The Role of Alveolar Macrophage Beta-2 Adrenergic Receptors in Acute Lung Injury
Abstract
Acute lung injury, which clinically presents as Acute Respiratory Distress Syndrome (ARDS) is characterized by pulmonary edema, a condition during which lungs fill up with excess fluid. Excessive accumulation of fluid in the lungs results in decreased oxygen levels and consequently shortness of breath. ARDS typically occurs after an infection such as pneumonia or after trauma, and large amounts of blood transfusion. Many patients who develop ARDS do not survive. The risk of death increases with the severity of ARDS, and age. Despite three decades of research, the management of ARDS remains supportive and the death rate remains unacceptably high (>40% in severe ARDS). In experimental models, beta2-agonists, which are commonly used as an inhaler therapy for asthma, have been shown to improve pulmonary edema by increasing the rate of fluid clearance out of lungs. Based on these studies, beta2-agonists have been proposed as a potential therapy for ARDS. However, two large clinical trials evaluating the role of beta2-agonists as a therapy for ARDS not only failed to demonstrate any benefit but also showed harm. The central critical question to be addressed in this application is why the beta2-agonists failed as a therapy for ARDS despite their beneficial effects on resolution of pulmonary edema. Understanding the reasons behind this failure may allow us to improve care that is being delivered to patients with ARDS. In a model of air pollution-induced lung inflammation, we have recently shown that beta2-agonists may worsen lung injury by increasing the release of an inflammatory molecule called interleukin-6 further from alveolar macrophages, which are the primary immune cells in the lungs. In preliminary experiments, we have found that beta2-agonists increased death due to ARDS in mice following flu virus, which is a frequently used model of ARDS. In contrast, prevention of the effects of beta2-agonists by giving commonly used heart medication, beta-blockers, or genetically deleting the beta2-adrenergic receptors attenuated flu-induced ARDS and associated death. Similarly, beta2-agonist therapy increased IL-6 release, while loss of beta2-adrenergic receptors decreased it, suggesting a role for beta2-adrenergic receptor mediated regulation of IL-6 in the pathogenesis of flu-induced ARDS. We also found that inhibition of beta2-adrenergic receptors improved the recruitment of immune cells from blood in the lung. These cells called monocyte-derived or blood-borne macrophages have been shown to be important in the development of ARDS. Based on these findings, we hypothesized that the unexpected negative outcomes seen with beta2-agonists were due to their unwanted effects on alveolar macrophages promoting increased IL-6 release and preventing the recruitment of monocyte-derived immune cells. To test our hypothesis, we will use a mouse model of ARDS induced by flu virus. In the first aim of this proposal, we will determine whether beta2-agonists worsen flu virus-induced ARDS by affecting alveolar macrophages that are resident in the lungs and/or macrophages that are recruited from the blood. In the second aim, we will determine whether IL-6 and/or recruited monocyte-derived macrophages are required for the beta2-adrenergic receptor activation-induced worsening of flu virus-induced lung injury. In the third aim, we will investigate whether inhibition of beta2-adrenergic receptors will attenuate age-related worsening of flu-induced lung injury in mice. Impact: Our project will provide the mechanistic link between the use of beta2-agonists and adverse clinical outcomes in ARDS. We will determine the role of catecholamines and the beta2-adrenergic receptors on tissue-resident and monocyte-derived macrophages in acute lung injury. At the end of these studies, we will know whether targeting inhibiting beta2-adrenergic receptors to normalize an exaggerated IL-6 response and/or reversal of inhibition of monocyte
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610711
Entities
People
- Gokhan Mutlu
Organizations
- United States Army
- University of Chicago