Sensitive physiological readouts to evaluate countermeasures for lipopolysaccharide-induced lung alterations in mice

Abstract

Despite decades of research, studies investigating the physiological alterations caused by an acute bout of inflammation induced by exposing the lung to lipopolysaccharide have yielded inconsistent results. This can be attributed to small effects and/or a lack of fitted physiological testing. Herein, a comprehensive investigation of lung mechanics was conducted in 270 male C57BL/6 mice at 24, 48 or 96 h after an intranasal exposure to saline or lipopolysaccharide at either 1 or 3 mg/kg (30 mice per group). Traditional techniques that probe the lung using small-amplitude perturbations (i.e., oscillometry) were used, together with less conventional and new techniques that probe the lung using maneuvers of large amplitudes. The latter include a partial and a full-range pressure-volume maneuvers to measure quasi-static elastance, compliance, total lung volume, vital capacity and residual volume. The results demonstrate that lung mechanics assessed by oscillometry was only slightly affected by lipopolysaccharide, confirming previous findings. In contradistinction, lipopolysaccharide markedly altered mechanics when the lung was probed with maneuvers of large amplitudes. With the dose of 3 mg/kg at the peak of inflammation (48 h post-exposure), lipopolysaccharide increased quasi-static elastance by 26.7% (p<0.0001), and decreased compliance by 34.5% (p<0.0001). It also decreased lung volumes, including total lung capacity, vital capacity and residual volume by 33.3%, 30.5% and 43.3%, respectively (all p<0.0001). These newly reported physiological alterations represent sensitive outcomes to efficiently evaluate countermeasures (e.g., drugs) in the context of several lung diseases.

More airway smooth muscle in males versus females in a mouse model of asthma: A blessing in disguise?

“…Mice were weighed, and their respiratory mechanics were tested with the flexiVent (FX Module 2, SCIREQ, Montreal, QC, Canada) as described in our recent studies (Boucher, Dufour‐Mailhot et al., 2022 ; Boucher, Henry, Khadangi et al., 2021 ; Khadangi et al., 2021 , 2022 ). Briefly, they were anaesthetized and put under systemic analgesia using ketamine (100 mg/kg) and xylazine (10 mg/kg).…”

“…Mice were weighed, and their respiratory mechanics were tested with the flexiVent (FX Module 2, SCIREQ, Montreal, QC, Canada) as described in our recent studies Khadangi et al, 2021Khadangi et al, , 2022.…”

Lung stiffness of C57BL/6 versus BALB/c mice

“…Lung volumes were determined as previously described 32 , 33 . Briefly, three maneuvers of large amplitudes were used: (1) the deep inflation (DI) maneuver; (2) the stepwise, pressure-controlled, partial pressure–volume (P–V) maneuver; and (3) the dynamic, ramp-style, full-range P–V maneuver.…”

“…The dynamic, ramp-style, full-range P–V maneuver has been previously described 33 , 35 . Briefly, it starts by degassing the lung by ventilating with 100% oxygen for 5 min and then stopping the ventilation for 5 min.…”

“…This can be epitomized by comparing elastance and volume between the lung of humans and mice. The elastance of a human lung (~ 0.005 cmH 2 O/mL), is about 3.7 logs inferior to a mouse lung (~ 30 cmH 2 O/mL) 8 , 15 , mainly because it is also about 3.7 logs bigger (6000 vs. 1 mL).…”