Impact of inflammation, emphysema, and smoking cessation on V/Q in mouse models of lung obstruction

Abstract

BackgroundChronic obstructive pulmonary disease (COPD) is known to greatly affect ventilation (V) and perfusion (Q) of the lung through pathologies such as inflammation and emphysema. However, there is little direct evidence regarding how these pathologies contribute to the V/Q mismatch observed in COPD and models thereof. Also, little is known regarding how smoking cessation affects V/Q relationships after inflammation and airspace enlargement have become established. To this end, we have quantified V/Q on a per-voxel basis using single photon emission computed tomography (SPECT) in mouse models of COPD and lung obstruction.MethodsThree distinct murine models were used to investigate the impact of different pathologies on V/Q, as measured by SPECT. Lipopolysaccharide (LPS) was used to produce neutrophilic inflammation, porcine pancreatic elastase (PPE) was used to produce emphysema, and long-term cigarette smoke (CS) exposure and cessation were used to investigate the combination of these pathologies.ResultsCS exposure resulted in an increase in mononuclear cells and neutrophils, an increase in airspace enlargement, and an increase in V/Q mismatching. The inflammation produced by LPS was more robust and predominantly neutrophilic, compared to that of cigarette smoke; nevertheless, inflammation alone caused V/Q mismatching similar to that seen with long-term CS exposure. The emphysematous lesions caused by PPE administration were also capable of causing V/Q mismatch in the absence of inflammation. Following CS cessation, inflammatory cell levels returned to those of controls and, similarly, V/Q measures returned to normal despite evidence of persistent mild airspace enlargement.ConclusionsBoth robust inflammation and extensive airspace enlargement, on their own, were capable of producing V/Q mismatch. As CS cessation resulted in a return of V/Q mismatching and inflammatory cell counts to control levels, lung inflammation is likely a major contributor to V/Q mismatch observed in the cigarette smoke exposure model as well as in COPD patients. This return of V/Q mismatching to control values also took place in the presence of mild airspace enlargement, indicating that emphysematous lesions must be of a larger volume before affecting the lung significantly. Early smoking cessation is therefore critical before emphysema has an irreversible impact on gas exchange.

Disruption of Physiological Rhythms Persist Following Cessation of Cigarette Smoke Exposure in Mice

“…Mice were housed at 23 • C on a 12:12 h light-dark cycle (lights on 07:00 h) under specific pathogenfree conditions and provided food and water ad libitum. We opted to use female mice as we have previously validated the cigarette smoke exposure model in females (Jobse et al, 2013(Jobse et al, , 2014. Following telemetry implantation, animals were housed individually in Faraday cages connected to telemetry receivers (RPC-1; Data Science International).…”

Disrupting the Btk Pathway Suppresses COPD-Like Lung Alterations in Atherosclerosis Prone ApoE−/− Mice Following Regular Exposure to Cigarette Smoke

“…Animal models utilizing cigarette smoke exposure display the characteristic features of human COPD including accumulation of inflammatory cells, small airway fibrosis/remodeling, mucus hyper-secretion, lung dysfunction and development of emphysema [ 3 ]. In mouse models of COPD, chronic exposure of mice to cigarette smoke triggers typical pathological hallmarks of the disorder, such as pulmonary inflammation, airway remodeling and airspace enlargement caused by the destruction of alveolar walls [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ].…”

A Targeted Inhibitor of the Alternative Complement Pathway Accelerates Recovery From Smoke-Induced Ocular Injury

“… 21 In addition, we showed that C3d deposition could be identified in the RPE, BrM, and choriocapillaris, which was correlated with alterations in gene expression of complement components in the RPE-choroid fraction of the eye (increase in activators and a decrease in complement inhibitors). 21 Using a novel model of smoking cessation, 22 – 24 we expanded on these findings by investigating whether the detrimental effects caused by CSE are reversible following smoking cessation and treatment with the tissue-targeted AP inhibitor, CR2-fH. 25 CR2-fH consists of the N-terminus of mouse complement factor H (short consensus repeats [SCR] 1–5), which contains the AP-inhibitory domain, linked to a complement receptor 2 (CR2) targeting fragment that binds complement activation products.…”