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Alveolar macrophages orchestrate the response to viral infections. Age-related changes in these cells may underlie the differential severity of pneumonia in older patients. We performed an integrated analysis of single-cell RNA-Seq data that revealed homogenous age-related changes in the alveolar macrophage transcriptome in humans and mice. Using genetic lineage tracing with sequential injury, heterochronic adoptive transfer, and parabiosis, we found that the lung microenvironment drove an age-related resistance of alveolar macrophages to proliferation that persisted during influenza A viral infection. Ligand-receptor pair analysis localized these changes to the extracellular matrix, where hyaluronan was increased in aged animals and altered the proliferative response of bone marrow-derived macrophages to granulocyte macrophage colony-stimulating factor (GM-CSF). Our findings suggest that strategies targeting the aging lung microenvironment will be necessary to restore alveolar macrophage function in aging., Introduction Advanced age is the most important risk factor for severe disease or death in patients with viral pneumonia, including coronavirus disease 2019 (COVID-19) (1,2). Alveolar macrophages play central roles [...]

Influenza A viruses (IAV) can cause lung injury and acute respiratory distress syndrome (ARDS), which is characterized by accumulation of excessive fluid (edema) in the alveolar airspaces and leads to hypoxemia and death if not corrected. Clearance of excess edema fluid is driven mostly by the alveolar epithelial Na,K-ATPase and is crucial for survival of patients with ARDS. We therefore investigated whether IAV infection alters Na,K-ATPase expression and function in alveolar epithelial cells (AECs) and the ability of the lung to clear edema. IAV infection reduced Na,K-ATPase in the plasma membrane of human and murine AECs and in distal lung epithelium of infected mice. Moreover, induced Na,K-ATPase improved alveolar fluid clearance (AFC) in IAV-infected mice. We identified a paracrine cell communication network between infected and noninfected AECs and alveolar macrophages that leads to decreased alveolar epithelial Na,K-ATPase function and plasma membrane abundance and inhibition of AFC. We determined that the IAV-induced reduction of Na,K-ATPase is mediated by a host signaling pathway that involves epithelial type I IFN and an IFN-dependent elevation of macrophage TNF-related apoptosis-inducing ligand (TRAIL). Our data reveal that interruption of this cellular crosstalk improves edema resolution, which is of biologic and clinical importance to patients with IAV-induced lung injury., Introduction Influenza A viruses (IAV) infect cells in the alveolus and induce primary viral pneumonia, which can progress to acute respiratory distress syndrome (ARDS) with high mortality (1). IAV-induced lung [...]

Acute exposure to particulate matter (PM) air pollution causes thrombotic cardiovascular events, leading to increased mortality rates; however, the link between PM and cardiovascular dysfunction is not completely understood. We have previously shown that the release of IL-6 from alveolar macrophages is required for a prothrombotic state and acceleration of thrombosis following exposure to PM. Here, we determined that PM exposure results in the systemic release of catecholamines, which engage the [β.sub.2]-adrenergic receptor ([β.sub.2]AR) on murine alveolar macrophages and augment the release of IL-6. In mice, [β.sub.2]AR signaling promoted the development of a prothrombotic state that was sufficient to accelerate arterial thrombosis. In primary human alveolar macrophages, administration of a [β.sub.2]AR agonist augmented IL-6 release, while the addition of a beta blocker inhibited PM-induced IL-6 release. Genetic loss or pharmacologic inhibition of the [β.sub.2]AR on murine alveolar macrophages attenuated PM-induced IL-6 release and prothrombotic state. Furthermore, exogenous [β.sub.2]AR agonist therapy further augmented these responses in alveolar macrophages through generation of mitochondrial ROS and subsequent increase of adenylyl cyclase activity. Together, these results link the activation of the sympathetic nervous system by [β.sub.2]AR signaling with metabolism, lung inflammation, and an enhanced susceptibility to thrombotic cardiovascular events., Introduction Based on air pollution exposure estimates in the US from the late 1970s to the early 2000s, Pope et al. projected that a 10 µg/[m.sup.3] fall in the mean [...]

Byline: Gokhan M. Mutlu (1), Phillip Factor (2) Keywords: Vasopressin; Sepsis; Septic shock; Catecholamine; Norepinephrine Abstract: Vasopressin is a potent vasopressor for improving organ perfusion during septic shock. The rationale for the use of vasopressin is its relative deficiency of plasma levels and hypersensitivity to its vasopressor effects during septic shock. Growing evidence suggests that low-dose ( Author Affiliation: (1) Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Tarry 14--707, Chicago, IL 60611, USA (2) Pulmonary, Allergy and Critical Care Medicine, Columbia University College of Physicians and Surgeons, Room P&S 10-502, 630 W. 168th Street, New York, NY 10032, USA Article History: Registration Date: 12/03/2004 Online Date: 21/04/2004 Article note: This work was supported by the American Heart Association, HL-66211, and the Evanston Northwestern Healthcare Research Institute.

Byline: Gokhan M. Mutlu (1), Phillip Factor (2) Author Affiliation: (1) Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, 240 E. Huron, Chicago, IL, 60614, USA (2) Pulmonary, Allergy, and Critical Care Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA Article History: Registration Date: 09/07/2004 Accepted Date: 08/07/2004 Online Date: 23/07/2004