6. Autophagy-CFTR Dysfunction Induces Acute and Chronic Exacerbations
As discussed above, many patients with chronic respiratory diseases such as COPD and CF face acute and chronic exacerbations. These pulmonary exacerbations are characterized by a worsening lung function, significantly below what is normal for their conditions [4,31,173]. These exacerbations are caused by environmental exposures or bacterial and viral infections that result in further deterioration of the patient’s condition [4,31,173,174,175], leading to hospitalization for individuals causing increased morbidity and mortality [4,31,173]. Exacerbations also pose a significant financial burden for patients with chronic respiratory diseases [1,2,176,177].
Since pulmonary exacerbations are commonly triggered by infections, the autophagy dysfunction seen in these chronic conditions plays a role in the pathogenesis of this state via the mechanisms discussed above. A common pathogen that colonizes the lungs of individuals with chronic respiratory diseases and can lead to exacerbations is P. aeruginosa [4,31,44,58,173,178]. Studies have demonstrated that defects in CFTR impair the ability of cells to clear P. aeruginosa infections via autophagy, especially in patients with CF [22,40,53]. Furthermore, it has been shown that the induction of autophagy is able to ameliorate autophagy dysfunction and promote the clearance of P. aeruginosa infections [35,45,58]. As previously mentioned, CS exposure can also cause CFTR dysfunction, where a recent investigation demonstrated that CS exposure decreased CFTR expression while a treatment of CS-exposed macrophages with the autophagy inducer fisetin, which works by modulating autophagosome degradation, significantly recovered CFTR expression [35]. This same investigation showed that the CS-induced inhibition of CFTR decreased the clearance of P. aeruginosa [35]. This impaired clearance was then alleviated by autophagy induction with fisetin, supporting the findings of other previously mentioned studies [35]. Hence, CFTR-autophagy dysfunction in chronic lung diseases such as CF and COPD leads to P. aeruginosa exacerbations.
Similarly, Burkholderia cepacia (B. cepacia), an opportunistic infection that afflicts 3–5% of CF patients, can provoke exacerbations [151]. It has been found that macrophages can kill B. cepacia within autophagolysosomes; however, macrophages with ΔF508-CFTR lacked the bacteria in autophagolysosomes indicating dysfunction [151]. When these macrophages were treated with the autophagy inducer rapamycin, ΔF508-CFTR macrophages were able to fight the B. cepacia infection and reduce the resulting inflammation [153,179]. This demonstrates the importance of CFTR-dependent autophagy in not only clearing bacteria that can provoke pulmonary exacerbations, but also decreasing inflammation that can lead to worsened lung functions as well.
In regard to viral infections, CFTR-autophagy dysfunction limits viral clearance as well. In a recent study, it was determined that CFTR-deficient mice infected with RSV had an impaired ability to clear the virus compare to control mice [180]. Similarly, despite similar cytokine responses, respiratory epithelial cells with ΔF508-CFTR had a higher viral load when infected with rhinovirus in comparison to control cells [181]. From what we know about CFTR-autophagy’s role in pathogen clearance, it is likely that the observed findings in this study are a result of decreased autophagy in the ΔF508-CFTR cells that leads to decreased rhinovirus clearance and a higher viral load. Thus, proper CFTR-dependent autophagy function is necessary for the clearance of both bacterial and viral pathogens in the airway.
Besides infection, CFTR-autophagy dysfunction can lead to an impaired clearance of cellular debris and products that would normally be degraded. One such product is ceramide, which in response to CFTR-autophagy dysfunction can accumulate in aggresome bodies within cells [22,110,182,183,184,185]. Ceramide accumulation has been observed in both CF patients with CFTR mutations [182,183,186] and COPD patients who have acquired CFTR dysfunction due to CS exposure [22,110].
In the presence of CS, ceramide has been found to accumulate in p62+ aggresome bodies, indicating autophagy impairment [22]. As CFTR-autophagy becomes impaired in both CF and COPD, cells have chronically elevated intracellular levels of ROS altering cellular homeostasis, causing exacerbations and accelerating the pathogenesis and progression of these respiratory diseases [22,110,182]. Moreover, the deleterious effect of ceramide accumulation on CFTR-autophagy has been demonstrated to directly impair defenses against bacteria [52,184,186,187] and viruses [188]. As such, ceramide accumulation as a result of either inherent or acquired CFTR dysfunction leads to autophagy impairment causing a diminished immune response and bacterial colonization or viral replication. Hence, dysfunctional CFTR and autophagy dysfunction go hand in hand with an increased susceptibility of individuals to pathogens that significantly decrease lung function and cause acute and chronic exacerbations (Figure 1).