Monocytic/Macrophagic Pneumonitis after Intrabronchial Deposition of Vascular Endothelial Growth Factor in Neonatal Lambs

Abstract

Abstract. Preterm and young neonates are prone to inadequate surfactant production and are susceptible to respiratory distress syndrome characterized by alveolar damage and hyaline-membrane formation. Glucocorticoid therapy is commonly used in preterm and young infants to enhance lung maturation and surfactant synthesis. Recently, vascular endothelial growth factor (VEGF) was suggested to be a novel therapeutic agent for lung maturation that lacked adverse effects in mice. The purpose of this study was to assess the safety of incremental concentration (0.0005, 0.005, and 0.05 mg/ ml) and duration (16, 24, and 32 hours) of recombinant human VEGF after bronchoscopic instillation (10 ml) in neonatal lambs. High-dose VEGF caused locally extensive plum-red consolidation that was microscopically characterized by interstitial and alveolar infiltrates of cells that were morphologically and phenotypically (CD68 + ) consistent with monocytes/macrophages. T cells (CD3 + ) and B cells (CD79 + ) were located primarily in bronchus/bronchiole-associated lymphoid tissue and were not consistently altered by treatment with VEGF. The dose of VEGF had significant effects on both gross lesions (P , .0047) and microscopic monocyte/macrophage recruitment scores (P , .0001). Thus, the VEGF dose instilled into the lung greatly influenced cellular recruitment and lesion development. The post-dosing interval of VEGF in this study had minor impact (no statistical significance) on cellular recruitment. This study showed that airway deposition of VEGF in the neonatal lamb induces monocyte/macrophage recruitment to the lung and high doses can cause severe lesions. The cellular recruitment suggests further research is needed to define dosages that are efficacious in enhancing lung maturation while minimizing potential adverse effects.

Pretreatment with Recombinant Human Vascular Endothelial Growth Factor Reduces Virus Replication and Inflammation in a Perinatal Lamb Model of Respiratory Syncytial Virus Infection

“…This subtle (not detected clinically) vascular leakage could allow extravasation of antibodies or other innate immune components (e.g., mannose-binding protein) for antigen-antibody complex formation; an important source of pyrogenicity in viral infection (19). A second potential mechanism is related to the recruitment of monocytes and macrophages to sites of VEGF expression/administration (3,27). Monocytes/macrophages are important producers of pyrogenic cytokines after phagocytosis of antigen (38).…”

“…In a sheep model, intrabronchial deposition of exogenous rhVEGF induced a dose-dependent recruitment of monocyte/macrophages into the lung, causing gross and microscopic lesions (27). Although safety concerns regarding VEGF therapy are legitimate, studies of short-term and lower dose applications thus far have reported minimal clinical complications (8,27).…”

Gene profiling studies in the neonatal ovine lung show enhancing effects of VEGF on the immune response

“…The lambs in this study were the same animals used previously to characterize the bronchoscopic deposition of VEGF in the lungs of neonatal lambs [25]. The study was conducted in full-term lambs that did not have RDS.…”

“…The study was conducted in full-term lambs that did not have RDS. Briefly, healthy male and female neonatal lambs at 2–4 days of age (see [25]) were randomly assigned to three groups: a saline-inoculated group ( n = 3), a VEGF-inoculated group (for low dose VEGF n = 1 at all time points; for medium dose VEGF n = 2 for 16 h, n = 3 for 24 h, n = 2 for 32 h; for high dose VEGF, n = 1 for all time points), and a bovine serum albumin (BSA)-inoculated group ( n = 2). Lambs were sedated with xylazine (0.1 mg/kg) intravenously (i.v.…”

“…Previously, we have shown that although exogenous VEGF can induce leukocyte recruitment to the lung in a dose-dependent manner [25], in lower non-inflammatory doses, VEGF can reduce the severity of disease caused by RSV in the lungs of newborn lambs [26]. The precise mechanisms by which VEGF induces monocytic chemotaxis and inhibits viral replication are currently unknown.…”