Characterization of acute lung injury in the bleomycin rat model. Issue 5 (10th March 2023)

• Record Type: Journal Article
• Authors: Kadam, Anil Hari; Schnitzer, Jan E.
• Is Part Of: Physiological reports. Volume 11:Issue 5(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-03-10
• Subjects: acute lung injury (ALI) -- bleomycin -- bronchoalveolar lavage fluid (BALF) -- contributing mediators/factors -- detectable fibrogenesis -- efficacy testing -- experimental endpoints -- key experimental features of ALI -- mechanism of action -- neutrophilic inflammation -- progression of bleomycin‐induced ALI; Physiology -- Periodicals; 571
• DOI: 10.14814/phy2.15618
• Languages: English
• ISSNs: 2051-817X

Abstract

Abstract: The aim of this study was to describe and characterize the pathophysiological changes occurring during the early inflammatory phase (first 3 days) in the rat bleomycin model of lung injury preceding the development of fibrosis. Further, we wanted to understand the kinetics and factors contributing to bleomycin‐induced acute lung injury (ALI) and provide a robust, reliable and reproducible framework of features of ALI readouts to assess effects of therapeutics on bleomycin‐induced ALI in rats. We induced ALI in rats with intratracheal (i.t.) installation of bleomycin. The animals were sacrificed on predetermined time points, that is, Day 0, 1, 2, and 3 post the bleomycin challenge. We analyzed bronchoalveolar lavage fluid (BALF) and lung tissue to establish and assess relevant experimental features of ALI. We demonstrated that bleomycin induced key features of experimental ALI including a profound increase in neutrophils in BALF (50–60%), pulmonary edema, and lung pathology on Day 3 after challenge. Furthermore, we showed that TGF‐β1, IL‐1β, TNF‐α, IL‐6, CINC‐1, TIMP‐1, and WISP‐1 were induced by studying their kinetic profile during the first 3 days after bleomycin injury consistent with their known role ALI. We also confirmed that detectable fibrogenesis occurs at the earliest on Day 3 after injury based on collagen content, along with changes in the TGF‐β/Smad signaling pathway and increased expression of Galectin‐3, Vimentin, and Fibronectin in lung homogenate. Our report presents robust features and contributing mediators/factors to the pathology of bleomycin‐induced ALI in rats on Day 3. The kinetic data provide insights on the progression of ALI and a detailed understanding of early events before actual fibrosis development. This set of experimental endpoints is very appropriate and invaluable for efficacy testing of potential novel therapeutic treatments (single or combined) in ALI and understanding their mechanism of action. Abstract : We demonstrate that bleomycin induces key features of experimental ALI including a profound increase in neutrophils in BALF (50–60%), pulmonary edema, and lung pathology on Day 3 after the challenge. Furthermore, we showed that key inflammatory markers including TGF‐β1, IL‐1β, TNF‐α, IL‐6, CINC‐1, TIMP‐1, and WISP‐1 were induced by studying their kinetic profile during the first 3 days after bleomycin injury. Our work adds to the knowledge of current ALI models and provides a set of experimental endpoints appropriate for efficacy testing of potential novel therapeutic treatments in ALI and for understanding mechanisms of action of therapeutics under investigation.