Immunopathological characteristics and therapeutic effects of UC-MSCs in a pigeon breeder’s lung mouse model

Abstract

Hypersensitivity pneumonitis (HP), including pigeon breeder’s lung (PBL), often progresses from acute inflammation to fibrosis, impairing lung function and limiting targeted therapeutic strategies. Mechanistic studies on PBL progression are limited by the lack of preclinical animal models and a predominant focus on patient data. This study explores the immunopathological characteristics of all stages of PBL in mice and evaluates the therapeutic potential of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) during the non-fibrotic stage. PBL models are created in A/J mice through tracheal instillation of pigeon dropping extract (PDE) protein powder. Different doses (0.4 × 106, 0.8 × 106, and 1.6 × 106 cells per animal) and frequencies (1–2 times) are administered to the model. The immunopathological characteristics of PBL and the therapeutic effects of UC-MSCs are assessed using micro-CT, pulmonary function, histopathology, cell counts in BALF, HYP levels, inflammatory factor levels, immunohistochemistry, and fibrosis marker expression in lung tissues. The results show that PDE exposure consistently impairs pulmonary function and increases the levels of inflammation and fibrosis markers as the disease progresses. Model mice experience non-fibrotic stages (acute inflammation) from days 0–36, mild fibrosis from days 37–77, and severe fibrosis from day 78 onwards. UC-MSCs, particularly at the highest dose (1.6 × 106 cells), effectively treat non-fibrotic PBL by improving pulmonary function (lung ventilation area recovers) and reducing inflammation and fibrosis. This study successfully establishes PBL mouse models reflecting both the acute (inflammatory) and chronic (fibrotic) stages, and UC-MSCs have the potential to delay fibrosis, providing new therapeutic options for PBL and other inflammation-induced lung fibrotic diseases.

1. Introduction

Pigeon breeder’s lung (PBL) is the predominant form of hypersensitivity pneumonitis (HP) [1]. It is an immune-mediated interstitial lung disease characterized by bronchial and alveolar inflammation caused by repeated exposure of susceptible individuals to proteins in pigeon droppings [2,3]. PBL is particularly prevalent in Xinjiang Kashi, which is closely related to the daily hobbies and living habits of local residents. The region not only has a high number of free-range pigeons, leading to frequent human-pigeon contact but also serves as a crucial protein source and a key income for local farmers [4]. Additionally, Kashi has a dry climate, with low annual precipitation and frequent gusty winds and dusty weather [5]. This makes pigeon droppings difficult to condense and settle. As a result, these droppings remain suspended in the air for extended periods, leading to continuous and low-level exposure to bird antigens for both pigeon owners and their neighbors. As a result, the incidence of PBL is increasing, particularly in regions where avian contact is prevalent, such as Kashi, Xinjiang.

PBL can be categorized into two distinct phases: acute/non-fibrotic (inflammation) and chronic/fibrotic (inflammation with fibrosis or fibrosis alone) [6]. The non-fibrotic phase is predominantly inflammatory and often reversible with antigen avoidance, triggered by intermittent high-level antigen exposure [7]. In contrast, the fibrotic phase involves sustained, low-dose antigen exposure, leading to irreversible lung damage characterized by fibrosis [8]. Given the similarities between PBL and other inflammation-induced lung fibrotic diseases, understanding the pathogenesis of PBL is crucial. Without effective intervention, patients in the fibrotic stage face irreversible lung function loss and potential death from respiratory failure if not treated with a lung transplant [9]. To improve the diagnosis and prognosis of PBL patients, it is essential to develop comprehensive disease models that reflect various stages of progression. These models will help identify key pathophysiological features and guide early therapeutic interventions, preventing progression to the irreversible fibrotic stage.

Mesenchymal stem cells (MSCs) have demonstrated potential in the areas of tissue regeneration, anti-inflammation, and anti-fibrosis [10,11]. In particular, human umbilical cord-derived MSCs (UC-MSCs) offer advantage such as wide availability, non-invasive collection, ethical acceptance, and low immunogenicity [12]. Its use in regenerative medicine [13], especially in lung diseases, has increased, including in clinical trials and basic research on idiopathic pulmonary fibrosis (IPF) [14,15]. Given the parallels between PBL progression and lung damage from IPF, UC-MSCs may also have therapeutic potential in PBL.