Benefits of ACEI/ARB use in reducing pulmonary injury
Numerous studies have assessed the effects of inhibition of ANG II signaling by the administration of ACEIs or ARBs as ways to mitigate lung injury in a range of experimental models, including ARDS and pulmonary fibrosis. Bleomycin, a natural product-derived peptide used for cancer chemotherapy, is a widely used model in rodents for the study of pulmonary fibrosis. Bleomycin damages the pulmonary epithelium, which then initiates a fibrotic response; the pulmonary injury and fibrosis can be mitigated by treatment with ACEIs or ARBs (e.g., Li et al., 2003; Wang et al., 2000; Otsuka et al., 2004; Yao et al., 2006; Uhal et al., 2012). Other models of lung fibrosis, e.g. γ-irradiation, also show deceased injury and fibrosis in response to ARBs (Mohammadi-Karakani et al., 2006; Molteni et al., 2007; Uhal et al 2012). ACEIs/ARBs appear to blunt the degree of apoptosis of epithelial and other cell types, indicating that initiating events of lung injury require ANG II signaling to drive a pathological response.
How might this occur? As shown in Figures 2 and 3 , increase in local RAS signaling within the lung, i.e., injury-induced production of RAS signaling components by epithelial cells and activated fibroblasts, promotes pulmonary injury and helps explain the efficacy of ACEIs/ARBs in blunting this pathology. Further evidence for this mechanism is the reduction in bleomycin-induced injury and fibrosis by antisense oligonucleotides against AGT (Li et al., 2007).
Data from other in-vivo models supports the utility of ACEIs/ARBs in blunting lung injury, especially of the epithelium, thus further implicating the role of ANG II in mediating these effects. Examples include acute lung injury induced by oleic acid in rats (in which use of the ACEI captopril reduced alveolar damage/epithelial disruption, endothelial damage and infiltration of neutrophils (He et al., 2007), the protective effect of ACEI/ARB treatment in reducing pneumocyte death in surfactant-depleted rat lungs (Lukkarinen et al., 2005), and the efficacy of ACEIs in the treatment of radiation-induced lung injury (Medhora et al., 2012). This benefit has also been shown in human studies, for example, a reduction in pulmonary-related mortality by captopril administered to patients receiving total body irradiation prior to hematopoietic stem cell transplantation (Cohen et al., 2012). ACEI administration also reduces radiation-induced pneumonitis in lung cancer patients (Kharofa et al., 2012).
Further evidence for effects of sepsis has been obtained from animal models of acute lung injury (ALI) induced by lipopolysaccharide (LPS): treatment with the ARB losartan reduced pro-inflammatory cytokine secretion and lung injury and improved survival, while also reducing ANG II production in the lungs (Shen et al., 2009). The protective effects of losartan in LPS-induced ALI are associated with reduced contribution by dendritic cells to inflammation (Liu et al., 2012). Captopril was protective in a rat LPS-induced ALI model, reducing immune cell infiltration, edema, and hemorrhage in alveoli (Li et al, 2015). The latter study also showed that the ratio of ACE1/ACE2 expression increased in injury and that captopril attenuated injury and decreased that ratio. These findings were replicated in a study in which captopril reduced inflammatory cytokines and monocyte infiltration in bronchoalveolar fluid (Boskabadi et al., 2019). In addition, in a murine H5N1 influenza infection model. treatment with losartan improved survival and reduced edema, lung injury and immune cell infiltration (Yan et al., 2015). Other studies showed that ACEIs or ARBs inhibit ventilator-induced lung injury (Jiang et al., 2007, Wösten-van Asperen et al., 2008, Jerng et al., 2007, Chen et al, 2014). Also, treatment of rats with losartan in chronic cigarette-smoke-induced injury model reduced pulmonary remodeling and pulmonary arterial hypertension (Han et al., 2010).
Data from retrospective studies in humans show that ACEIs can prevent or reduce the severity of pneumonia (e.g., Mortensen et al., 2005; van de Garde et al., 2007; Mortensen et al., 2012 and Caldeira et al., 2012). In addition, reatment with ACEIs/ARBs in COPD (chronic obstructive pulmonary disease) reduces inflammation, comorbidities and disease complications (Shrikrishna et al., 2012). Retrospective analyses also suggest that ACEI/ARB treatment may reduce mortality in ARDS/ALI (Noveanu et al., 2010) and mitigate the effects of radiation pneumonitis (Harder et al., 2015). However, evidence is lacking from prospective clinical studies with ACEIs/ARBs in these types of pulmonary injury.
Cell-based assays provide additional support for the importance of ANG II in mediating lung injury. ANG II induces apoptosis in a human epithelial cell line (A459) and in rat type-II pneumocytes, effects that are blocked by treatment with ACEIs or ARBs (Wang et al., 1999b, Wang et al., 1999c). Such findings were replicated using losartan in the same cell types, results that confirmed AGTR1 as the receptor that promotes apoptosis in pulmonary epithelial cells (Papp et al, 2002). Moreover, treatment of human and rat lung epithelial cells with FAS protein (an apoptosis-inducing ligand) induced apoptosis by increasing AGT and ANG II expression/secretion, effects blocked by ANG II antibodies (Wang et al., 1999b). The latter authors further showed that pro-fibrotic human lung fibroblasts induce epithelial cell apoptosis by producing ANG II and that these myofibroblasts express the components necessary to drive a local RAS signaling cascade (Wang et al., 1999a; Wang et al., 1999c). In addition, the ARB telmisartan blunts ANG II-promoted EMT of A549 cells (Buckley et al., 2010).
Thus, the available data provide consistent evidence indicating that ANG II signaling, via AGTR1, has a central role in lung injury. Blunting this signaling by ACEIs or ARBs has beneficial effects in modulating such damage, including in the context of acute pulmonary injury caused by infection.