Macrophage Chitinase 1 Stratifies Chronic Obstructive Lung Disease

Agapov, Eugene; Battaile, John T.; Tidwell, Rose M.; Hachem, Ramsey R.; Patterson, G. Alexander; Pierce, Richard A.; Atkinson, Jeffrey J.; Holtzman, Michael J.

doi:10.1165/2009-0122r

Cited by 50 publications

(63 citation statements)

References 22 publications

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“…Thus, our data suggested the hypothesis that changes in the activation level of PNECs or the responsiveness of other airway cell types to stimulation by PNEC contents could contribute to olfactory hypersensitivity in airway disease. We therefore determined the levels of PNECs in lung tissues obtained from lung transplant recipients with severe COPD versus corresponding tissues from lung transplant donors without COPD (42,43). In agreement with our hypothesis, we found increased numbers of OR2W1-and proprotein convertase subtilisin/kexin type 2-expressing PNECs in lung tissues from subjects with COPD relative to control subjects without COPD, without any detectable differences in PNEC morphology ( Figures 5A-5C).…”

Section: Resultssupporting

confidence: 82%

Chemosensory Functions for Pulmonary Neuroendocrine Cells

Karp

Brody

et al. 2014

Am J Respir Cell Mol Biol

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120

108

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The mammalian airways are sensitive to inhaled stimuli, and airway diseases are characterized by hypersensitivity to volatile stimuli, such as perfumes, industrial solvents, and others. However, the identity and function of the cells in the airway that can sense volatile chemicals remain uncertain, particularly in humans. Here, we show that solitary pulmonary neuroendocrine cells (PNECs), which are morphologically distinct and physiologically undefined, might serve as chemosensory cells in human airways. This conclusion is based on our finding that some human PNECs expressed members of the olfactory receptor (OR) family in vivo and in primary cell culture, and are anatomically positioned in the airway epithelium to respond to inhaled volatile chemicals. Furthermore, apical exposure of primaryculture human airway epithelial cells to volatile chemicals decreased levels of serotonin in PNECs, and the led to the release of the neuropeptide calcitonin gene-related peptide (CGRP) to the basal medium. These data suggest that volatile stimulation of PNECs can lead to the secretion of factors that are capable of stimulating the corresponding receptors in the lung epithelium. We also found that the distribution of serotonin and neuropeptide receptors may change in chronic obstructive pulmonary disease, suggesting that increased PNEC-dependent chemoresponsiveness might contribute to the altered sensitivity to volatile stimuli in this disease. Together, these data indicate that human airway epithelia harbor specialized cells that respond to volatile chemical stimuli, and may help to explain clinical observations of odorant-induced airway reactions.

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Section: Resultssupporting

confidence: 82%

Chemosensory Functions for Pulmonary Neuroendocrine Cells

Karp

Brody

et al. 2014

Am J Respir Cell Mol Biol

Self Cite

120

108

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“…In this case, we again found no difference in acute illness in Il33 Gt/Gt versus WT mice (Figure 4, A-C), but observed significant blockade of the expected development of chronic disease, signified by IL-13 and mucus production and M2 differentiation (Figure 4, D-F). Together with our previous work (11,12), these 3 approaches (anti-IL1RL1 mAb, IL1RL1 deficiency, and IL-33 deficiency) served to demonstrate a specific role for IL-33/IL-33 receptor signaling in driving lung IL-13 and mucus production in the postviral mouse model of chronic obstructive lung disease.…”

Section: Resultsmentioning

confidence: 86%

“…Analysis of this model uncovered an innate immune axis involving semi-invariant NKT cells and alternatively activated (M2) macrophages that resulted in IL-13 expression and consequent airway hyperreactivity (monitored by methacholine-induced bronchoconstriction) and mucus overproduction (signified by mucin MUC5AC expression) (11). We also found initial evidence of IL-13 expression along with M2 monocyte/macrophage accumulation and MUC5AC production in the lungs of patients with severe COPD (11)(12)(13). These results identified an innate immune response to translate viral infection into chronic obstructive lung disease, but still did not explain how the response could be perpetuated.…”

