**5. Chronic lung allograft dysfunction**

*Perioperative Care for Organ Transplant Recipient*

acute rejection [30].

acute lung rejection.

inflammation in ALR.

inflammation. IL-1, which consists of both IL-1a and IL-1b, is a ubiquitous cytoplasmic cytokine that is associated with a plethora of disease states, including allograft rejection [23]. This family is associated with general acute phase reactions. Because the IL-1 family has been linked to several disease states, it is no surprise that lung transplant rejection bears an association to its expression. Specifically, Patella and associates recently found BAL IL-1β elevated in acute rejection episodes [24]. In another study, Rizzo and associates found significant increases in IL-1a and IL-1b expressions from alveolar macrophages of acute lung rejection patients compared to patients without acute rejection [25]. IL-6 is another acute phase marker and pro-inflammatory cytokine that is involved in hematopoiesis and immune regulation [26]. Its role in immunity is similar to that of IL-1 cytokines, which leads it to also be elevated in acute rejection. The literature supports this claim. Whitehead and associates also found IL-6 significantly elevated in the BAL of acute lung rejection patients [27]. Patella and associates examined IL-6 in BAL samples of lung transplant recipients and found IL-6 to be higher in acute rejection cases [24]. The last of the acute phase cytokines is TNF-a. TNF-α has been associated with many disease processes, including infections, septic shock, and allograft rejection [28]. Hodge and associates found TNF-α was elevated in BAL CD4+ and CD8+ cells in acute lung rejection cases [29]. Magnan and associates measured TNF-α in alveolar macrophages and lung transplant recipients and found increased TNF-α in

In addition to acute phase cytokines, IL-8 is a known mediator of inflammation and neutrophil chemotaxis [31]. Its role in ALR, however, is minor. A recent study

Along with Th1, Th2 differentiation occurs with IL-2 activation of naive T cells. In addition, Th2 cell differentiation is activated by IL-4, a cytokine normally released by mast cells and basophils [32]. The literature is currently conflicting on the role of IL-4 in acute lung rejection. Whitehead and associates found BAL IL-4 elevated in acute lung rejection patients compared to patients without rejection [27]. On the other hand, another study looking at pro-inflammatory cytokine expression in lung transplant recipients found no difference in BAL, plasma, or bronchial brushing IL-4 levels between acute rejection and stable patients [29]. Based on conflicting literature, the Th2 response may not have a significant role in

The Th1 response is regulated by anti-inflammatory cytokines. IL-10 is an anti-inflammatory cytokine that is involved in immune response regulation and limiting of immune destruction to host tissues [33]. Patella and associates found that IL-10 was actually elevated in acute rejection cases compared to stable patients [24]. This evidence suggests IL-10 is elevated in an attempt to limit

Monocyte and macrophage activity is strongly associated with activation of the Th1 response and is responsible for secretion of pro-inflammatory cytokines. IL-17, also known as IL-17A, is released by Th17 cells and induces monocytes and stromal cells to produce cytokines in addition to stimulating granulopoiesis. It is also involved in the pathogenesis of several autoimmune diseases [34]. In a study analyzed IL-17 mRNA and protein levels in BAL samples of lung transplant recipients, the authors found both IL-17 mRNA and protein levels significantly elevated in acute lung rejection [35]. MCP-1, also known as CCL-2, is a chemokine with strong mononuclear cell chemotaxis properties involved in chronic inflammation [36]. Belperio and associates evaluated BAL fluid from lung transplant recipients and found increased levels of MCP-1 in acute rejection cases compared to stable patients [37]. The role of MCP-1 and IL-17 suggest that mononuclear immune cell

found no association between IL-8 and acute rejection [22].

regulation occurs concomitantly to the Th1 response in ALR.

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Airway inflammation is the main contributor to CLAD. CLAD encompasses many manifestations of chronic rejection, including BOS and RAS (restrictive allograft syndrome). Currently, it is characterized by a decrease in FEV1 and/or FVC by at least 20% compared to baseline, which is determined as a mean of two optimal postoperative measurements taken 3 weeks apart [38].

