GHRH-R antagonist MIA-602 reduces bleomycin-induced lung inflammation and fibrosis in mice

Pulmonary fibrosis, particularly idiopathic pulmonary fibrosis (IPF), is a chronic, progressive lung disease with limited treatment options and a poor prognosis. Current therapies often slow progression but do not reverse the damage. Bleomycin-induced lung injury in mice is a widely used preclinical model for studying fibrotic lung disease, mimicking key aspects of human IPF. Growth hormone-releasing hormone (GHRH) is a 44-amino acid peptide primarily known for stimulating growth hormone (GH) secretion. However, GHRH receptors (GHRH-R) are also found in various non-pituitary tissues, including the lung, suggesting potential roles in local cellular processes like inflammation and tissue remodeling, which could be targeted to address the unmet needs in fibrotic lung diseases.

Researchers investigated the GHRH receptor antagonist MIA-602 in a bleomycin-induced lung injury model using C57Bl/6J mice. Mice received MIA-602 (5 µg) or vehicle via subcutaneous (SC) injection daily for 21 days. Bleomycin (0.8 units) was administered intraperitoneally (IP) on days 1, 3, 7, 10, 14, and 21 to induce lung injury. Primary endpoints included assessment of lung inflammation at day 14 using histopathologic scores and lung fibrosis at day 28 by measuring hydroxyproline (HP) content. Gene expression analysis was performed on lung tissue to identify molecular changes related to immune response and inflammation, providing insights into the mechanism of action.

Treatment with MIA-602 significantly mitigated bleomycin-induced lung pathology. At day 14, histopathologic scores showed inflammation was visibly less evident in mice treated with MIA-602 compared to vehicle-treated controls. This suggests an early anti-inflammatory effect. By day 28, lung hydroxyproline (HP) content, a marker of collagen deposition and fibrosis, increased significantly in vehicle-treated mice. In stark contrast, lung HP levels in MIA-602-treated mice did not increase significantly compared to naïve controls, indicating a robust anti-fibrotic effect. This demonstrates MIA-602's ability to prevent the progression of fibrosis. Gene expression analysis revealed that MIA-602 treatment led to the upregulation of multiple genes related to chemotaxis, IL-1, chemokines, regulation of inflammation, and extracellular signal-regulated kinases (ERK) in bleomycin-injured lungs. Conversely, MIA-602 prominently suppressed multiple genes associated with the cellular immune response, including those involved in T-cell differentiation, receptor signaling, activation, and cytokine production.