1991 — 1993 |
Lee, Lu-Yuan |
F06Activity Code Description: Undocumented code - click on the grant title for more information. |
Lung Afferents and Sensory Neuropeptides |
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1994 |
Lee, Lu-Yuan |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Airway Responses Mediated by Nociceptive Afferents
Bronchial hyperreactivity is a characteristic feature of asthma which causes impairment and disability in millions of Americans. The experiments proposed in this application are specifically aimed to determine the role of vagal bronchopulmonary C-fiber afferents in the enhanced bronchomotor responses to inhaled irritants caused by exposure to ozone and toluene diisocyanate (TDI). The major working hypothesis of this proposal is that the C-fiber endings are sensitized by certain arachidonic acid metabolites which are released as a result of the airway epithelial injury caused by exposure to ozone or TDI. Thus, a given level of stimulation to these sensory endings, either chemical or mechanical, may evoke an exaggerated afferent stimulation and a greater release of sensory neuropeptides which can in turn lead to neurogenic inflammation in the airways. Series of studies are designed to answer the following questions: 1) Is the sensitivity of bronchopulmonary C-fiber endings enhanced when airway inflammation and bronchial hyperreactivity are induced by ozone or TDI? 2) Arachidonic acid metabolites PGE2, PGI2 and LTB4 are known to sensitize the C-fiber endings in cutaneous and other tissue beds. Is the release of these inflammatory mediators involved in enhancing the sensitivity of bronchopulmonary C.fiber endings during airway inflammation? 3) Is the tissue content and/or the irritants-induced release of sensory neuropeptides (substance P, neurokinin A and calcitonin gene.related peptide) increased in the ozone- or TDI-induced hyperreactive airways? These proposed experiments will be carried out in anesthetized guinea.pigs. Activity of the C-fiber afferents arising from endings in the lungs and airways will be measured directly using the "single-fiber" recording technique while chemical and mechanical stimulations (e.g., cigarette smoke and lung inflation) are applied. Release of sensory neuropeptides from these endings will be measured with the radioimmunoassay technique in an isolated perfused lung preparation, and the changes in lung mechanics will be measured simultaneously. Results obtained from these studies will improve our understanding of: 1) the basic physiological and pharmacological properties of the bronchopulmonary C-fiber afferents, and 2) the mechanisms by which these endings are involved in the development of bronchial hyperreactivity induced by epithelial injury and airway inflammation.
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1996 — 1999 |
Lee, Lu-Yuan |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Pulmonary Afferents in Regulation of Airway Functions
The long-range goal of our research is to elucidate the underlying neurohumoral mechanisms of airway irritation and its pathophysiological effects. The experiments proposed in this application are specifically aimed to determine the role of vagal bronchopulmonary C-fiber afferents in the enhanced bronchomotor responses to inhaled irritants caused by exposure to environmental air pollutants such as ozone and toluene (TDI). Our major working hypothesis is that the C-fiber endings are sensitized by certain arachidonic acid metabolites which are released as a result of the airway epithelial injury caused by ozone or TDI. Thus, a given level of stimulation to these sensory endings, either chemical or mechanical, may evoke an exaggerated afferent stimulation and a greater release of sensory neuropeptides which can in turn cause neurogenic inflammation in the airways. Series of studies are designed to answer the following questions: 1) Is the sensitivity of bronchopulmonary C- fiber endings enhanced when airway inflammation and bronchial hyperreactivity are induced by ozone or TDI? 2) Arachidonic acid metabolites PGE2, PGI2 and LTB4 are known to sensitize the C-fiber endings in cutaneous and other tissue beds. Is the release of these inflammatory mediators involved in enhancing the sensitivity of bronchopulmonary C-fiber endings during airway inflammation? 3) Is the tissue content and/or the irritants-induced release of sensory neuropeptides (substance P, neurokinin A and calcitonin gene-related peptide) increased in the ozone- or TDI-induced hyperreactive airways? These proposed experiments will be carried out in anesthetized guinea- pigs. Activity of the C-fiber afferents arising from endings in the lungs and airways will be measured directly using the 'single-fiber' recording technique while chemical and mechanical stimulations (e.g., cigarette smoke and lung inflation) are applied. Release of sensory neuropeptides from these endings will be measured with the radioimmunoassay technique in an isolated perfused lung preparation, and the changes in lung mechanics will be measured simultaneously. Results obtained from these studies will improve our understanding of the basic physiological and pharmacological properties of the bronchopulmonary C- fiber afferents, and the mechanisms by which these endings are involved in the development of bronchial hyperreactivity induced by epithelial injury and airway inflammation.