Pro-inflammatory cytokines IL-1, IL-6, and TNF-α are all upregulated in CLAD. Firstly, IL-1 has been studied in the setting of chronic rejection in lung transplantation. Suwara and associates studied cytokine expression in BAL fluid of lung transplant recipients with respect to different phenotypes of CLAD. They found IL-1a and IL-1b were elevated in lymphocytic bronchiolitis and persistent airway neutrophilia cases [39]. Verleden and associates also analyzed BAL fluid cytokines in different chronic lung rejection phenotypes and found IL-1b was significantly elevated in neutrophilic BOS and RAS episodes compared to stable patients [40]. In persistent airway neutrophilia, a specific phenotype of CLAD, BAL IL-6 was found to be significantly elevated [39]. Verleden and associates studied cytokine expression in BAL fluid of lung transplant recipients and found that IL-6 levels were elevated in RAS patient and correlated with survival among lung transplantation patients with RAS [40]. Lastly, TNF-α has been linked to CLAD. Suwara and associates studied cytokine expression in the context of several CLAD phenotypes. They found that BAL TNF-α levels were increased in patients with primary airway neutrophilia [39]. Additionally, Bharat and associates measured serum cytokines in patients with and without BOS after lung transplantations. They found that IL-10 *decreased* threefold during the onset of BOS [41]. This evidence suggests that inflammation in the absence of regulation may contribute to airway inflammation in CLAD which likely arises from uninhibited pro-inflammatory cytokines.

Pro-inflammatory cytokine expression in CLAD may be a result of increased monocyte/macrophage chemotaxis. IFN-y, which activates macrophages to induce inflammation, has been indicated in chronic lung rejection. Hodge and associates found that, compared to BOS patients, stable lung transplant recipients displayed significant reductions in blood IFN-γ levels [42]. Both IL-17 and MCP-1, which are macrophage-recruiting cytokines, have been indicated in CLAD. MCP-1 was found elevated in patients before and during BOS indicating elevated MCP-1 posttransplantation is predictive of BOS [13]. Fisichella and associates found increases in BAL IL-17 as an indicator of early onset BOS [43].

Unlike ALR, neutrophil-associated airway damage is strongly associated with CLAD development. IL-8 is known to facilitate neutrophil chemotaxis and has shown to be involved in chronic rejection among lung transplant recipients. DiGiovine and associates first established the contribution of IL-8 expression to airway neutrophilia and BOS development [44]. BAL IL-8 levels in lung transplantation patients were elevated in neutrophilic BOS and RAS compared to stable patients in a recent study [40]. Elssner and associates found that IL-8 mRNA expression from bronchial cells was significantly elevated in BOS cases compared to stable patients [45].

The activity of IL-12 in CLAD is also contrary to ALR. IL-12 appears to attenuate the development of CLAD, specifically BOS. Meloni and associates measured BAL cytokines in 44 lung transplant recipients and identified significant decreases in IL-12 to be correlative with BOS development [46]. Krenn and associates determined that azithromycin administration in lung transplant recipients reduced overall fibrosis and kept IL-12 levels from decreasing [47]. The authors remarked on the future significance of macrolide therapy in reduction of BOS development

through effects on IL-12. The Th2 cytokine IL-4 has also shown to contribute to CLAD. Kastelijn and associates measured serum IL-4 levels in lung transplant recipients and found IL-4 levels were significantly lower in patients with BOS than BOS-negative patients [48]. The importance of IL-12 as a negative regulator as well as the potential role of IL-4 in CLAD indicates that the Th1 response may be downregulated in CLAD.

Chronic inflammation from persistent airway damage eventually leads to airway remodeling. TGF-β is an anti-inflammatory cytokine involved in tissue remodeling and scar formation [49]. Several studies have correlated TGF-β with the development of chronic lung rejection episodes, including El-Gamel and associates who discovered elevated TGF-β levels in biopsies in patients with BOS [50]. Elssner and associates studied BAL fluid and respiratory epithelial lining fluid in lung transplant recipients and found that BOS patients had elevated TGF-β levels in both samples [45]. Another study correlated TGF-β levels with BOS, which validated the author's claims that the biological role of TGF-β in tissue repair may also lead to airway fibrosis and obliteration [51].
