Reduced surfactant protein B levels impede unfolding of the pulmonary blood-gas barrier during inspiration in mice

Abstract

Surfactant protein B (SP-B) contributes to surface tension reduction at the pulmonary air-liquid interface. In lung injury, downregulation of alveolar SP-B is an early finding. During inspiration, unfolding processes of the interalveolar septa are considered as physiological micromechanical mechanisms that might become injurious in the presence of high surface tension, thus propagating injury. The aim of the present study was to quantify SP-B deficiency-related alterations in micromechanics of the blood-gas-barrier (BGB) during inspiration at physiological lung volumes. Our transgenic mouse line expressed SP-B under control of a doxycycline-dependent promoter. Two days after withdrawal of doxycycline (Dox-off), the mean SP-B level declined by 86%. In Dox-on and Dox-off groups, lung mechanics were assessed before the lungs were fixed at increasing airway opening pressures on inspiration or subjected to broncho-alveolar lavage (BAL) and gene expression analyses. Fixed lungs were investigated by design-based stereology. In Dox-off the BAL-albumin, alveolar hypophase volume and tissue elastance slightly increased concomitantly with proinflammatory gene-expression profiles while inflammatory cells remained unchanged. Stereology demonstrated increased derecruited septa and folded BGB in Dox-off. Although in Dox-on inspiratory unfolding of the BGB resulted in an increase of air-exposed alveolar epithelium, this mechanism was not prevalent in Dox-off where, instead, dilation of acinar airspaces occurred (mainly in the alveolar duct compartment). Inspiratory increases in surface area of the epithelial basal lamina were absent in both groups. In essence, while stretching was not observed in any group, inspiratory unfolding of the BGB is a dominant mechanism in healthy lungs but absent in SP-B deficiency.NEW & NOTEWORTHY Surfactant protein B (SP-B) deficiency is an early feature in experimental and clinical acute lung injury and might contribute to injury progression via mechanical stress of the blood-gas barrier (BGB) even at physiological lung volumes. Although in healthy mice, inspiratory micromechanics was dominated by unfolding processes of the BGB, this mechanism was absent in SP-B deficiency. Instead interalveolar septa appeared to be stiffened, resulting in a dilation of alveolar ducts. Stretching of the BGB was not found.

Keywords: acute lung injury; atelectrauma; design-based stereology; micromechanics; surfactant protein B.