TNF-Induced Death Signaling Triggers Alveolar Epithelial Dysfunction in Acute Lung Injury

Abstract

The ability of the alveolar epithelium to prevent and resolve pulmonary edema is a crucial determinant of morbidity and mortality in acute lung injury (ALI). Tumor necrosis factor (TNF) has been implicated in ALI pathogenesis, but the precise mechanisms remain undetermined. We evaluated the role of TNF signaling in pulmonary edema formation in a clinically-relevant mouse model of ALI induced by acid aspiration and investigated the effects of TNF p55 receptor deletion, caspase-8 inhibition, and alveolar macrophage depletion on alveolar epithelial function. We found TNF playing a central role in the development of pulmonary edema in ALI, through activation of p55-mediated death signaling, rather than previously well-characterized p55-mediated proinflammatory signaling. Acid aspiration produced pulmonary edema with significant alveolar epithelial dysfunction, as determined by alveolar fluid clearance (AFC) and intraalveolar levels of receptor for advanced glycation end-products. The impairment of AFC was strongly correlated with lung caspase-8 activation, which was localized to type 1 alveolar epithelial cells by flow cytometric analysis. p55-deficient mice displayed markedly attenuated injury, with improved AFC and reduced caspase-8 activity but no differences in downstream cytokine/chemokine production and neutrophil recruitment. Caspase-8 inhibition significantly improved AFC and oxygenation, while depletion of alveolar macrophages attenuated epithelial dysfunction with reduced TNF production and caspase-8 activity. These results provide in vivo evidence for a novel role for TNF p55 receptor-mediated caspase-8 signaling, without substantial apoptotic cell death, in triggering alveolar epithelial dysfunction and determining the early pathophysiology of ALI. Blockade of TNF-induced death signaling may provide an effective early-phase strategy for ALI.

Blueberry anthocyanins-enriched extracts attenuate the cyclophosphamide-induced lung toxicity

“…TNF-a is a crucial cytokine for inflammatory and fibrotic responses in the lung following toxicant exposure, which induces death signaling and triggers alveolar epithelial dysfunction in acute lung injury [28]. IL-1b is produced by activated macrophages, is an important mediator of the inflammatory response, and is involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis [32].…”

Maresin 1 biosynthesis during platelet–neutrophil interactions is organ-protective

“…Because LTB 4 is a neutrophil product that is linked to neutrophil activation in ARDS (26), the MaR1 pathway can use this additional mechanism to regulate neutrophil recruitment and activation to protect the lung from bystander tissue injury from these "first responders." Along these lines, MaR1 reduced levels of several cytokines with known roles in recruitment and activation of neutrophils in ALI, such as GM-CSF and TNFα, which are reported to play important roles in acid-induced lung injury (27,28). Indeed, MaR1's antineutrophil actions in the lung, including P-selectin expression, were recently reported in an LPS model of lung inflammation (29).…”

Soluble Receptor for Advanced Glycation End-Products Predicts Impaired Alveolar Fluid Clearance in Acute Respiratory Distress Syndrome

“…In a recently published mouse model of acid-induced lung injury reproducing several features of the pathophysiology of ARDS, alveolar levels of sRAGE were elevated on days 1 and 2 and seemed to correlate with a decrease in alveolar fluid clearance on the same days(13), although this correlation was not demonstrated for alveolar sRAGE only during the acute phase of acid-lung injury in mice (15). Measurement of AFC has not been routinely performed in small-animal ARDS studies, but it adds insights into the function of the alveolar epithelium.…”

“…In addition, in an ex vivo model of isolated perfused human lungs declined for transplantation, the rate of AFC was inversely correlated with the level of sRAGE in alveolar fluid, but not with perfusate sRAGE levels (14). Apart from one recent study in mice, in which alveolar sRAGE correlated with AFC during the acute phase of acid-induced lung injury (15), sRAGE has not been comprehensively assessed as a marker of AFC in both animal and clinical studies on ARDS.…”