Human Epidermal Growth Factor Receptor Signaling in Acute Lung Injury

Abstract

Acute lung injury (ALI) is a syndrome marked by increased permeability across the pulmonary epithelium resulting in pulmonary edema. Recent evidence suggests that members of the human epidermal growth factor receptor (HER) family are activated in alveolar epithelial cells during ALI and regulate alveolar epithelial barrier function. These tyrosine kinase receptors, which also participate in the pathophysiology of pulmonary epithelial malignancies, regulate cell growth, differentiation, and migration as well as cellcell adhesion, all processes that influence epithelial injury and repair. In this review we outline mechanisms of epithelial injury and repair in ALI, activation patterns of this receptor family in pulmonary epithelial cells as a consequence injury, how receptor activation alters alveolar permeability, and the possible intracellular signaling pathways involved. Finally, we propose a theoretical model for how HER-mediated modulation of alveolar permeability might affect lung injury and repair. Understanding how these receptors signal has direct therapeutic implications in lung injury and other diseases characterized by altered epithelial barrier function.Keywords: acute lung injury; human epidermal growth factor receptor; inflammation; alveolar epithelial cell Acute lung injury (ALI) is a devastating illness with an annual incidence of approximately 200,000 in the United States and a mortality rate between 25 and 40% (1). A complex inflammatory syndrome, ALI is marked by leukocyte recruitment and activation; release of cytotoxic reactive oxygen species, proteolytic enzymes, and cytokines; and activation of the coagulation cascade (2, 3). The net result is damage to the alveolar capillary barrier leading to airspace flooding with protein-rich fluid (4-6). Radiographically, this is manifested as pulmonary edema in the absence of left ventricular dysfunction. Clinically, ALI presents as life-threatening hypoxemia (7). Despite recent advances in understanding the pathogenic mechanisms of ALI, no specific pharmacologic therapy exists, and treatment remains supportive. Pulmonary epithelial cell damage resulting in loss of alveolar epithelial barrier function with increased permeability across the alveolo-capillary membrane is an initial step in ALI development. Rapid and efficient restoration of the epithelial barrier is essential to repair of the injured lung (4). These facts highlight the importance of understanding the processes that regulate epithelial cell injury and repair in ALI. Increasing evidence suggests that members of the Human Epidermal Growth Factor Receptor (HER) family, which are expressed by alveolar and airway epithelial cells, are activated in the setting of ALI and regulate epithelial barrier function during injury and repair. This review outlines the current understanding of the HER family's role in epithelial biology during ALI. ALVEOLAR EPITHELIAL INJURY AND REPAIRThe alveolar epithelial surface is comprised of alveolar type I (ATI) and type II (ATII) cells, and injury to these cells i...

HER2 activation results in β-catenin-dependent changes in pulmonary epithelial permeability

“…A member of the epidermal growth factor receptor (EGFR or HER1) family of receptor tyrosine kinases (RTKs), HER2 is activated when the ligand neuregulin-1 (NRG-1) binds the receptor HER3, inducing HER2/3 heterodimerization, and activates the HER2 kinase domain, leading to HER2 autophosphorylation and initiation of subsequent HER2-dependent downstream signaling cascades (12). HER2 signaling has been demonstrated to participate in numerous cellular processes, including lung growth and development, cell proliferation, and migration (5,33).…”

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“…It may also be used as a marker of receptor; E-cadherin: epithelial cadherin; TGF: transforming growth factor. Reproduced and modified from [20] with permission from the publisher.…”

“…More recently, neuregulin-1 has been implicated in the activation of human EGF receptor (HER)-2, which has been associated with increased cell permeability and lung injury both in vitro and in vivo in animal studies [18,19]. A model for HER-2 signalling in alveolar epithelial cells recently was presented by FINIGAN et al [20], in which they proposed that upregulation of IL-1b in the setting of lung injury is associated with activation of ADAM-17, which leads to shedding of membrane-bound neuregulin-1 and subsequent activation of the HER-2/HER-3 complex ( fig. 2).…”