Lung response to inhaled highly toxic chemicals.

The purpose of this program announcement (PA) is to investigate acute mucosal irritation in the upper and lower respiratory tract occurring after aerosol exposure to toxic chemicals with the goals to: 1) minimize initial injury promptly, 2) retard and ameliorate progressive mucosal irritation or inflammation, and 3) offer prophylaxis against pulmonary edema, if created by acute lung injury.

The National Heart, Lung, and Blood Institute (NHLBI) and the NIEHS are concerned about the U.S. population's potential inhalational exposure to aerosolized harmful chemicals, possibly liberated as part of bioterrorism attacks against assembled groups of the civilian populace. Therefore, research is needed on how humans and relevant animal models respond to inhaled toxic chemicals. The goals of this PA are to develop better bioprotective therapies and to minimize respiratory injury and illness.

Many volatile toxic chemicals are produced and utilized in industry. Some of these are considered hazardous when they are inhaled in ambient air, introduced into food and water supplies, or make contact with body skin surfaces. Among toxic industrial materials that are considered highly hazardous are ammonia, chlorine, formaldehyde, hydrogen cyanine, fuming nitric acid, phosgene, and sulfur dioxide.

From a pulmonary perspective, inhalation exposure to some of these highly hazardous and irritative chemicals induces initial choking, inability to breathe deeply, and excessive output of secretions in the nose and throat from acute irritation. Other chemicals that have neurological effects--including such nerve agents as sarin, certain organophosphate-based pesticides, soman, and others-enter the body through absorption from the airways.

The NHLBI has a limited portfolio of existing research applicable to the respiratory exposures discussed. This PA will stimulate and build research against airborne chemical threats that affect the upper and lower respiratory tract, and will suggest potential therapy to prevent or limit development of pulmonary edema, which is a major complication of airway chemical irritation. Examples of research topics that are of interest include the following: 1) investigating mechanisms of chemical injury (including minimal threshold levels to establish injury) and subsequent effects at a cellular and molecular level causing airway inflammation or hypersensitivity; 2) identifying host responses to initial or immediate effects, and to long-term low-level exposure effects; 3) assessing systematic amount or dose of chemical absorbed from the airways; 4) developing preexposure preventive treatment or early use of antidotes; and 5) devising therapeutic strategies, especially if acute alveolar lung injury occurs and pulmonary edema ensues; specific therapies to prevent onset of pulmonary edema are sought. Development of physical protection (including facial masks and respirators) or environmental detectors for documenting exposure are not within the purview of this announcement.

The NIEHS encourages applications to study chemical exposures relating to civilian terrorism attack, industrial sabotage, or large-scale accidental exposure to toxic chemicals. Applications should focus on research that will develop or support development of treatment strategies that prevent or minimize respiratory track injury following exposure or that maximize repair of injured tissue. To be considered responsive to the NIEHS, the chemical exposure should be acute.

Multiple routes of chemical exposure (respiratory tract, skin, eye, digestive tract) are acceptable if injury resulting from the exposure is specific to the lung. Use of animal models and appropriate human biological specimens is encouraged. Examples of research topics for the NIEHS include but are not limited to the following: 1) the relationship between exposure, route of exposure, and absorbed dose to onset and magnitude of respiratory symptoms in a young, adult, and senior model; 2) cellular and molecular mechanisms of lung injury following acute chemical exposure, including induction of mucosal injury, pulmonary inflammation, acute alveolar injury, and pulmonary edema; 3) cellular and molecular mechanisms of lung tissue repair following acute chemical-induced lung injury; 4) development of postexposure strategies that prevent or minimize lung injury, including early use of antidotes; and 5) development of therapeutic strategies that promote lung tissue repair and that prevent or treat pulmonary edema.

This funding opportunity will use the NIH R01 award mechanism. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. This funding opportunity uses just-in-time concepts. It also uses the modular as well as the nonmodular budget formats (see http://grants.nih.govlgrants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular budget format described in the PHS 398 application instructions. Otherwise, follow the instructions for nonmodular research grant applications.

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. The PHS 398 application instructions are available at http:/Igrants.nih.gov/grants/funding/phs398/ phs398.html in an interactive format. For further assistance contact GrantsInfo at 301-4350714 or by e-mailing [e-mail]. Applications must have a Dun & Bradstreet Data Universal Numbering System (DUNS) number as the universal identifier when applying for federal grants or cooperative agreements. This number can be obtained by calling 1-866-705-5711 or through the website at http://www.dnb.com/us/.

Applications must be mailed on or before the receipt date described at http://grants.nih. gov/grants/funding/submissionschedule.htm. The complete version of this PA is available online at http://grants.nih.gov/grants/guide/ pa-files/PA-05-058.html.

Contact: Herbert Y. Reynolds, Division of Lung Diseases, NHLBI, 6701 Rockledge Dr, Two Rockledge Ctr, Ste 10018, MSC 7952, Bethesda, MD 20892 USA, 301-435-0218, fax: [phone], e-mail: Reynoldh@ nhlbi.nih.gov; Sally S. Tinkle, Cellular, Organ and Systems Pathobiology Branch, Division of Extramural Research and Training, NIEHS, 111 TW Alexander Dr, PO Box 12233, MD EC-23, Research Triangle Park, NC 27709 USA, 919-541-5327, fax: [phone], email: [e-mail]. Reference PA No. PA-05-058