Asthma, emphysema, COVID-19 and other lung-impacting diseases cause the remodeling of tissue structural properties and can lead to changes in conducting pulmonary volume, viscoelasticity, and air flow distribution. Whole organ experimental inflation tests are commonly used to understand the impact of these modifications on lung mechanics. Here we introduce a novel, automated, custom-designed device for measuring the volume and pressure response of lungs, surpassing the capabilities of traditional machines and built to range size-scales to accommodate both murine and porcine tests. The software-controlled system is capable of constructing standardized continuous volume-pressure curves, while accounting for air compressibility, yielding consistent and reproducible measures while eliminating the need for pulmonary degassing. This device uses volume-control to enable viscoelastic whole lung macromechanical insights from rate dependencies and pressure-time curves. Moreover, the conceptual design of this device facilitates studies relating the phenomenon of diaphragm breathing and artificial ventilation induced by pushing air inside the lungs. System capabilities are demonstrated and validated via a comparative study between ex vivo murine lungs and elastic balloons, using various testing protocols. Volumepressure curve comparisons with previous pressure-controlled systems yield good agreement, confirming accuracy. This work expands the capabilities of current lung experiments, improving scientific investigations of healthy and diseased pulmonary biomechanics. Ultimately, the methodologies demonstrated in the manufacturing of this system enable future studies centered on investigating viscoelasticity as a potential biomarker and improvements to patient ventilators based on direct assessment and comparisons of positive-and negative-pressure mechanics.

Chronic obstructive pulmonary disease (COPD) is a lung disorder characterized by progressive airflow obstruction associated with inflammation and emphysema, and it is currently one of the leading causes of death worldwide. Recent studies with genetically engineered mice reported that during pulmonary inflammation, basophil-derived interleukin-4 can act on lung-infiltrating monocytes causing aberrant expression of the matrix metalloproteinase-12 (MMP-12). MMP-12 activity in turn causes the destruction of alveolar walls leading to emphysema, making it potentially a valid target for pharmacological intervention. Using nuclear magnetic resonance (NMR)- and structure-based optimizations, the current study reports on the optimized novel, potent, and selective MMP-12 inhibitors with single-digit nanomolar affinity in vitro and in vivo efficacy. Using a murine model of elastase-induced emphysema we demonstrated that the most potent agents exhibited a significant decrease in emphysema-like pathology compared to vehicle-treated mice, thus suggesting that the reported agents may potentially be translated into novel therapeutics for the treatment of COPD.

In agriculture industries, workers are at increased risk for developing pulmonary diseases due to inhalation of agricultural dusts, particularly when working in enclosed confinement facilities. Agricultural dusts inhalation leads to unresolved airway inflammation that precedes the development and progression of lung disease. We have previously shown beneficial effects of the omega-3 polyunsaturated fatty acid (ω-3 PUFA) DHA in protecting against the negative inflammatory effects of repetitive dust exposure in the lung. Dietary manipulation of pulmonary disease risk is an attractive and timely approach given the contribution of an increased ω-6 to ω-3 PUFA ratio to low grade inflammation and chronic disease in the Western diet. To prevent any confounding factors that comes with dietary supplementation of ω-3 PUFA (different sources, purity, dose, and duration), we employed a Fat-1 transgenic mouse model that convert ω-6 PUFA to ω-3 PUFA, leading to a tissue ω-6 to ω-3 PUFA ratio of approximately 1:1. Building on our initial findings, we hypothesized that attaining elevated tissue levels of ω-3 PUFA would attenuate agricultural dust-induced lung inflammation and its resolution. To test this hypothesis, we compared wild-type (WT) and Fat-1 transgenic mice in their response to aqueous extracts of agricultural dust (DE). We also used a soluble epoxide hydrolase inhibitor (sEH) to potentiate the effects of ω-3 PUFA, since sEH inhibitors have been shown to stabilize the anti-inflammatory P450 metabolites derived from both ω-3 and ω-6 PUFA and promote generation of specialized pro-resolving lipid mediators from ω-3 PUFA. Over a three-week period, mice were exposed to a total of 15 intranasal instillations of DE obtained from swine confinement buildings in the Midwest. We observed genotype and sex-specific differences between the WT vs. Fat-1 transgenic mice in response to repetitive dust exposure, where three-way ANOVA revealed significant main effects of treatment, genotype, and sex. Also, Fat-1 transgenic mice displayed reduced lymphoid aggregates in the lung following DE exposure as compared to WT animals exposed to DE, suggesting improved resilience to the DE-induced inflammatory effects. Overall, our data implicate a protective role of ω-3 FA in the lung following repetitive dust exposure.

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