What is Pulmonary Function Testing? Explanation of Types, Preparation Methods, and Evaluation Indicators

Pulmonary function testing is a crucial method for evaluating the efficacy of new drugs for respiratory diseases at the biological level. In recent years, treatments targeting not only symptom improvement but also tissue repair and fibrosis inhibition have gained attention, necessitating the development of more accurate evaluation systems. This article outlines representative disease models, evaluation indices, and key points for conducting trials, explaining the concepts for enhancing clinical predictability.

Overview of Pulmonary Function Tests

Background for Requiring Pulmonary Function Tests

Until recently, respiratory disease treatment has mainly focused on symptomatic relief, such as for cough and difficulty breathing, but in recent years,A shift toward treatment strategies that intervene in the progression of the disease itselfprogress is being made. In particular, the development of new therapeutic agents targeting the promotion of lung tissue repair and the inhibition of fibrosis is highly anticipated, and the importance of appropriate indicators for evaluating their efficacy is increasing. Against this backdrop, lung function measurement is positioned as an important evaluation method that can quantitatively grasp the severity and progression of diseases.

In non-clinical studies, obtaining lung function data that has a high correlation with human clinical parameters contributes to improving the accuracy of Proof of Concept (POC), thereby enhancing the quality of decision-making in the early stages of development. As a result, the importance of lung function measurement is increasingly growing, leading to a reduction in the risk of development discontinuation and the realization of efficient drug discovery processes.

List of common lung function measurement types

There are multiple methods for measuring lung function, depending on the purpose and experimental conditions. These can be broadly classified into non-invasive measurements that can be performed under spontaneous breathing, and invasive measurements that obtain detailed respiratory mechanics parameters under tracheotomy or artificial ventilation management. The former is less burdensome to animals and suitable for repeated evaluation, while the latter is useful for detailed mechanism analysis.

Characteristics and Production Methods by Disease Model

Asthma Model

The asthma model is a representative experimental system for evaluating airway hyperresponsiveness (AHR) induced by allergen sensitization. It is widely used to reproduce the pathogenesis of human asthma. In this model,Correlation analysis between airway inflammation mainly characterized by eosinophilic infiltration and accompanying bronchial constriction is an important evaluation point.It will be.

As for the method of preparation, experimental animals such as mice are sensitized multiple times by intraperitoneal administration of ovalbumin (OVA) or house dust mite (HDM) antigens. Subsequently, the same allergen is administered via inhalation challenge using a nebulizer, etc., to induce acute or chronic airway inflammation. This process reproduces enhanced AHR and inflammatory cell infiltration, serving as a useful model for efficacy evaluation and pathological analysis.

COPD model

COPD models are experimental systems used to evaluate emphysema pathology due to alveolar destruction and airway obstruction associated with increased mucus production. A characteristic feature is that many models require long-term intervention to reflect the progressive and irreversible nature of human COPD. In evaluation,In addition to changes in lung compliance and airflow limitation, the degree of inflammatory cell infiltration and tissue remodeling are important indicators.It will be.

As for the preparation method, a widely used approach involves administering elastase once via the airway to induce alveolar structure destruction in a short period. In addition, as a chronic model that more closely resembles clinical pathology, a common technique involves repeated exposure to tobacco smoke over several weeks to months to induce persistent inflammation and structural changes in the airways and alveoli.

Idiopathic Pulmonary Fibrosis (IPF) Model

Idiopathic pulmonary fibrosis (IPF) models are used to reproduce the progressive fibrosis and hardening of lung tissue, and to evaluate decreases in lung compliance and lung volume. A characteristic feature is the demonstration of restrictive ventilatory impairment, which is similar to human IPF.Analysis from both pulmonary function indicators and histological changeswill be held.

As for the production method, the standard approach involves the transbronchial administration of the antitumor drug bleomycin, with intranasal and endotracheal administration being widely used. After administration, fibrosis progresses through an inflammatory phase, generally peaking at 14-21 days. Pulmonary function tests conducted during this period, along with collagen quantification using methods like the Sircol assay and histological staining, allow for a detailed evaluation of the relationship between the degree of fibrosis and functional decline.

Evaluation Indicators and Key Points for Pulmonary Function Testing

To obtain reliable data in pulmonary function testing, it is important to correctly understand the meaning of each evaluation index and to operate it appropriately. Furthermore, the reproducibility and stability of measurement techniques greatly affect the results. To perform highly accurate measurements, understanding the following parameters and stabilizing measurement techniques are indispensable.