Section: Introductionmentioning

confidence: 72%

Long-term IL-33–producing epithelial progenitor cells in chronic obstructive lung disease

Byers

Alexander‐Brett²,

Patel³

et al. 2013

J. Clin. Invest.

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274

255

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Chronic obstructive lung disease is characterized by persistent abnormalities in epithelial and immune cell function that are driven, at least in part, by infection. Analysis of parainfluenza virus infection in mice revealed an unexpected role for innate immune cells in IL-13-dependent chronic lung disease, but the upstream driver for the immune axis in this model and in humans with similar disease was undefined. We demonstrate here that lung levels of IL-33 are selectively increased in postviral mice with chronic obstructive lung disease and in humans with very severe chronic obstructive pulmonary disease (COPD). In the mouse model, IL-33/IL-33 receptor signaling was required for Il13 and mucin gene expression, and Il33 gene expression was localized to a virus-induced subset of airway serous cells and a constitutive subset of alveolar type 2 cells that are both linked conventionally to progenitor function. In humans with COPD, IL33 gene expression was also associated with IL13 and mucin gene expression, and IL33 induction was traceable to a subset of airway basal cells with increased capacities for pluripotency and ATP-regulated release of IL-33. Together, these findings provide a paradigm for the role of the innate immune system in chronic disease based on the influence of long-term epithelial progenitor cells programmed for excess IL-33 production.

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“…A proof-of-concept analysis of a small number of these patients provided preliminary evidence of increased numbers of iNKT cells and IL-13-positive macrophages in the lung in concert with mucus overproduction (109). Subsequent analysis defined chitinase 1 as a relatively selective marker of M2 macrophage activation and found increased chitinase 1 levels in lung as well as peripheral blood samples in a larger group of COPD patients (112). Here again, the M2 macrophage abnormality was most prominent in those with severe disease.…”

Section: Innate Immune Cells and Viral Diseasementioning

confidence: 97%

“…Particular challenges for the goal of innate immune blockade include the built-in redundancy of the innate response, the capacity to do harm as well as good when this response is unbalanced, and the requirement for noninvasive clinical biomarkers and imaging approaches to stratify as well as monitor this response in vivo in patients. Initial application of clinical biomarkers for innate immune responses suggests that only a subset of asthma or COPD patients is likely to manifest any given molecular target as a component of their disease (112,118). The application of high-fidelity experimental models in conjunction with validation in these models and in humans will be required to develop new therapeutics and corresponding clinical biomarkers that target the proper subset in asthma or other common inflammatory diseases.…”

Section: Improving Innate Immunity For Prevention and Curementioning

confidence: 99%

Asthma as a chronic disease of the innate and adaptive immune systems responding to viruses and allergens

Holtzman¹

2012

J. Clin. Invest.

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143

119

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Research on the pathogenesis of asthma has traditionally concentrated on environmental stimuli, genetic susceptibilities, adaptive immune responses, and end-organ alterations (particularly in airway mucous cells and smooth muscle) as critical steps leading to disease. The focus of this cascade has been the response to allergic stimuli. An alternative scheme suggests that respiratory viruses and the consequent response of the innate immune system also drives the development of asthma as well as related inflammatory diseases. This conceptual shift raises the possibility that sentinel cells such as airway epithelial cells, DCs, NKT cells, innate lymphoid cells, and macrophages also represent critical components of asthma pathogenesis as well as new targets for therapeutic discovery. A particular challenge will be to understand and balance the innate as well as the adaptive immune responses to defend the host against acute infection as well as chronic inflammatory disease.

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Macrophage Chitinase 1 Stratifies Chronic Obstructive Lung Disease

Cited by 50 publications

References 22 publications

Chemosensory Functions for Pulmonary Neuroendocrine Cells

Chemosensory Functions for Pulmonary Neuroendocrine Cells

Long-term IL-33–producing epithelial progenitor cells in chronic obstructive lung disease

Asthma as a chronic disease of the innate and adaptive immune systems responding to viruses and allergens

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