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

Abstract

Pulmonary inflammation is associated with the development of bronchopulmonary dysplasia in premature infants. We have previously shown that perinatal pulmonary expression of human IL-1b 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 avb6 integrin plays a critical role in regulating inflammation in the adult lung. To study the role of the b6 integrin subunit in neonatal inflammatory lung disease, we compared the pulmonary development in IL-1b-expressing infant mice with wild-type or null b6 integrin loci. Absence of the b6 integrin subunit decreased the mortality and improved the postnatal growth of IL-1b-expressing pups. The disrupted alveolar development of IL-1b-expressing mice was improved by b6 integrin deficiency. IL-1b-expressing b6 2/2 pups had shorter alveolar chord length and thinner alveolar walls than IL-1b-expressing b6 1/1 pups. In addition, the absence of the b6 integrin subunit reduced IL-1b-induced neutrophil and macrophage infiltration into the alveolar spaces. b6 integrin subunit deficiency suppressed inflammation and goblet cell hyperplasia in the airways and alleviated airway remodeling in IL-1b-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-1b-expressing b6 2/2 than in IL-1b-expressing b6 1/1 mice. We conclude that absence of the b6 integrin subunit protects the infant murine lung against IL-1b-induced inflammation and injury.

Titanium oxide nanoparticle instillation induces inflammation and inhibits lung development in mice

“…These results are consistent with our observations that TiO 2 exposure resulted in macrophage and neutrophil recruitment, although it is not certain from which cell type each of these cytokines are produced or released. Overexpression of proinflammatory cytokines such as IL-1␤ is known to impair lung alveolarization (6,17,20). VEGF is important for normal lung development, and a reduction in VEGF such as that we noted may contribute to the impairment of alveolarization (4).…”

Developmental Stage Is a Major Determinant of Lung Injury in a Murine Model of Bronchopulmonary Dysplasia

“…Five-micrometer tissue sections were stained with hematoxylin and eosin or Alcian blue/ Periodic acid Schiff (PAS) (pH 2.5) and counterstained with Mayer's hematoxylin (7). Immunohistochemical staining for neutrophils, macrophages, and the proliferation marker Ki-67 was performed using monoclonal rat antimouse neutrophil, clone 7/4 (1:50; Serotec, Oxford, UK), monoclonal rat anti-mouse Mac3, clone M3/84 (1:50; BD Biosciences Pharmingen, San Diego, CA), and polyclonal rabbit anti-human (cross-reacts with mouse) Ki-67 antibodies as described (1:500; Novocastra Laboratories Ltd. Newcastle-upon-Tyne, UK) (9,10). In situ DNA nick-end labeling (TUNEL) for detection of apoptotic cells was performed as described (11).…”

Thrown off balance: the effect of antenatal inflammation on the developing lung and immune system

“…63 Conversely, blockade of IL-1 signaling following LPS exposure partially inhibited fetal lung and systemic inflammation and lung maturation. 64,67 Expert Reviews Obstetrics…”