Inflammatory alveolitis leading to interstitial fibrosis is called fibrosing alveolitis, and it is a prominent feature of systemic sclerosis. This condition occurs in patients with diffuse cutaneous disease as well as in patients with limited cutaneous systemic sclerosis. Progressive fibrosis leads to altered lung architecture and a decrease in lung volumes and oxygen exchange across the alveolocapillary membrane. Pulmonary involvement in the form of basilar interstitial fibrosis is present at postmortem examination in up to 75% of subjects with scleroderma (1). Lung disease, especially pulmonary fibrosis and pulmonary hypertension, is the largest cause of disease-related mortality in systemic sclerosis (2).
The pathogenesis of interstitial pulmonary fibrosis in scleroderma is poorly understood. A number of processes are clearly taking place, including the accumulation of polymorphonuclear leukocytes, eosinophils, and mononuclear cells in the alveolar spaces and small airways, mononuclear cell infiltration in the pulmonary interstitium, and activation of lung fibroblasts, with the formation of myofibroblasts and increased matrix protein synthesis (3, 4). The temporal and causative relationships among these events are unclear. Immune cells and immune cell products are known to stimulate fibrosis and repair. However, once activated, fibroblasts and myofibroblasts may exhibit a profibrotic phenotype that is independent of continued immune stimulation. Furthermore, lung remodeling and matrix degradation also occur and lead to the release of collagen peptides that are chemotactic for immune cells. Interactions between acute inflammatory cells (neutrophils and eosinophils) and lymphocytes and monocytes are mediated by the release of cytokines, which activate a number of processes, including the expression of adhesion ligands, chemotaxis, and cellular activation. Thus, there is a complex interplay among cellular, matrix, and soluble factors.
Similar to pulmonary fibrosis in other diseases, the pulmonary fibrosis in scleroderma is generally thought to begin with an inflammatory alveolitis. Silver and colleagues (5) have demonstrated increased numbers of activated alveolar macrophages, polymorphonuclear cells, eosinophils, and lymphocytes in bronchoalveolar lavage (BAL) fluid from patients with scleroderma and pulmonary involvement. Proinflammatory cytokines, such as interleukin-8 (IL-8), macrophage inflammatory protein 1α, and tumor necrosis factor α (TNFα), have been shown to be elevated in BAL fluid from patients with scleroderma-associated alveolitis (6).
Recent studies using DNA array technology have examined gene expression profiles of BAL cells from scleroderma patients with and without lung inflammation as well as from control subjects (7). Gene expression profiles in patients without lung inflammation were similar to those in control subjects. In contrast, profiles in patients with lung inflammation showed increased expression of chemokines and chemokine receptor genes, which would lead to the migration of T cells, especially type 2 T cells, and phagocytic cells. Specifically, gene expression of pulmonary and activated-response chemokine and monocyte chemoattractant protein 1 was found to be elevated in scleroderma-associated alveolitis. Furthermore, expression of two antiinflammatory cytokines, IL-1 receptor antagonist and transforming growth factor β1, were also increased, consistent with other human fibrotic lung diseases and with animal models of fibrosis (7).
Leukotrienes play a major role in the inflammatory response to injury and have been implicated in the pathogenesis of a number of inflammatory diseases, including asthma, psoriasis, rheumatoid arthritis, and inflammatory bowel disease (8). Leukotrienes are biologically active 5-lipoxygenase products that are synthesized from membrane phospholipids via an enzyme cascade that begins with arachidonic acid, the common precursor of all eicosanoids. Leukotriene B4 (LTB4) and the sulfidopeptide leukotrienes C4, D4, and E4 exert their biologic actions via specific ligand–receptor interactions (8). The initial step in the genesis of eicosanoid biosynthesis is the activation of phospholipase, which in turn, hydrolyzes arachidonic acid. Proinflammatory cytokines such as TNFα and IL-1 can increase the activity of phospholipase A2, leading to leukotriene formation by leukocytes.
