Balance between alveolar macrophage IL-6 and TGF-beta in lung-transplant recipients. Marseille and Montréal Lung Transplantation Group.

Abstract

Acute inflammation in the lung is characterized by a phase of tissue injury followed by a phase of tissue repair. When the latter is excessive, fibrosis occurs. Alveolar macrophages (AM) can produce cytokines involved in both phases of acute lung inflammation, notably interleukin-6 (IL-6), involved in injury and transforming growth factor-beta (TGF-beta), mediating repair. We hypothesized that AM were activated in both phases, and studied IL-6 and TGF-beta production by AM during complications of lung transplantation, acute rejection (AR), and cytomegalovirus pneumonitis (CMVP). In addition, we analyzed these cytokines in bronchiolitis obliterans (BO), a fibrotic complication of lung transplantation linked to previous AR and CMVP. At the onset of AR and CMVP, IL-6 secretion increased, whereas AM TGF-beta content was increased, but not its secretion. In contrast, with time, IL-6 reached control value whereas TGF-beta secretion rose significantly. In BO, IL-6 was not oversecreted, but TGF-beta increased, notably before functional abnormalities occurred. These results show that during acute complications of lung transplantation, AM display an early activation with oversecretion of IL-6, which is involved in tissue injury, counterbalanced by a late activation in which TGF-beta predominates, mediating tissue repair. The results provide new insights into the pathogenesis of BO, which is linked to acute complications of lung transplantation through this biphasic AM activation.

Bronchoalveolar Cellularity and Interleukin-8 Levels in Measles Bronchiolitis Obliterans

“…22,28 Vast arrays of cytokine and chemokine networks (those implicated include tumor necrosis factor-␣, IL-2, IL-8, RAN-TES [regulated upon activation, normal T-cell expressed and secreted], platelet-derived growth factor, transforming growth factor, and fibroblast growth factor) are activated, perpetuating an inflammatory response. 29,30 In the investigation of pathogenic mechanisms involved in adenovirus infection, Mistchenko et al 31 found that high serum values for IL-6, IL-8, and tumor necrosis factor-␣ are associated with severity of adenovirus infection. We previously showed a significantly elevated percentage of neutrophils in BAL fluid from children with BO following adenovirus or Mycoplasma infection.…”

Transforming growth factor-β1 is a potent inhibitor of secretory leukoprotease inhibitor expression in a bronchial epithelial cell line

“…Not surprisingly, it could be shown that the expression of TGF-b 1 by alveolar macrophages and BALF cells from lung transplant recipients suffering from OB is enhanced [9,10].…”

“…The TGF-bs are able to act as negative and positive regulators of cell growth and induce differentiation, transformation, tissue repair, fibrosis and inflammatory responses [2±7]. Apart from this pathophysiological role of TGF-b in several fibrotic lung diseases [4±8], recent reports emphasize that alveolar macrophages and bronchoalveolar lavage fluid (BALF) cells obtained from patients with obliterative bronchiolitis (OB) after lung transplantation show an increased expression of TGF-b compared to patients free from OB [9,10]. OB is the most important complication in the long-term follow-up after lung and heart-lung transplantation, limiting life expectancy and quality of life [11].…”

Tissue remodelling in chronic bronchial diseases: from the epithelial to mesenchymal phenotype

“…Studies in the inflammatory environment of BO have shown that TGF-b is one of the most important factors involved in the fibrotic process and high levels of TGF-b are found in the BAL from BO patients [148,[161][162][163][164][165]. Other pro-inflammatory cytokines, such as IL-8, TNF-a and IL-1b, are also highly expressed in BO patients [127,148,165].…”