Jihane A. Faress

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

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-1β (IL-1β) 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-1β 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.

Subacute Invasive Pulmonary Aspergillosis Associated with Ankylosing Spondylitis

A 72-year-old smoker with a history of ankylosing spondylitis, who was not receiving immunosuppressants, was hospitalized for severe influenza pneumonia in January. He was treated with oseltamivir and antibiotics and enrolled in a clinical trial that evaluated steroids for the treatment of community-acquired pneumonia. It is unknown whether he was in the placebo or treatment group; however, treatment involved an initial methylprednisolone 40mgbolus, followed by 40mg/d for 5 days, and then a rapid taper over 1week. He then presented in March with worsening dyspnea, productive cough, weight loss, lethargy, and an overall decline in clinical status. Imaging during this admission revealed bilateral upper lobe cavitary lesions with fungus balls and associated infiltrates. Multiple sputum cultures were positive for Aspergillus fumigatus, and Aspergillus antibodies were detected by immunodiffusion and complement fixation (1:64). He was diagnosed presumptively with subacute invasive pulmonary aspergillosis and began treatment with voriconazole. Patients with ankylosing spondylitis can develop pulmonary manifestations of their disease, including apical fibrobullous disease (1). They are more likely to develop apical superinfections with mycobacterial or fungal infections as well, the most common of which is Aspergillus (2, 3). Influenza is associated with increased risk for invasive aspergillosis; this is believed to be because of the disruption of the bronchial mucosa, which leads to an impaired immune response (4). This, possibly coupled with the use of steroids, could have promoted further immune dysregulation and facilitated an environment for Aspergillus to grow. n