Lung Physiology in Response to Chemical and Mechanical Assaults
Acute lung injury (ALI) arises from factors as diverse as endotoxin exposure, chemical assault, acute particulate exposures or mechanical impacts, as seen in ventilator induced lung injury (VILI). ALI and VILI studies push the understanding of both fundamental breathing mechanics and general lung physiology to describe how damage occurs in the hopes of mitigating of damage. VILI in particular, is an explosive area of research following the COVID disease outbreak due to the large number of critically ill patients in hospitals requiring ventilation and concomitant increases in clinical VILI occurrences. Recent ALI studies are examining how VILI and subject specific parameters such as obesity or a history of surgical interventions affect outcomes1, 2.
Bleomycin is a glyxopeptide with a clinical oncological use that can generate a fibrotic lung disease phenotype in pre-clinical pulmonary research animal models. While both merits and areas of concern of bleomycin use are known3, 4, the well-defined disease progression after instillation, as well as operational ease of use, contributes to its popularity.
During the initial week following instillation, bleomycin contributes to an acute lung inflammation response3. Krischer et al. employ this response in their most recent paper which examines structural changes in surfactant producing cells and the blood-gas barrier, across six experimental groups of rats. Experimental conditions start with a healthy (H) vs. bleomycin exposure (B) split. These groups are further split into 3 groups each: 2 groups with ventilation using Positive End Expiratory Pressures (PEEPs) of either 1 or 5 cmH2O or where no ventilation is done before data collection.
Krischer et al. are able to show the effect of both bleomycin and VILI damage on the lung through beautiful images of the lungs under each condition (ex. Figure 1).
Figure 1. Light Microscopy of tissue harvested from the left lung of healthy (H) or bleomycin (B) treated subjects, emphasizing the blood-gas barrier. Representative images for each ventilation group are presented and structures of note are indicated. Alveolar epithelial cell (AE); extracellular matrix (ECM); endothelium (endo); interstitial cells (IC); basal lamina (bl); alveolar airspace (Air); capillary lumen (caplumen); erythrocyte (ery); collagen fibrils (col). From Krischer et al. 2020 Figure 1[/caption]
They are further able to find a negative correlation between the mean thickness of the blood gas barrier and quasi-static compliance (Figure 2). In contrast, tissue elastance (H) demonstrates a strong positive correlation with the volume of electron lucent multivesicular bodies; a specialized type of endosome that contains membrane-bound extracellular vesicles.
Figure 2. Correlations between histological data and lung mechanics data measured with the flexiVent. In particular, a negative correlation of mean thickness of the blood–gas barrier with Cst and positive correlation between volume of electron lucent multivesicular bodies with tissue elastance (H) are noted. From Krischer et al. 2020 Figure 8.
Overall, Krischer et al. show that mechanical ventilation-induced alterations in cellular ultrastructure occur after inflammatory response following bleomycin assault. Bleomycin injury causes decreases in static compliance (Cst) and these appear to be linked to interstitial changes. Low (PEEP = 1 cmH2O) but not higher (PEEP = 5 cmH2O) ventilation settings appear to aggravate these septal interstitial abnormalities following bleomycin exposure. This study is an excellent example of the depth of insight possible when imaging, histological and gene expression assays are used in combination with lung mechanics parameters with the flexiVent.
Maia, L. de A., Cruz, F. F., de Oliveira, M. V., Samary, C. S., Fernandes, M. V. de S., Trivelin, S. de A. A., Rocha, N. de N., Gama de Abreu, M., Pelosi, P., Silva, P. L., & Rocco, P. R. M. (2019). Effects of Obesity on Pulmonary Inflammation and Remodeling in Experimental Moderate Acute Lung Injury. Frontiers in Immunology, 10, 1215. https://doi.org/10.3389/fimmu.2019.01215
Maia, L., Fernandes, M. V. de S., Santos, A. C., Rocha, N. de N., Oliveira, M., Santos, C., Morales, M., Capelozzi, V., Souza, S., Gutfilen, B., Schultz, M., Gama de Abreu, M., Pelosi, P., Silva, P., & Rocco, P. R. M. (2019). Effects of Protective Mechanical Ventilation With Different PEEP Levels on Alveolar Damage and Inflammation in a Model of Open Abdominal Surgery: A Randomized Study in Obese Versus Non-obese Rats. Frontiers in Physiology, 17(10), 1513. https://doi.org/10.3389/fphys.2019.01513
Izbicki, G., Segel, M. J., Christensen, T. G., Conner, M. W., & Breuer, R. (2002). Time course of bleomycin-induced lung fibrosis: Bleomycin-induced lung fibrosis. International Journal of Experimental Pathology, 83(3), 111–119. https://doi.org/10.1046/j.1365-2613.2002.00220.x
Liu, T., De Los Santos, F. G., & Phan, S. H. (2017). The Bleomycin Model of Pulmonary Fibrosis. In L. Rittié (Ed.), Fibrosis (Vol. 1627, pp. 27–42). Springer New York. https://doi.org/10.1007/978-1-4939-7113-8_2
Krischer, J.-M., Albert, K., Pfaffenroth, A., Lopez-Rodriguez, E., Ruppert, C., Smith, B., & Knudsen, L. (2020). Mechanical ventilation-induced alterations of intracellular surfactant pool and blood–gas barrier in healthy and pre-injured lungs. Histochemistry and Cell Biology, 108. https://doi.org/10.1007/s00418-020-01938-x
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