As countries continue to industrialize, major cities experience diminished air quality, whereas rural populations also experience poor air quality from sources such as agricultural operations. These exposures to environmental pollution from both rural and populated/industrialized sources have adverse effects on human health. Although respiratory diseases (e.g., asthma and chronic obstructive pulmonary disease) are the most commonly reported following long-term exposure to particulate matter and hazardous chemicals, gastrointestinal complications have also been associated with the increased risk of lung disease from inhalation of polluted air. The interconnectedness of these organ systems has offered valuable insights into the roles of the immune system and the micro/mycobiota as mediators of communication between the lung and the gut during disease states. A topical example of this relationship is provided by reports of multiple gastrointestinal symptoms in patients with coronavirus disease 2019 (COVID-19), whereas the rapid transmission and increased risk of COVID-19 has been linked to poor air quality and high levels of particulate matter. In this review, we focus on the mechanistic effects of environmental pollution on disease progression with special emphasis on the gut-lung axis.

Breathing involves fluid-solid interactions in the lung; however, the lack of experimental data inhibits combining the mechanics of air flow to airway deformation, challenging the understanding of how biomaterial constituents contribute to tissue response. As such, lung mechanics research is increasingly focused on exploring the relationship between structure and function. To address these needs, we characterize mechanical properties of porcine airways using uniaxial tensile experiments, accounting for bronchial orientation- and location- dependency. Structurally-reinforced constitutive models are developed to incorporate the role of collagen and elastin fibers embedded within the extrafibrillar matrix. The strain-energy function combines a matrix description (evaluating six models: compressible NeoHookean, unconstrained Ogden, uncoupled Mooney-Rivlin, incompressible Ogden, incompressible Demiray and incompressible NeoHookean), superimposed with non-linear fibers (evaluating two models: exponential and polynomial). The best constitutive formulation representative of all bronchial regions is determined based on curve-fit results to experimental data, accounting for uniqueness and sensitivity. Glycosaminoglycan and collagen composition, alongside tissue architecture, indicate fiber form to be primarily responsible for observed airway anisotropy and heterogeneous mechanical behavior. To the authors' best knowledge, this study is the first to formulate a structurally-motivated constitutive model, augmented with biochemical analysis and microstructural observations, to investigate the mechanical function of proximal and distal bronchi. Our systematic pulmonary tissue characterization provides a necessary foundation for understanding pulmonary mechanics; furthermore, these results enable clinical translation through simulations of airway obstruction in disease, fluid-structure interaction insights during breathing, and potentially, predictive capabilities for medical interventions. STATEMENT OF SIGNIFICANCE: The advancement of pulmonary research relies on investigating the biomechanical response of the bronchial tree. Experiments demonstrating the non-linear, heterogeneous, and anisotropic material behavior of porcine airways are used to develop a structural constitutive model representative of proximal and distal bronchial behavior. Calibrated material parameters exhibit regional variation in biomaterial properties, initially hypothesized to originate from tissue constituents. Further exploration through biochemical and histological analysis indicates mechanical function is primarily governed by microstructural form. The results of this study can be directly used in finite element and fluid-structure interaction models to enable physiologically relevant and more accurate computational simulations aimed to help diagnose and monitor pulmonary disease.

Introduction: Over 1 billion humans carry infectious helminth parasites that can lead to chronic comorbidities such as anemia and growth retardation in children. Helminths induce a T-helper type 2 (Th2) immune response in the host and can cause severe tissue damage and fibrosis if chronic. We recently reported that mice infected with the soil-transmitted helminth, Nippostrongylus brasiliensis, displayed elevated levels of endocannabinoids (eCBs) in the lung and intestine. eCBs are lipid-signaling molecules that control inflammation; however, their function in infection is not well defined. Materials and Methods: A combination of pharmacological approaches and genetic mouse models was used to investigate roles for the eCB system in inflammatory responses and lung injury in mice during parasitic infection with N. brasiliensis. Results: Hemorrhaging of lung tissue in mice infected with N. brasiliensis was exacerbated by inhibiting peripheral cannabinoid receptor subtype-1 (CB₁Rs) with the peripherally restricted CB₁R antagonist, AM6545. In addition, these mice exhibited an increase in nonfunctional alveolar space and prolonged airway eosinophilia compared to vehicle-treated infected mice. In contrast to mice treated with AM6545, infected cannabinoid receptor subtype-2-null mice (Cnr2^-/-) did not display any changes in these parameters compared to wild-type mice. Conclusions: Roles for the eCB system in Th2 immune responses are not well understood; however, increases in its activity in response to infection suggest an immunomodulatory role. Moreover, these findings suggest a role for eCB signaling at CB₁Rs but not cannabinoid receptor subtypes-2 in the resolution of Th2 inflammatory responses, which become host destructive over time.