LTB4 is probably the most important neutrophil chemotactic agent produced by the arachidonic acid cascade. It is released from human neutrophils and alveolar macrophages in response to a variety of stimuli (9, 10). Pulmonary or cutaneous administration of LTB4 leads to the rapid accumulation of neutrophils in either BAL fluid or subcutaneous tissue, respectively. LTB4 also plays an important role in the induction of neutrophil–endothelial cell adherence, the induction of neutrophil degranulation, and the release of lysosomal enzymes. LTE4 and the other sulfidopeptide leukotrienes (LTC4 and LTD4) increase vascular permeability and produce contraction of smooth muscle.
Elsewhere in this issue of Arthritis & Rheumatism, Kowal-Bielecka and colleagues present evidence that LTB4 and LTE4 levels are increased in BAL fluid obtained from patients with scleroderma lung disease (11). Additionally, they show that high levels of LTB4 and LTE4 are correlated with an increased percentage of neutrophils in BAL fluid. Normal control subjects and scleroderma patients without lung disease had similar, and significantly lower, levels of LTB4 and LTE4. In a subset of patients who received 6 monthly treatments with intravenous cyclophosphamide combined with daily oral prednisone, a reduction in BAL fluid levels of LTB4 was observed.
Together, these findings suggest that LTB4 and LTE4 could play an important role in the inflammatory process that characterizes scleroderma lung disease. They suggest that these signaling molecules play a central role in the accumulation of inflammatory cells in the lung. Is the coordinate increase in leukotriene levels in the BAL fluid and the percentage of neutrophils really a cause-and-effect relationship? Are there fewer neutrophils as a result of decreased chemotactic leukotriene activity, or conversely, are the levels of LTB4 and LTE4 merely an index or reflection of the number of neutrophils? Of course, these possibilities are not mutually exclusive: LTB4 and LTE4 could lead to neutrophil accumulation, which in turn, leads to more leukotriene synthesis and higher leukotriene levels in BAL fluid.
What role do LTB4 and LTE4 play in the hierarchical cascade that leads to pulmonary fibrosis? Is leukotriene release an early event that is critical to neutrophil accumulation, subsequent accumulation of lymphocytes and monocytes, and ensuing fibrosis? It is quite possible that the fundamental processes involve events occurring in the tissue and not the alveolar space. Immune cell activation by as-yet-unrecognized antigens might lead directly to fibrosis; in this construct, the role of leukotrienes and neutrophil accumulation in the alveolar spaces might be much less critical. A parallel situation may occur in rheumatoid arthritis, where inflammation in the synovial fluid and proliferation in the synovial tissue are related but separate events. Polymorphonuclear leukocyte accumulation in the synovial space is responsible for acute symptoms, but mononuclear cell–driven events in the synovial pannus are central to the destruction and alteration of the architecture of cartilage and bone.
Therapeutic approaches to scleroderma lung disease have thus far focused on suppressing inflammation with corticosteroids and cytotoxic agents, such as cyclophosphamide (12, 13). While retrospective studies suggest that improved lung function and survival may occur with this approach, a definitive answer concerning its value must await a multicenter prospective trial of cyclophosphamide. One such trial is currently in progress. Furthermore, cyclophosphamide therapy with or without corticosteroids carries significant potential therapeutic risks, and additional agents are urgently needed. The findings reported by Kowal-Bielecka (11) are important because they represent the first evidence of a strong therapeutic rationale for evaluating inhibitors of lipoxygenase and leukotriene synthesis as well as receptor antagonists in scleroderma lung disease. Such studies are important not only in developing new therapy, but also in understanding the sequence of pathogenetic events in fibrosing alveolitis. Inhibition of leukotrienes, as a focused and targeted approach to therapy, is attractive because of lower toxicity compared with cyclophosphamide therapy. Furthermore, on the basis of insightful studies such as those reported by Kowal-Bielecka and colleagues, a treatment role in combination with other approaches might be advantageous. We look forward to a potentially expanding therapeutic armamentarium in scleroderma lung disease.