Angiotensin II plays a critical role in diabetic pulmonary fibrosis most likely via activation of NADPH oxidase-mediated nitrosative damage

Abstract

Diabetic patients have a high risk of pulmonary disorders that are usually associated with restrictive impairment of lung function, suggesting a fibrotic process (van den Borst B, Gosker HR, Zeegers MP, Schols AM. Chest 138: 393-406, 2010; Ehrlich SF, Quesenberry CP Jr, Van Den Eeden SK, Shan J, Ferrara A. Diabetes Care 33: 55-60, 2010). The present study was undertaken to define whether and how diabetes causes lung fibrosis. Lung samples from streptozotocin-induced type 1 diabetic mice, spontaneously developed type 1 diabetic OVE26 mice, and their age-matched controls were investigated with histopathological and biochemical analysis. Signaling mechanism was investigated with cultured normal human lung fibroblasts in vitro. In both diabetes models, histological examination with Sirius red and hemotoxylin and eosin stains showed fibrosis along with massive inflammatory cell infiltration. The fibrotic and inflammatory processes were confirmed by real-time PCR and Western blotting assays for the increased fibronectin, CTGF, PAI-1, and TNFα mRNA and protein expressions. Diabetes also significantly increased NADPH oxidase (NOX) expression and protein nitration along with upregulation of angiotensin II (Ang II) and its receptor expression. In cell culture, exposure of lung fibroblasts to Ang II increased CTGF expression in a dose- and time-dependent manner, which could be abolished by inhibition of superoxide, NO, and peroxynitrite accumulation. Furthermore, chronic infusion of Ang II to normal mice at a subpressor dose induced diabetes-like lung fibrosis, and Ang II receptor AT1 blocker (losartan) abolished the lung fibrotic and inflammatory responses in diabetic mice. These results suggest that Ang II plays a critical role in diabetic lung fibrosis, which is most likely caused by NOX activation-mediated nitrosative damage.

Assessment of Pulmonary Function in Patients with Type 2 Diabetes Mellitus: A Case-Control Study.

“…36 For such fibrotic process Angiotensin II plays an important factor for diabetic lung fibrosis resulted due to NOX activation-mediated nitrosative damage. 35 Thus, our study has demonstrated clear cut negative effect on mechanical lung function in diabetic subjects suggesting lung as a target organ, but could not establish its relationship to the glycaemic control and the other microvascular complications. Although there is significant derangement of spirometric functions in diabetic patients, this dysfunction is not severe enough to be clinically significant.…”

“…33,34 Recent epidemiological studies and systematic reviews clearly indicate that DM as an independent risk factor for pulmonary dysfunction. 35 Histopathological findings in a study reported pulmonary fibrosis among type-1 diabetic patients with significant reduction in pulmonary function parameters. 33 Such microvasculature changes in the form of tissue fibrosis not only observed in lung parenchyma but also in heart myocardium as well, evidence mentioned that such myocardial fibrosis, cardiomyocyte hypertrophy and altered microvasculature was resulted due to DM.…”

Interfacial stress affects rat alveolar type II cell signaling and gene expression

“…Rho-associated kinase is a promising candidate for transmitting extracellular mechanical stimuli (stretch, interfacial forces) into the alveolar type cell gene expression due to its pivotal role in regulating the actin cytoskeleton and in mechanotransduction-mediated differentiation (21,60). Since plasminogen activator inhibitor-1 and Ctgf contribute to the pathogenesis of several interstitial lung diseases like lung fibrosis, detailed studies focusing on the nature of the stimuli and its related downstream mechanism could be essential for the invention of novel therapeutic targets (75).…”

Beyond TGFβ – Novel ways to target airway and parenchymal fibrosis

“…ANGII production is triggered by oxidative [231] and nitrosative stress [232] in AECs and both processes are known to play a role in the development of fibrosis. The ANGII found in the lungs after injury is considered to result from de novo synthesis by apoptotic AECs as well as myofibroblasts [233] within the lung.…”

“…Expression levels of the receptors for ANGII, AT-1 and AT-2, are elevated in IPF patients [234]. In addition, levels of ANGII and ACE are increased [232] and the newly synthesized ANGII can act on AT-1 receptor-expressing fibroblasts to induce collagen production and promote further ANGII production by these cells [235,236]. The AT-2 receptor is also involved in fibroblast function by regulating migration and proliferation of this cell type [234].…”