Key indicators

Raw, Cdyn, and FEV as representative indicators in lung function assessmentExamples include Raw (airway resistance), which reflects the degree of airway narrowing or obstruction and is useful for evaluating bronchoconstriction in models such as asthma. Cdyn (dynamic compliance) is an indicator of lung distensibility during breathing and shows changes according to the pathological condition, such as an increase in emphysema and a decrease in fibrosis. FEV (forced expiratory volume, especially FEV0.1 and FEV1) indicates how much air can be exhaled within a certain time and is an important indicator for evaluating the degree of airflow limitation. By analyzing these parameters in combination, it is possible to comprehensively grasp changes in airway resistance and lung parenchyma.

Key points for implementation

To ensure the accuracy of pulmonary function tests,Appropriate management of anesthesia, thermal regulation, and intubation procedures is important.Anesthesia directly affects respiratory status, so it is necessary to maintain a stable depth while avoiding excessive suppression or variations. Specifically, if the anesthesia is too light, spontaneous breathing can remain, and if it is too deep, respiratory suppression will be stronger, necessitating optimization of conditions. It is important to maintain body temperature at a constant level using a heater or the like, as a drop in temperature can cause fluctuations in respiratory rate and metabolism, affecting measurements. Furthermore, intubation technique is directly linked to airway resistance and ventilation efficiency, making reliable intubation in the correct position and prevention of leaks essential. Stabilizing these factors allows for highly reproducible data acquisition.

Challenges and countermeasures for improving the clinical predictive power of pulmonary function tests

Strengthening of anatomical and physiological correlation of the germinal vesicle (mouse and human)

Interpretation that takes into account the species differences between mice and humans is an important challenge in improving the clinical predictability of pulmonary function measurements. Mice have fewer airway generations compared to humans, and there are also differences in peripheral airways and lung alveolar structure, which may result in different disease manifestations even with the same index. Therefore, a multifaceted evaluation that combines multiple indices, rather than relying on a single parameter, is required. In particular, evaluating the pressure-volume relationship, which comprehensively captures the mechanical properties of the lungs, is useful and is assessed as the "pressure-volume curve (P-V curve)."

Like thisBy analyzing the entire P-V curve, changes in compliance and hysteresis can be understood.This allows for interpretation that is closer to human pathophysiology. Consideration of species differences in the selection of indicators and ingenuity in analytical methods contribute to improved clinical translatability.

Introduction to Non-Invasive Longitudinal Study

The introduction of non-invasive longitudinal studies is a crucial approach for improving the clinical predictive power of lung function measurements. Traditional invasive measurements, which require tracheotomy and artificial respiration management, often limit measurements to the endpoint, making it difficult to continuously understand the progression of a disease within the same individual. In contrast, by combining non-invasive methods such as micro-CT image analysis and double-chamber plethysmography,It is possible to track disease progression and drug response over time within the same individual.It will be.

Acquiring longitudinal data reduces the influence of individual differences, enhancing data consistency and reliability, and contributing to the development of evaluation systems closer to clinical practice.

Phenotype-based model selection and optimization of evaluation systems

Respiratory diseases exhibit high heterogeneity in their pathologies, and models based on a single stimulus may not fully replicate the diverse clinical phenotypes. Therefore,The selection of a model and the optimization of an evaluation system according to the target pathology are important.This is because, for example, using aged mice can reflect age-related functional decline and the effects of chronic inflammation, bringing us closer to the clinical picture. Furthermore, combination models that combine viral infection and allergen exposure are useful for reproducing complex pathological conditions with exacerbation.

In evaluations, it is necessary to analyze not only a single indicator but also lung function, inflammatory cells, and tissue changes in an integrated manner. This phenotype-oriented approach enables the construction of highly predictive evaluation systems tailored to targeted clinical subgroups.

Summary

Pulmonary function measurements are a crucial process for substantiating the efficacy of new drug candidates from the perspective of "biological function." It is essential to correctly understand the characteristics of each disease model, such as asthma, COPD, and pulmonary fibrosis, and to select appropriate evaluation parameters like Raw, Cdyn, and FEV. Furthermore, optimizing anesthesia management and intubation techniques, considering interspecies differences in analysis, introducing non-invasive longitudinal evaluations, and selecting models based on phenotypes contribute to improving data reliability and clinical predictability. By comprehensively implementing these measures, it becomes possible to generate high-quality preclinical data that enhances the probability of clinical trial success.