Neuregulin-1-Human Epidermal Receptor-2 Signaling Is a Central Regulator of Pulmonary Epithelial Permeability and Acute Lung Injury

Abstract

The mechanisms behind the loss of epithelial barrier function leading to alveolar flooding in acute lung injury (ALI) are incompletely understood. We hypothesized that the tyrosine kinase receptor human epidermal growth factor receptor-2 (HER2) would be activated in an inflammatory setting and participate in ALI. Interleukin-1␤ (IL-1␤) exposure resulted in HER2 activation in human epithelial cells and markedly increased conductance across a monolayer of airway epithelial cells. Upon HER2 blockade, conductance changes were significantly decreased. Mechanistic studies revealed that HER2 trans-activation by IL-1␤ required a disintegrin and metalloprotease 17 (ADAM17)-dependent shedding of the ligand neuregulin-1 (NRG-1). In murine models of ALI, NRG-1-HER2 signaling was activated, and ADAM17 blockade resulted in decreased NRG-1 shedding, HER2 activation, and lung injury in vivo. Finally, NRG-1 was detectable and elevated in pulmonary edema fluid from patients with ALI. These results suggest that the ADAM17-NRG-1-HER2 axis modulates the alveolar epithelial barrier and contributes to the pathophysiology of ALI. Acute lung injury (ALI)3 is a severe clinical disorder with an annual incidence of ϳ200,000 and a mortality of 40% in the United States (1). Most commonly seen in the setting of sepsis (2-4), ALI is marked by disruption of the alveolar barrier, leukocyte activation, release of inflammatory cytokines, and hypercoagulability. The net effect is an increase in alveolar epithelial permeability, resulting in alveolar flooding with proteinrich edema and life-threatening hypoxemia (5). An intact epithelial barrier is essential to maintaining normal pulmonary fluid balance. Indeed, damage to the endothelium alone is insufficient to cause pulmonary edema, whereas epithelial injury results in severe lung injury (6 -8). The epithelium provides a greater resistance to proteins and fluid than the capillary endothelium and is responsible for the active ion transport-dependent removal of edema fluid from the distal air spaces of the lung (9 -11).The tyrosine kinase receptor human epidermal growth factor receptor-2 (HER2) is expressed by pulmonary bronchial epithelial cells and is involved in multiple physiologic processes, including cell proliferation and wound repair. The HER receptor family consists of four type 1, membrane-bound tyrosine kinase receptors: HER1 or epidermal growth factor receptor (EGFR), HER2, HER3, and HER4 (12). HER2 has no known ligand and requires partnering with another HER family member for activation. HER2 and 3 are highly expressed in pulmonary bronchial epithelial cells (compared with HER1 and 4) (13). HER3 is the receptor for the ligand neuregulin-1 (NRG-1), but HER3 has no intrinsic signaling properties (14). Upon NRG-1 binding, HER3 heterodimerizes with HER2, resulting in activation of the HER2 tyrosine kinase domain, HER2 autophosphorylation, and initiation of downstream intracellular signaling cascades (13). NRG-1 is expressed in bronchial epithelial cells (13,15,16) and is shed from the cell ...

Human Epidermal Growth Factor Receptor Signaling in Acute Lung Injury

“…In contrast, HER3 lacks a functional tyrosine kinase domain and also only signals as part of a heterodimer with another HER member ( Figure 1) (42). Members of the HER ligand-receptor family are expressed by a variety of cells, including pulmonary alveolar epithelial cells (43).…”

“…In the quiescent state, HER family ligands are expressed at the apical surface of polarized epithelia, whereas expression of their cognate receptors is restricted to the basolateral aspect of cells, creating a natural segregation of ligands and receptors that favors receptor inactivation (43)(44)(45). Given that receptor activation influences cell proliferation, this spatial separation maintains cells in a dormant, differentiated state.…”

“…Members of the HER family can serve as signaling intermediaries for extracellular stimuli such as hormones, neurotransmitters, and cytokines, translating them into an intracellular response. For example, IL-1b, a central regulator of epithelial barrier function in ALI (43,(86)(87)(88)(89)(90)(91)(92)(93), enhances repair of wounded epithelium in an EGFR-dependent fashion. In rat ATII monolayers wounded in a scratch model, exogenous IL-1b hastens wound closure through IL-1b-mediated TGF-a and EGF release, with subsequent EGFR activation leading to cell spreading (18).…”

“…IL-1b activates HER2 in airway and alveolar epithelial cells (43). This occurs through IL-1b-mediated shedding of the HER3 ligand, NRG-1, from pulmonary epithelial cells, resulting HER2/3 activation and HER2-dependent loss of epithelial barrier function.…”

Neuregulin-1 as a potentially novel biomarker in acute respiratory distress syndrome

“…This model suggests at least three potential targets that could help attenuate lung injury, which include the protease (ADAM-17), the ligand (neuregulin-1) or the receptors (HER-2/HER-3). Indeed, pharmacological blockade of HER-2/HER-3 in vivo using 2C4 (a monoclonal antibody targeting the extracellular domain of HER-2, which prevents heterodimerisation) has been associated with attenuated fibrosis and improved survival in a bleomycin lung injury C57BL/6 murine model [21], and blockade of ADAM-17 in bleomycin injured-mice resulted in decreased lung injury in vivo [22].…”