Inflammation via Distinct ADAM17/ErbB Smooth Muscle Cells Relay Acute Pulmonary

In acute pulmonary inflammation, danger is first recognized by epithelial cells lining the alveolar lumen and relayed to vascular responses, including leukocyte recruitment and increased endothelial permeability. We supposed that this inflammatory relay critically depends on the immunological function of lung interstitial cells such as smooth muscle cells (SMC). Mice with smooth muscle protein-22a promotor-driven deficiency of the disintegrin and metalloproteinase (ADAM) 17 (SM22-Adam17 2/2) were investigated in models of acute pulmonary inflammation (LPS, cytokine, and acid instillation). Underlying signaling mechanisms were identified in cultured tracheal SMC and verified by in vivo reconstitution experiments. SM22-Adam17 2/2 mice showed considerably decreased cytokine production and vascular responses in LPS-or acid-induced pulmonary inflammation. In vitro, ADAM17 deficiency abrogated cytokine release of primary SMC stimulated with LPS or supernatant of acid-exposed epithelial cells. This was explained by a loss of ADAM17-mediated growth factor shedding. LPS responses required ErbB1/epidermal growth factor receptor transactivation by TGFa, whereas acid responses required ErbB4 transactivation by neuregulins. Finally, LPS-induced pulmonary inflammation in SM22-Adam17 2/2 mice was restored by exogenous TGFa application, confirming the involvement of transactivation pathways in vivo. This highlights a new decisive immunological role of lung interstitial cells such as SMC in promoting acute pulmonary inflammation by ADAM17-dependent transactivation. A cute respiratory distress syndrome (ARDS) develops as a result of acute pulmonary inflammation caused, for example, by bacteria or aspiration of acidic gastric juice (1). The inflammatory response, coordinated by cytokines, chemo-kines, and growth factors, leads to the recruitment and activation of inflammatory cells and diminished barrier function. Epithelial cells and alveolar macrophages are among the first cells to encounter inflammatory insults. To coordinate leukocyte recruitment and barrier permeability, signals from the activated airway epithelium must be relayed to the vascular endothelium through the intersti-tial cell layer, including vascular and airway smooth muscle cells (SMC). SMC are capable of releasing a large variety of proin-flammatory factors in vitro and in vivo. This includes cytokines (TNF-a, IL-6), chemokines (CXCL8/IL-8/murine CXCL1), and growth factors (neuregulins [NRGs] and TGFa) (2). However, the significance of SMC and their mediators for acute pulmonary inflammation are essentially unknown. Several of these mediators are tightly regulated by the proteolytic cleavage of their transmembrane precursors into soluble forms by a disintegrin and metalloproteinase (ADAM) family member ADAM17 (3, 4), a process termed shedding. For example, shed TGFa or NRGs act both paracrine and autocrine by binding to epidermal growth factor receptor (EGFR)/ ErbB1 or ErbB3 …