In the present study, we established an asthma rat model to explore potential structural and molecular changes in the prostate and bladder associated with LUTS. Our findings revealed significant epithelial thickening in the prostates of asthmatic rats, suggesting hyperplasia, accompanied by molecular changes indicative of a shift toward a more contractile smooth muscle phenotype. For the bladder, although its overall weight and structure remained similar between groups, detrusor contractions induced by acetylcholine were significantly enhanced in asthmatic rats, pointing to increased sensitivity rather than structural remodeling. These results indicate that asthma may contribute to LUTS by inducing both structural alterations in the prostate and functional changes in bladder smooth muscle.

In male patients, LUTS could be caused by disorders in the prostate or bladder, or both [23]. BPH is one of the most common etiologies for male LUTS, as the enlarged prostate and the increased prostate smooth muscle tone may impair bladder emptying and cause LUTS [24]. OAB, caused by spontaneous and exaggerated contractions in bladder smooth muscle, is the most bothersome symptoms in LUTS [25]. In men with BPH, the bladder is usually an innocent organ of BPH, therefore, LUTS could be caused by both BPH and secondary OAB [26]. A clinical study on a Korean population indicated a significantly higher prevalence of BPH in asthmatic patients (17.1%) than in individuals without asthma (8.7%) [27]. The underlying pathophysiologic mechanisms of the association between BPH and asthma have not yet been determined. However, previous studies have reported significant elevated levels of several cytokines such as IL-2, IL-4, and IL-17 both in BPH specimen [28, 29] and bronchoalveolar lavage fluid of symptomatic asthma patients [30, 31]. These findings may indicate a possible immune-mediated inflammatory mechanism linking BPH and asthma. Another study on a Taiwan population indicated that the risk of BPH, and the need of receiving transurethral resection of the prostate (TURP) in the asthma group were 1.40 and 1.30 folds higher than non-asthma group, respectively [32]. However, a direct link between asthma and the risk of BPH and TURP is still undetermined, as inhaled anticholinergic drugs could cause acute urinary retention and therefore increase the risk of BPH and the need for surgery [33, 34]. In our present study, we observed that the PI of asthmatic rats showed a trend toward an increase (0.724 ± 0.14 mg/g) compared with rats in the control group; however, this difference was not statistically significant (P = 0.09). Despite the lack of significant weight change, H&E staining revealed a notable thickening of the prostate epithelium in the asthma group. These findings suggest that while asthma may not significantly alter prostate weight, it could induce structural changes in the prostate, potentially indicative of early proliferative alterations. Further investigation with larger sample sizes is needed to clarify the extent and clinical implications of these changes within the context of prostatic pathology. Additionally, western blot analysis revealed that the expression of smooth muscle contraction-related proteins desmin and TPM were significantly increased, while synthesis-related protein vimentin was significantly decreased, which indicated that smooth muscle cells in the prostate of asthmatic rats may undergo a phenotypic shift towards a more contractile phenotype, leading to enhanced contraction ability [35]. Chronic inflammation and hypoxia, both hallmarks of asthma, may drive the observed phenotypic shift in the prostate towards a more contractile state. Elevated levels of Th2 cytokines, such as IL-4 and IL-13, can promote the expression of contraction-related proteins and suppress synthetic markers through calcium signaling pathways and receptor upregulation [36]. Hypoxia exacerbates this process by activating the RhoA-ROCK signaling pathway, which increases myosin light chain (MLC) phosphorylation and inhibits myosin phosphatase, leading to sustained and amplified contraction in smooth muscle cells [37]. These combined factors may contribute to the enhanced contractile phenotype observed in the prostate of asthmatic rats. While our findings suggest a potential link between asthma-induced systemic changes, such as chronic inflammation and hypoxia, and alterations in prostate smooth muscle contraction and proliferation, this remains a hypothesis that requires further validation. Further studies are needed to confirm these mechanisms and their role in prostate pathophysiology.

We observed that the muscarinic agonist acetylcholine induced concentration-dependent bladder smooth muscle contractions, which were significantly enhanced in strips from asthmatic rats. This may indicate a role of asthma in the storage symptoms of LUTS, as enhanced contraction in detrusor might cause frequency, urgency and OAB [12]. However, we observed that other muscarinic agonists, carbachol and acetyl-β-methylcholine induced concentration- dependent bladder smooth muscle contractions, which were not significantly enhanced in stripes from asthmatic rats. Muscarinic receptors (M1–M5) are widely distributed in the human body and mediate various physiological functions [38]. Acetylcholine is the predominant endogenous neurotransmitter that activates all muscarinic receptor subtypes, while synthetic agonists like carbachol or acetyl-β-methylcholine have varying affinities for these receptors. Studies suggest that acetylcholine exhibits a higher efficacy for activating certain muscarinic receptor subtypes (e.g., M2 and M3) compared to synthetic agonists, which may explain its stronger contractile response in the bladder [39, 40]. In asthma, elevated parasympathetic activity increases acetylcholine release, leading to exaggerated smooth muscle responses [41]. We hypothesize that this enhanced acetylcholine signaling may extend beyond the airways, affecting the bladder by upregulating or sensitizing specific muscarinic receptor subtypes. Unlike acetylcholine, carbachol and acetyl-β-methylcholine may not fully replicate this enhanced signaling due to differences in receptor subtype activation or downstream signaling pathways [42]. Further studies are needed to investigate muscarinic receptor subtype expression and function in the bladder of asthmatic models to confirm these mechanisms.

Although detrusor contraction in asthmatic rats was enhanced compared to normal control rats, the BI was similar in both groups. MT staining in bladder tissues revealed that the ratio of smooth muscle to collagen fibers was similar in both groups. These results may indicate that the enhanced contraction in detrusor might be caused by increased sensitivity to acetylcholine, rather than by bladder remodeling. However, the possibility of asthma affecting bladder remodeling could not be fully excluded, as the duration of rat model establishment is relatively short, therefore, a longer observation duration would be helpful for a comprehensive evaluation. Additionally, unlike humans, rats lack a prostatic capsule, so prostate enlargement and subsequent BOO, which are common in human BPH, are unlikely to contribute to the enhanced detrusor contraction in our model. This further supports the idea that the observed changes in bladder function are more likely related to asthma-induced alterations in muscarinic receptor sensitivity or other mechanisms.

In conclusion, our findings suggest a potential association between asthma and LUTS, with asthma possibly contributing to organ-specific changes, including prostate enlargement and increased smooth muscle contractions in both the prostate and bladder. These results provide evidence for a biological link between asthma and LUTS, highlighting the potential impact of asthma-associated systemic and local changes on LUTS. Furthermore, this study offers a promising foundation for exploring new therapeutic strategies to manage LUTS in patients with asthma.