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1998 — 2001 |
Lee, Lu-Yuan |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Chemosensitivity of Tachykinin Containing Lung Afferents
Bronchial hyperreactivity is a prominent feature of asthma. Indirect but compelling evidence suggests the possible involvement of increased pulmonary C-fiber excitability in the manifestation of bronchial hyperreactivity induced by airway mucosal injury. The objectives of this proposal are the following: 1) to characterize the stimulatory effect of hydrogen ions on pulmonary C-fibers, 2) to elucidate the mechanisms underlying this effect, and 3) to explore its potential role in the development of bronchial hyperreactivity. Proposed experiments are focused on two sources of H+ ions that are produced by tissue metabolism: lactic acid and CO2. An elevated level of lactic acid occurs commonly during severe exercise, tissue ischemia, and various pathologic conditions, but whether pulmonary C-fibers can be activated by excessive production of lactic acid is not known. The following three hypotheses will be tested: 1) pulmonary C-fibers can be activated by an increase in H+ concentration in pulmonary interstitial fluid (PIF), and lactic acid is particularly effective in stimulating these endings; 2) a substantial increase of CO2 tension in the alveolar gas can also exert a stimulatory effect on these afferents, and this action is brought about by an increase in the H+ concentration in the PIF; and 3) the stimulatory effect of H+ ions on these afferents can be potentiated by airway mucosal inflammation, in which the production and release of both cyclooxygenase metabolites and tachykinins are involved. In the proposed studies, mucosal inflammation will be induced by acute exposure of the lung to ozone or by hyperventilation with cold dry air. Pulmonary C-fiber afferent activity will be recorded in anesthetized rats by using a single-fiber recording technique, whereas pH in pulmonary venous blood will be measured continuously for estimation of the changes of pH in PIF during various experimental conditions. The relationship between changes in fiber activity and pulmonary venous pH will be established, and from this the threshold pH for stimulation can be determined. The feasibility and potential significance of the proposed studies have already been demonstrated in the preliminary experiments. These results will provide a more in-depth understanding of the chemosensitive properties of pulmonary C-fibers and their role in regulating the airway functions in various pathophysiological conditions.
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2002 — 2005 |
Lee, Lu-Yuan |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Pulmonary C-Neuron Hypersensitivity:Cellular Mechanisms
DESCRIPTION (provided by applicant): The long-range goal of this research project is to understand the neurogenic mechanisms underlying the bronchial hyperreactivity caused by inflammation of airway mucosa. Increasing evidence suggests an involvement of hypersensitivity of bronchopulmonary C-fiber afferents in the manifestation of bronchial hyper-reactivity induced by airway epithelial injury. The primary objective of this proposal is to investigate the role of endogenous prostaglandin E2 (PGE2), a potent autacoid, in the sensitization of bronchopulmonary C fibers caused by airway mucosal inflammation, and to elucidate the cellular mechanisms involved in this action. PGE2 is locally synthesized and releases from airway epithelium during various inflammatory reactions, and our recent studies have demonstrated a sensitizing effect of exogenous PGE2 on the pulmonary C fibers. The central hypothesis of this study is that endogenous PGE2 increases the sensitivity of the pulmonary C-fiber endings by activating EP2 and/or EP4 prostanoid receptors; activation of these EP receptors enhances the neuronal excitability by activating the cyclic AMP/protein kinase A signaling pathway that leads to modulation of the function of tetrodotoxin-resistant sodium channel. Proposed experiments will be carried out to test these hypotheses in rats using both in vivo (single-fiber recording) and in vitro (whole-cell patch-clamp recording) preparations; the latter will be performed in isolated nodose and jugular ganglion neurons innervating the lung and airways. The results obtained from this study should provide crucial information for gaining new insight into the signaling transduction mechanisms underlying the PGE2-induced sensitization of pulmonary C neurons. This information may, therefore, help to develop new therapeutic strategies for alleviating the symptoms of bronchial hyperreactivity associated with airway mucosal inflammation.
