**2. Methods**

PubMed was explored using MeSH terms "lung transplantation," "cytokines," "biomarkers," "acute rejection," "chronic allograft dysfunction," and "primary graft dysfunction." Inclusion criteria consisted of studies through May 2018 that provided information on plasma and/or BAL cytokines and acute rejection, chronic rejection, or primary graft dysfunction in lung transplant recipients. Prospective, retrospective, and review articles were included. The references of searched articles were also examined for potential studies to include. We focused on the following cytokines: interleukin (IL)-1a, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-15, and IL-17; interferon-gamma (IFN-y); tumor necrosis factor-alpha (TNF-a); transforming growth factor-beta (TGF-b); and monocyte chemotactic protein (MCP)-1.

### **3. Primary graft dysfunction**

PGD typically occurs within the first 72 h posttransplantation and is identified as ischemia-reperfusion injury with pulmonary edema that presents as increasing hypoxia in the affected patient [3].

Lung transplantation, and any other major surgeries, constitutes massive damage to patient tissues.

TNF-α is one of the first cytokines to be released into circulation from such an injury, peaking in serum concentration around 1 h after the beginning of injury. IL-6, IL-8, and IL-10 are expressed and released in circulation shortly after, with peaks in concentration between 2 and 4 h after injury. Additionally, if injury severity increases, there is an associated shift away from a cell-mediated response to a humoral immune response [8].

Macrophage-associated cytokines IFN-y, TNF-a, and MCP-1 have all been strongly associated with PGD development in lung transplant recipients. Bharat and associates identified elevated serum IFN-γ in PGD positive patients [9]. Early release of TNF-α was associated with early hemodynamic failure posttransplantation [10]. In another study, elevated systemic TNF-α concentrations were associated with PGD development [11]. MCP-1, a macrophage chemotactic agent, has demonstrated a strong role in PGD. Shah and associates measured plasma MCP-1 at various time points in lung transplant recipients. They found elevated MCP-1 levels at 24 h posttransplantation were associated with PGD grade 3. These results attested to the importance of monocyte chemotaxis in PGD [12]. Another group of authors found similar results with elevated serum MCP-1 in PGD positive lung transplant recipients [13]. INF-γ is a potent activator of macrophages. Elevations in IFN-γ

**117**

inflammation.

*Cytokine Biomarkers as Indicators of Primary Graft Dysfunction, Acute Rejection, and Chronic…*

along with increases in MCP-1, a strong monocyte chemotactic agent, suggest that

ing IL-6 and IL-8. PGD is linked to concomitant increases in IL-6 and IL-8 in lung transplant recipients. Early hemodynamic failure posttransplantation was associated with increases in both IL-6 and IL-8 [10]. A different study had similar results, in which IL-6 and IL-8 were both elevated in patients with PGD [11]. Moreno and associates found elevated BAL and blood IL-6 and IL-8 in patients with PGD. They are subsequently treated with inhaled nitric oxide, which lowered IL-6 and IL-8 and also decreased PGD incidence [14]. Increases in IL-6 often occur as a result of upstream macrophage-induced activation of Th1 immunity. In addition to macrophage activation, neutrophil chemotaxis from IL-8 upregulation is associated with increased PGD incidence. Increases in other pro-inflammatory cytokines caused by macrophage activation lead to pulmonary vasoconstriction and increased pulmonary vascular permeability, precipitating hemodynamic

In the weeks to months following transplantation, the allograft recipient's T-cell-mediated immunity intensifies, potentially leading to the development of ALR. ALR is understood to be originally caused by mismatched MHC recognition

Acute lung rejection is precipitated by the adaptive T-cell response. MHC mismatch and the adaptive immune response are associated with T-cell activation and differentiation, which is facilitated by IL-2 [16]. It is expected that IL-2 would be increased in acute rejection; however the literature is conflicting on its association with lung rejection. Jordan and associates analyzed the serum of 17 lung transplant recipients and found serum IL-2 significantly elevated in patients with acute rejection confirmed; however, Moudgil and associates found no correlation between IL-2 levels and acute rejection in lung transplant recipient [17, 18]. In addition to IL-2, IL-15 is a cytokine derived from stromal cells that behaves similarly to IL-2 in terms of biological function and is involved in T-cell chemoattraction to allografts [23]. Bhorade and associates measured IL-15 levels in BAL fluid of lung transplants and found that IL-15 was significantly elevated in patients experiencing acute rejection when the patients were given anti-CD25 monoclonal antibodies [19]. This study along with the evidence for IL-2 activation suggests the potential importance of

T helper (Th) cells orchestrate the immune response and are divided into two subsets, Th1 and Th2 cells. T-cell differentiation into Th1 cells leads to increased expression of IFN-γ by Th1 cells. IFN-γ is involved in many important immune mechanisms and is a main component of the Th1 immune response, as it is a strong activator of macrophage-mediated antimicrobial and antitumor activity [20]. Its role in ALR is supported by a study measuring IFN-γ in BAL fluid of lung transplantation patients, which found IFN-γ levels were significantly elevated in early acute rejection [18]. IL-12 is a known mediator of interferon-gamma expression [21]. D'ovidio and associates found IL-12 in BAL fluid elevated in acute rejection patients, which suggests it influences IFN-γ in ALR [22]. Ultimately, IFN-γ activation of macrophages induces pro-inflammatory cytokine release to cause

IL-1, IL-6, and TNF-α are all acute phase pro-inflammatory cytokines that occur in most disease states and are secreted by activated macrophages to induce

Macrophage activation leads to release of pro-inflammatory cytokines, includ-

ischemia-reperfusion injury increases macrophage activation.

*DOI: http://dx.doi.org/10.5772/intechopen.84661*

instability characteristic of PGD.

and adaptive immune response [15].

IL-2 and IL-2 receptors in ALR immune responses.

**4. Acute lung rejection**

*Cytokine Biomarkers as Indicators of Primary Graft Dysfunction, Acute Rejection, and Chronic… DOI: http://dx.doi.org/10.5772/intechopen.84661*

along with increases in MCP-1, a strong monocyte chemotactic agent, suggest that ischemia-reperfusion injury increases macrophage activation.

Macrophage activation leads to release of pro-inflammatory cytokines, including IL-6 and IL-8. PGD is linked to concomitant increases in IL-6 and IL-8 in lung transplant recipients. Early hemodynamic failure posttransplantation was associated with increases in both IL-6 and IL-8 [10]. A different study had similar results, in which IL-6 and IL-8 were both elevated in patients with PGD [11]. Moreno and associates found elevated BAL and blood IL-6 and IL-8 in patients with PGD. They are subsequently treated with inhaled nitric oxide, which lowered IL-6 and IL-8 and also decreased PGD incidence [14]. Increases in IL-6 often occur as a result of upstream macrophage-induced activation of Th1 immunity. In addition to macrophage activation, neutrophil chemotaxis from IL-8 upregulation is associated with increased PGD incidence. Increases in other pro-inflammatory cytokines caused by macrophage activation lead to pulmonary vasoconstriction and increased pulmonary vascular permeability, precipitating hemodynamic instability characteristic of PGD.
