β6 Integrin Subunit Deficiency Alleviates Lung Injury in a Mouse Model of Bronchopulmonary Dysplasia

Pulmonary inflammation is associated with the development of bronchopulmonary dysplasia in premature infants. We have previously shown that perinatal pulmonary expression of human IL-1 beta is sufficient to cause a lung disease similar to bronchopulmonary dysplasia, characterized by inflammation, impaired alveolarization, poor postnatal growth, and increased mortality in infant mice. The alpha v beta 6 integrin plays a critical role in regulating inflammation in the adult lung. To study the role of the beta 6 integrin subunit in neonatal inflammatory lung disease, we compared the pulmonary development in IL-1 beta-expressing infant mice with wild-type or null beta 6 integrin loci. Absence of the beta 6 integrin subunit decreased the mortality and improved the postnatal growth of IL-1 beta-expressing pups. The disrupted alveolar development of IL-1 beta-expressing mice was improved by beta 6 integrin deficiency. IL-1 beta-expressing beta 6(-/-)pups had shorter alveolar chord length and thinner alveolar walls than IL-1 beta-expressing beta 6(+/+) pups. In addition, the absence of the beta 6 integrin subunit reduced IL-1 beta-induced neutrophil and macrophage infiltration into the alveolar spaces. beta 6 integrin subunit deficiency suppressed inflammation and goblet cell hyperplasia in the airways and alleviated airway remodeling in IL-1 beta-expressing mice. The expression of the chemoattractant proteins, keratinocyte-derived chemokine, macrophage-inflammatory protein-2, calgranulin A, and calgranulin B, of osteopontin, and of the chitinase-like lectins, Ym1 and Ym2, was lower in IL-1 beta-expressing beta 6(-/-) than in IL-1 beta-expressing beta 6(+/+) mice. We conclude that absence of the beta 6 integrin subunit protects the infant murine lung against IL-1 beta-induced inflammation and injury.