Acute lung injury (ALI) is a common pathologic consequence of numerous forms of insult to the lung, including acute exposure to environmental irritants. The influx of neutrophils in response to the initiating stimuli of ALI is a hallmark of the pathologic process and a major contributor to the destructive changes wrought in the ALI lung. Our preliminary studies have suggested that receptors for the biogenic amine histamine, produced by mast cells in peripheral tissues, is important to recruitment immune cells to the lung. Using a mouse model of acute lung injury initiated by intratracheal instillation of an irritant such as fine particulate matter or bacterial lipopolysaccharide, we propose to study histamine's role in neutrophil influx and inflammation, identifying histamine producers, responders, and specific receptors involved in the ALI inflammatory process. Previous reports have demonstrated histamine receptor expression by neutrophils, a mast-cell dependence of the neutrophil response, and the capacity of neutrophils to produce histamine on an inducible basis. Therefore, we propose the following hypothesis: in response to initial insult, mast cells release preformed histamine, which diffuses into the bloodstream. Circulating neutrophils recognize and respond to histamine, via specific histamine receptors on their surface, by becoming active and migrating into the lung. These activated neutrophils are then capable of producing histamine, which further drives the development of disease. We will address this hypothesis via the following three specific aims: 1) to determine whether histamine reception by neutrophils is necessary for neutrophil influx and activation in ALI. 2) to determine the cellular source and dynamics of histamine release in ALI. 3) to characterize the contribution of neutrophil-derived histamine to ALI pathology.
These aims will be accomplished through extensive use of the lipopolysaccharide-induced model of ALI in mice lacking either types of histamine receptor or the ability to produce histamine in specific cell populations. Acute lung injury is a fairly common occurrence in intensive care situations and is associated with substantial morbidity and mortality, and the destructive infiltration of neutrophils is a key component of disease evolution. Techniques for therapeutic attenuation of this process are thus of intense clinical interest. This proposal will help to build a theoretical case for or against the use of histamine-directed therapies in clinical management of ALI.
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