The role of pulmonary free fatty acid receptor 4 (FFAR4) is not fully elucidated and we aimed to clarify the impact of FFAR4 on the pulmonary immune response and return to homeostasis. We employed a known high-risk human pulmonary immunogenic exposure to extracts of dust from swine confinement facilities (DE). WT and Ffar4-null mice were repetitively exposed to DE via intranasal instillation and supplemented with docosahexaenoic acid (DHA) by oral gavage. We sought to understand if previous findings of DHA-mediated attenuation of the DE-induced inflammatory response are FFAR4-dependent. We identified that DHA mediates anti-inflammatory effects independent of FFAR4 expression, and that DE-exposed mice lacking FFAR4 had reduced immune cells in the airways, epithelial dysplasia, and impaired pulmonary barrier integrity. Analysis of transcripts using an immunology gene expression panel revealed a role for FFAR4 in lungs related to innate immune initiation of inflammation, cytoprotection, and immune cell migration. Ultimately, the presence of FFAR4 in the lung may regulate cell survival and repair following immune injury, suggestive of potential therapeutic directions for pulmonary disease.

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. Volume-pressure 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.

Air pollution poses a significant threat to the environment and human health. Most in vivo health studies conducted regarding air pollutants, including particulate matter (PM) and gas phase pollutants, have been either through traditional medical intranasal treatment or using a tiny chamber, which limit animal activities. In this study, we designed and tested a large, whole-body, multiple animal exposure chamber with uniform dispersion and exposure stability for animal studies. The chamber simultaneously controls particle size distribution and PM mass concentration. Two different methods were used to generate aerosol suspension through either soluble material (Alternaria extract), liquid particle suspension (nanosilica solution), or dry powder (silica powder). We demonstrate that the chamber system provides well controlled and characterized whole animal exposures, where dosage is by inhalation of particulate matter.

Nutritional status is a well-recognized prognostic indicator in chronic obstructive pulmonary disease (COPD); however, very little is known about the relationship between lung function and saturated fat intake. We used data from the cross-sectional National Health and Nutrition Examination Surveys (NHANES) to assess the relationship between saturated fatty acid (SFA) intake and lung function in the general US adult population. Adults in NHANES (2007⁻2012) with pre-bronchodilator spirometry measurements and dietary SFA intake were included. Primary outcomes were lung function including forced expiratory volume in one second (FEV₁)_, FEV₁, forced vital capacity (FVC), FEV₁/FVC ratio, percent predicted FEV₁ and percent predicted FVC. Multivariable regression models in the general population as well as those with spirometry-defined airflow obstruction were used to assess the relationship between lung function measurements and dietary SFA intake after adjustment for confounders. 11,180 eligible participants were included in this study. Univariate analysis revealed a statistically significant positive association between total SFA intake and lung function outcomes; however, these relationships were attenuated after adjustment for covariates. A secondary analysis of individuals with spirometry-defined airflow obstruction (FEV₁/FVC < 0.7) revealed that a lower intake of SFA was associated with reduced FEV₁ (β = -126.4, p = 0.04 for quartile 1 vs. quartile 4), FVC (β = -165.8. p = 0.01 for quartile 1 vs. quartile 4), and percent predicted FVC (β = -3.3. p = 0.04 for quartile 1 vs. quartile 4), after adjustment for relevant confounders. No associations were observed for the FEV₁/FVC ratio and percent predicted FEV₁. It is possible that characteristics such as food source and fatty acid chain length may influence associations between saturated fatty acid intake and health outcomes.