goblet cell hyperplasia lasting at least a year after complete viral clearance. During the acute response to virus, same-strain ICAM-1-null mice are protected from airway inflammation and hyperreactivity despite similar viral infection rates, but the chronic response proceeds despite ICAM-1 deficiency. Neither response is influenced by IFN-γ deficiency, but the chronic response is at least partially prevented by glucocorticoid treatment. In contrast to viral infection, allergen challenge caused only short-term expression of asthma phenotypes. Thus, paramyxoviruses cause both acute airway inflammation/hyperreactivity and chronic airway remodeling/hyperreactivity phenotypes (the latter by a hit-and-run strategy, since viral effects persist after clearance). These two phenotypes can be segregated by their dependence on the ICAM-1 gene and so depend on distinct controls that appear critical for the development of lifelong airway diseases such as asthma. Conflict of interest:No conflict of interest has been declared. Nonstandard abbreviations used: Sendai virus (SeV); 50% egg infectious dose (EID50); periodic acid-Schiff (PAS); enhanced pause (Penh); ovalbumin (Ova).newly described yet invariant feature of asthma: an intrinsic abnormality in cellular programming of the airway epithelium toward an anti-viral Th1 response (26). In particular, airway epithelial cells are specially programmed with anti-viral networks, and the behavior of these cells in asthma resembles a persistent antiviral response (27)(28)(29)(30)(31). It is also not certain how the Th2 hypothesis reconciles its insights into the allergic response -a short-term response -with the development of a lifelong disease.In that context, a relationship between viral infection and the development of chronic inflammatory disease has been proposed for diverse clinical syndromes, but the mechanistic basis for this relationship is still uncertain. Relevant to asthma, paramyxoviral infections are the leading cause of lower respiratory tract illness in infants and young children (32,33), and children with clinically significant viral bronchiolitis appear to be marked for the subsequent development of a chronic wheezing illness that is independent of allergy (34). Presumably paramyxoviral infection triggers an abnormal host response, since paramyxoviruses (and other respiratory RNA viruses) are not thought to persist in airway tissue as an ongoing stimulus of chronic respiratory disease (35). In either case (i.e., with or without viral persistence), the role of specific host factors in the development of acute or chronic wheezing or lifelo...

Paramyxoviral infections cause most of the acute lower respiratory tract illness in infants and young children and predispose to the development of chronic wheezing, but the relationship between these short-and long-term viral effects are uncertain. Here we show that a single paramyxoviral infection of mice (C57BL6/J strain) not only produces acute bronchiolitis, but also triggers a chronic response with airway hyperreactivity and goblet cell hyperplasia lasting at least a year after complete viral clearance. During the acute response to virus, same-strain ICAM-1-null mice are protected from airway inflammation and hyperreactivity despite similar viral infection rates, but the chronic response proceeds despite ICAM-1 deficiency. Neither response is influenced by IFN-γ deficiency, but the chronic response is at least partially prevented by glucocorticoid treatment. In contrast to viral infection, allergen challenge caused only short-term expression of asthma phenotypes. Thus, paramyxoviruses cause both acute airway inflammation/hyperreactivity and chronic airway remodeling/hyperreactivity phenotypes (the latter by a hit-and-run strategy, since viral effects persist after clearance). These two phenotypes can be segregated by their dependence on the ICAM-1 gene and so depend on distinct controls that appear critical for the development of lifelong airway diseases such as asthma. Conflict of interest:No conflict of interest has been declared. Nonstandard abbreviations used: Sendai virus (SeV); 50% egg infectious dose (EID50); periodic acid-Schiff (PAS); enhanced pause (Penh); ovalbumin (Ova).newly described yet invariant feature of asthma: an intrinsic abnormality in cellular programming of the airway epithelium toward an anti-viral Th1 response (26). In particular, airway epithelial cells are specially programmed with anti-viral networks, and the behavior of these cells in asthma resembles a persistent antiviral response (27)(28)(29)(30)(31). It is also not certain how the Th2 hypothesis reconciles its insights into the allergic response -a short-term response -with the development of a lifelong disease.In that context, a relationship between viral infection and the development of chronic inflammatory disease has been proposed for diverse clinical syndromes, but the mechanistic basis for this relationship is still uncertain. Relevant to asthma, paramyxoviral infections are the leading cause of lower respiratory tract illness in infants and young children (32,33), and children with clinically significant viral bronchiolitis appear to be marked for the subsequent development of a chronic wheezing illness that is independent of allergy (34). Presumably paramyxoviral infection triggers an abnormal host response, since paramyxoviruses (and other respiratory RNA viruses) are not thought to persist in airway tissue as an ongoing stimulus of chronic respiratory disease (35). In either case (i.e., with or without viral persistence), the role of specific host factors in the development of acute or chronic wheezing or lifelo...

Primary pulmonary hypertension (PPH) is still a refractory disease, and patients deteriorate despite any treatment. We hypothesized that neovascularization in the lung could increase the volume of the vascular bed in the pulmonary circulation and thus reduce the development of pulmonary hypertension (PH). Endothelial progenitor cells (EPCs) might be a potential cell source for neovascularization. We examined the effects of EPC transplantation into the lungs of dogs with dehydromonocrotaline-induced PH. The lung parenchyma of PH model dogs was injected with ex vivo-expanded, autologous EPCs originated from peripheral blood (experiments, n=4) or culture medium (control, n=3), using a bronchoscope. EPC transplantation gave significant improvements in mean pulmonary artery pressure, cardiac output, and pulmonary vascular resistance. Histological evaluation revealed both improvement in the medial thickness of the small pulmonary artery and neovascularization of the lung tissue. These results indicate that EPC transplantation into the lung is effective at preventing the progression of dehydromonocrotaline-induced PH in dogs, and suggest a new therapeutic option for PPH.