Elevation of IL-6 and IL-33 Levels in Serum Associated with Lung Fibrosis and Skeletal Muscle Wasting in a Bleomycin-Induced Lung Injury Mouse Model

By 4 November 2020November 6th, 2020IPF


Pulmonary fibrosis is a chronic and progressive interstitial lung disease characterized by the dysregulated deposition of ECM with the destruction of normal tissue, resulting in end-stage organ failure. Idiopathic pulmonary fibrosis (IPF), a progressive disease with poor prognosis, is considered the most common severe form of pulmonary fibrosis, with a median survival of three years after diagnosis and no proven effective therapy [1]. The abnormal fibroblastic proliferation and accumulation of ECM proteins, such as collagen, have been highlighted by recent therapeutic exper- iments for IPF [2]. Although several potential drugs for IPF treatment, including corticosteroids [3], azathioprine plus prednisolone [4], cyclophosphamide [5], bosentan [6], and interferon (IFNγ1b) [7], are in clinical trials, there is no effective pharmacological therapy to improve the survival of patients with IPF [8].
Weight loss due to skeletal muscle atrophy in patients with various diseases, such as cancer cachexia and chronic pulmonary disease, is negatively correlated with clinical out- come [9]. Recent reports have demonstrated that muscle atrophy may be due to muscle protein degradation by the ubiquitin-proteasome system (UPS), which is activated by diverse catabolic stimuli, including growth hormone, cyto- kines, and nutritional status. Two ubiquitin ligases, muscle- specific RING finger 1 (MuRF1) and Atrogin-1 (FBXO32), are markedly increased in atrophied muscle tissue and serve as muscle-specific proteolysis markers [10]. However, the molecular mechanism modulating muscle loss through the activation of the ubiquitin-proteasome system in patients with chronic lung diseases remains unclear.

IL-6 mediates many inflammatory processes in the lungs, and its dysregulated release has been implicated in the path- ogenesis of a variety of respiratory disorders [11, 12]. The cytokine IL-6 is elevated in mice and humans with pulmo- nary fibrosis [13, 14]. Several genetic studies in both animals and humans have shown the potential association between IL-6 and the development of fibrosis [15, 16]. Blockade of the second increase in IL-6 by IL-6-neutralizing antibody during the fibrotic stage of BLM-induced lung injury can improve lung fibrosis [17, 18]. Many reports have shown that the increased circulation of IL-6 can regulate muscle mass by decreasing protein synthesis and increasing proteolysis dur- ing cancer cachexia [19, 20]. Recent studies have shown that STAT3 activation can promote protein degradation and muscle atrophy through the myostatin pathway to induce the expression of Atrogin-1; conversely, inhibition of SAST3 activity may attenuate the loss of muscle mass [21, 22].

IL-33 is expressed in various organ tissues in the human body, including endothelial cells, bronchial cells, and intesti- nal epithelial cells [23]. Recent studies have demonstrated IL-33 expression in type 2 inflammatory diseases, such as severe asthma [24] and inflammatory bowel disease [25]. IL-33/ST2 signaling is involved in various types of lung disease, including ventilator-induced lung injury (VILI), chronic obstructive pulmonary disease (COPD), and lung fibrosis [26–28]. Studies have demonstrated that IL-33 promotes ST2-dependent organ tissue fibrosis in several animal models, including lung [26], pancreas [29], and liver [30] models.

BLM-induced fibrosis is a common model for the patho- genesis of pulmonary fibrosis, characterized by inflammation and excessive ECM deposition [31]. Recent studies in murine lung injury models support the pathogenic role of an early inflammatory response involving danger signals in the form of uric acid production [32]. In addition, several genes encoding chemokines and cytokines that are not associated with acute inflammatory pathways are upregulated in IPF [33]. Therefore, the selective modulation of key inflamma- tory pathways has also been proposed as a research focus in future studies [34]. The present study investigated the poten- tial mechanism of cytokines induced by the intratracheal administration of bleomycin and the relationship between lung fibrosis and muscle mass loss based on a lung injury mouse model.