Lymphangiogenesis is Critical for Healing and Survival in a Murine Model of Laryngotracheal Injury

This research explores the crucial role of lymphatic vessels in healing and survival following laryngotracheal injury in a mouse model. Lymphatic dysfunction is often associated with worsening fibrosis in various diseases, but its impact on laryngotracheal injury has not been investigated before. The study aimed to examine lymphatic vascular remodeling and the effects of lymphangiogenesis inhibition on airway healing after mucosal damage.

To achieve this, the scientists induced laryngotracheal stenosis (LTS) in C57BL6 mice using a chemomechanical injury model. They measured lymphatic density using LYVE-1 immunohistochemistry. After injury, the mice were treated with a VEGFR-3-selective tyrosine kinase inhibitor, SAR131675, to block lymphangiogenesis.

The researchers assessed several outcomes, including survival, histopathology, immunohistochemistry, and Evans blue dye vascular leakage. Their results showed that laryngotracheal injury led to a significant rise in subepithelial lymphatic vessel density alongside fibrotic remodeling. When the lymphangiogenic response was inhibited with SAR131675, the lymphangiogenic response was halted, resulting in higher mortality rates, impaired epithelial repair with obstructive sloughing, increased edema, and persistent histopathologic signs of tissue injury.

Additionally, the study observed a qualitative increase in pathologic fibrocellular remodeling, though without a measurable difference in lamina propria thickness. These findings demonstrate that lymphatic remodeling is a vital element in successful airway repair following mucosal injury. Lymphatic dysfunction is a known risk factor for LTS, often exacerbated by conditions like diabetes, obesity, and prematurity, and can be further intensified by positive pressure ventilation.

The researchers conclude that disrupting the lymphangiogenic response to airway injury may lead to stasis of pro-inflammatory factors, resulting in chronic inflammation, maladaptive remodeling, and pathological tissue changes. Consequently, the lymphatic vasculature presents a promising target for future mechanistic studies and potential therapeutic interventions following airway injury.