Development of a non-infectious rat model of acute exacerbation of idiopathic pulmonary fibrosis

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease with severe pulmonary fibrosis. The main cause of IPF-associated death is acute exacerbation of IPF (AE-IPF).This study aims to develop a rat model of AE-IPF by two intratracheal perfusions with bleomycin (BLM).Methods: Ninety male Sprague Dawley (SD) rats were randomized into three groups: an AE-IPF model group (BLM + BLM group), an IPF model group (BLM group), and a normal control group. Rats in the BLM + BLM group underwent a second perfusion with BLM on day 28 after the first perfusion with BLM.Rats in the other two groups received saline as the second perfusion. Six rats in each group were sacrificed on day 31, day 35, and day 42 after the first perfusion, respectively. Additional 18 rats in each group were observed for survival.Results: Rats in the BLM + BLM group had significantly worse pulmonary alveolar inflammation and fibrosis than rats in the BLM group. Rats in the BLM + BLM group also developed large amounts of hyaline membrane, showed high levels of albumin (ALB) and various inflammatory factors in the bronchoalveolar lavage fluid (BALF), and had markedly increased lung water content. Furthermore, rat survival was reduced in the BLM + BLM group. The pathophysiological characteristics of rats in the BLM + BLM group resemble those of patients with AE-IPF.Conclusions: A second perfusion with BLM appears to induce acute exacerbation of pulmonary fibrosis and may be used to model AE-IPF in rats.

Development and assessment of the efficacy and safety of human lung-targeting liposomal methylprednisolone crosslinked with nanobody

“…Each group was further divided into two subgroups: one-week exposure and two-week exposure (10 rats in each subgroup). AE-IPF was established by two intratracheal injection with BLM in rats under a laryngoscope (Chen et al, 2017 ). The normal control group was injected with saline in the similar manner.…”

“…The current study aimed to use hSPANbs as the lung targeting molecule, the clinically commonly used GC hormone methylprednisolone (MPS), and nano-sterically stable liposome (NSSLs) as the drug delivery vector to first develop a GC hormone agent (MPS-NSSLs-SPANb) that specifically targets the human lung. We also tested the toxicity and efficacy of the agent in a rat model of bleomycin (BLM)-induced AE-IPF (Chen et al, 2017 ). Our study provides experimental evidence for possible clinical translation of the agent.…”

Surfactant protein B (SP-B) enhances the cellular siRNA delivery of proteolipid coated nanogels for inhalation therapy

“…Nevertheless, the maximally measured 2-fold increase compared to PBS is indicative of an acceptable degree of toxicity. [27] Importantly, when combining DPPC with SP-B as proteolipid coat, no elevated albumin levels were detected. Altogether, these data indicate that selecting a formulation that more closely mimics the endogenous surfactant composition is preferred from a toxicological point of view.…”

A New Model of Acute Exacerbation of Experimental Pulmonary Fibrosis in Mice

“…In this chronic pulmonary fibrosis model, AE was produced by doubling the dose of BLM (1.6 instead of 0.8 UI/g) for the last two instillations in the last 30 days of the experiment (BLM-AE group) which induced a strong oxidative injury. Based on previous reports in rats [ 31 ] or mice [ 15 ], we anticipated that the oxidative stress generated by a higher dose of BLM would promote an inflammatory environment in the distal lung, which is characteristic of AE. This procedure has been chosen to get as close as possible to the clinical description of AE in IPF patients, where a degradation of lung function is observed typically within less than a month [ 3 ].…”