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2005 — 2008 |
Lee, Lu-Yuan |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Chemosensitivity of Tachykinin-Containing Lung Afferents
[unreadable] DESCRIPTION (provided by applicant): Vagal bronchopulmonary C-fiber sensory nerves play an important role in regulating airway functions. Hypersensitivity of these afferents is believed to be involved in the manifestation of airway hyperresponsiveness associated with mucosal injury, a prominent feature of asthma. During airway inflammatory reaction, a number of low molecular weight, highly cationic proteins are secreted by inflammatory cells such as eosinophils that infiltrate into the airways. It is well documented that the release of these proteins can induce mucosal injury and airway hyperresponsiveness. Our recent studies have established the first direct evidence demonstrating an intense and sustained effect of both human eosinophil granule-derived and synthetic cationic proteins on vagal bronchopulmonary C-fiber endings. However, the mechanism underlying both the initial stimulatory and the sustained sensitizing effects of cationic proteins on these sensory nerves is poorly understood. Our central hypothesis is that the cationic charge carried by these proteins acts on the airway mucosa, triggering the release of certain inflammatory mediators that in turn exert potent effects on the C-fiber terminals. The mast cells located in the airway mucosa probably play an important role in the interaction between cationic proteins and sensory endings. Sensitization of these afferents can then lead to airway hyperresponsiveness via both cholinergic reflex pathways and tachykininergic mechanisms. Single-fiber and whole-cell patch-clamp recording techniques will be employed to measure the activity of bronchopulmonary C fibers in anesthetized rats and in isolated neurons, respectively. The results obtained from this study should provide critical information for gaining new insights into the mechanisms underlying the airway hyperresponsiveness induced by cationic proteins. [unreadable] [unreadable]
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2007 |
Lee, Lu-Yuan |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Pulmonary C-Neuron Hypersensitivity: Cellular Mechanisms
prostaglandin E; prostaglandin endoperoxide synthase; respiratory epithelium; tissue /cell culture; voltage /patch clamp
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2009 — 2010 |
Lee, Lu-Yuan |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Trpv1 in Airway Hypersensitivity Induced by Inflammation
DESCRIPTION (provided by applicant): Airway hypersensitivity, characterized by exaggerated sensory and reflexogenic responses to inhaled irritants, is a prominent pathophysiological feature of various airway inflammatory diseases (e.g., asthma, bronchitis, etc). Increasing and compelling evidence indicates that vagal bronchopulmonary C-fibers play a pivotal role in the manifestation of airway hypersensitivity. Recent investigations further suggest that the TRPV1 receptor, a non-selective cation channel and a polymodal transducer selectively expressed in C-fiber afferents, is likely involved in the airway hypersensitivity generated by airway inflammatory reaction. Indeed, a recent study in our lab has demonstrated that allergen sensitization-induced airway inflammation markedly enhanced the sensitivity of pulmonary C-fiber afferents and, more importantly, induced TRPV1 expression in myelinated pulmonary afferents that normally do not exhibit any capsaicin sensitivity. However, the physiological implication and the mechanism underlying the TRPV1 over- expression during airway inflammation are yet not fully understood. In this proposal, a research plan is designed to characterize the role of TRPV1 in the development of airway hypersensitivity when chronic airway inflammation is induced by allergen sensitization. Our hypothesis is that the enhanced airway sensitivity results from a combination of increased expression and excitability of this channel in the vagal bronchopulmonary sensory terminals. We further hypothesize that tumor necrosis factor 1, a pro-inflammatory cytokine and known to be released in the lung during allergic airway inflammation, is an important contributor to the over-expression of TRPV1 in these sensory neurons. Results obtained from these studies should provide important information about the mechanism that up-regulates the expression and excitability of the TRPV1 channel in the airway sensory neurons, and bring a new insight into the pathogenesis and therapeutic strategy for alleviating the airway hypersensitivity caused by allergic airway inflammation. PUBLIC HEALTH RELEVANCE: In airway inflammatory diseases such as asthma and bronchitis, the respiratory tract becomes overly sensitive to inhaled irritants. This research proposal is designed to test our hypothesis that a specific ion channel, namely TRPV1, plays a major role in the exceedingly high excitability of airway sensory nerves caused by allergic inflammation. The results obtained from these studies should bring a new insight into the pathogenesis and therapeutic strategy for alleviating the airway hypersensitivity.
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2016 — 2018 |
Lee, Lu-Yuan |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Trpv1 in Asthma Exacerbation
? DESCRIPTION (provided by applicant): Inflammatory reaction is known to lead to an increase in tissue temperature, but whether airway tissue temperature increases during asthma exacerbation is not yet known. Transient receptor potential vanilloid type 1 receptor (TRPV1), a ligand gated non-selective cation channel with a distinct sensitivity to heat, is selectively and abundantly expressed in vagal bronchopulmonary C-fiber sensory nerves. A series of studies carried out in our lab have established the first evidence that an increase in temperature within the normal physiological range can activate and sensitize these TRPV1-expressing sensory neurons innervating the lung and airways; activation of these C-fiber afferents can elicit reflex bronchoconstriction, cough and other airway defense responses. Indeed, our recent study has demonstrated that an increase in airway temperature by hyperventilating humidified hot air triggered cough and bronchoconstriction in patients with mild and stable asthma, but not in healthy subjects. The airway constriction was mediated through cholinergic reflex because it was completely prevented by pretreatment with ipratropium. The accompanying airway irritation and coughing further suggested an involvement of airway sensory nerves, presumable TRPV1-expressing C-fiber afferents. In the light of these novel findings, this proposed study aims to tes the following hypotheses: 1) in patients with allergic asthma, the airway tissue temperature is elevated locally in the region when the inflammatory reaction is evoked by a segmental bronco-provocation with allergen. 2) Both the thermal sensitivity of these neurons and the expression of TRPV1 at the sensory nerve terminals are enhanced by chronic airway allergic inflammation. Thus, a slight increase in local tissue temperature can lower the activation thresholds and enhance the sensitivity of TRPV1-expressing C-fiber sensory nerves in the airways of asthmatics. The synergistic effects of these factors may play a major part in the development of the airway hypersensitivity during chronic inflammation. This translational study will be performed in both asthmatic patients and in an animal model of allergic asthma. Results obtained from these studies should provide novel insights into the involvement of TRPV1 in the pathogenic mechanisms of airway hypersensitivity, and help to uncover the mechanisms underlying the debilitating symptoms associated with airway inflammatory diseases.
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