Surfactant Proteins and Inflammation - ATS Journals

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Department of Anesthesiology, University of Alabama Birmingham, Birmingham, Alabama; ... like lectins (3), all of which have a four-domain primary structure.
Perspective Surfactant Proteins and Inflammation The Yin and the Yang Sadis Matalon and Jo Rae Wright Department of Anesthesiology, University of Alabama Birmingham, Birmingham, Alabama; and Duke University School of Medicine, Durham, North Carolina

Alveolar surfactant is a complex mixture of lipids and proteins that executes two disparate functions. First, surfactant reduces surface tension at the air–liquid interface of the lung thereby preventing lung collapse. Second, surfactant functions in pulmonary host defense. The host defense functions are mediated primarily by the hydrophilic protein constituents of surfactant, surfactant protein (SP)-A and SP-D (1–3). SP-A and SP-D are members of a family of proteins known as collectins, or collagenlike lectins (3), all of which have a four-domain primary structure consisting of a disulfide-forming NH2 terminus, a collagen-like region, a coiled neck region, and a COOH-terminal carbohydrate recognition domain (4). SP-A and SP-D bind via their carbohydrate recognition domains to sugar and glycolipid residues on microbial cell walls. SP-A and SP-D form trimers and oligomers, which greatly increase their valence and efficiency at binding pathogens (3). Both SP-A and SP-D have been shown to mediate phagocytosis and killing of pathogens both in vivo and in vitro (reviewed in Refs. 3 and 5). Transgenic mice, deficient in SP-A and SP-D, have enhanced susceptibility to bacterial and viral infections and develop more severe pulmonary lesions than do wild-type mice after inoculation of their lungs with various pathogens (reviewed in Refs. 3 and 5). A point of some controversy in the field has been whether SP-A and SP-D enhance or inhibit production of inflammatory mediators. The focus of this Perspective is to briefly summarize this controversy and to highlight new findings in the area, including those of Wu and coworkers published in this issue of AJRCMB (6), that provide some resolution to this controversy. Several lines of evidence show that SP-A either enhances or decreases the production of reactive nitrogen and inflammatory cytokines by immune cells. For example, SP-A enhanced the production of NO and nitric oxide synthase (NOS)2 (inducible NOS) expression in rat alveolar macrophages (AMs), previously activated with interferon ␥, but inhibited NO production and NOS2 expression by lipopolysaccharide (LPS)-activated macrophages (7). SP-A may exert differential effects depending on the type of stimulus or pathogen presented to the cell. For example, SP-A reduced the production of NO by AMs in the presence of Mycobacterium tuberculosis, and this was correlated with reduced killing of organisms (8). In contrast, SP-A enhanced the

(Received in original form September 27, 2004) Address correspondence to: Sadis Matalon, Ph.D., Department of Anesthesiology, University of Alabama at Birmingham, 1530 3rd Avenue South, Birmingham, Alabama 35294-2172. E-mail: [email protected] Abbreviations: alveolar macrophages, AMs; bronchoalveolar lavage, BAL; lipopolysaccharide, LPS; nuclear factor, NF; nitric oxide, NO; nitric oxide synthase, NOS; surfactant protein, SP. Am. J. Respir. Cell Mol. Biol. Vol. 31, pp. 585–586, 2004 DOI: 10.1165/rcmb.F286 Internet address: www.atsjournals.org

production of NO killing of pathogens by monocyte-derived macrophages in the presence of bacillus Calmette-Guerin (9) and by mouse AMs in the presence of Mycoplasma pulmonis (10). Congenic mice lacking SP-A had significantly higher levels of NO in their bronchoalveolar lavage (BAL) than did their wild-type controls under basal condition; however, significantly higher levels of NO were seen in the BAL of wild-type mice after infection with mycoplasmas (11). Finally, SP-A downregulated NO production by AMs from normal humans but upregulated NO production by a significant fraction of AMs harvested from the lungs of patients with transplanted lungs, presumably due to the presence of lung inflammation (12). Recent studies from two independent laboratories have provided at least partial explanations for these conflicting results. The work by Wu and coworkers published in this issue of AJRCMB (6) provides new evidence regarding the mechanism by which SP-A acts to suppress NO production. Herein, the authors demonstrate that SP-A decreases LPS-activation of nuclear factor (NF)-␬B by increasing protein expression of inhibitory (I) ␬B-␣ via posttranscriptional mechanisms. Based on experimental data, these authors propose that the effects of SP-A were due to the inhibition of the ubiquitin–proteasome pathway. Because this pathway is responsible for the degradation of a number of altered proteins, SP-A may also delay their clearance with unforeseen implications. The recent study by Gardai and coworkers (13) also contributes to our understanding of these seemingly contradictory findings. These authors proposed that SP-A binds to inflammatory cells either by the carbohydrate (“globular heads”) recognition domains or by their collagenous tails. Binding of the globular heads to signal inhibitory regulatory protein ␣ (SIRP␣) initiates a signaling cascade that blocks NF-␬B and decreases proinflammatory mediator production. On the other hand, when the collectin globular heads are bound by pathogens, interaction of the collagen tails with calreticulin/CD91 receptor complex results in activation of NF-␬B and increased production of inflammatory mediators. The predictions of this model are supported by the results of other studies. For example, SP-A had differential effects on LPS-induced production of cytokines by U-937 cells, depending on whether a rough or smooth serotype of LPS was used (14). Interaction of SP-A with the rough form of LPS, to which SP-A binds, downregulated tumor necrosis factor–␣ production, whereas SP-A upregulated tumor necrosis factor–␣ production induced by smooth LPS, which does not interact with SP-A’s globular head. On the other hand, Wu and colleagues (6) reported that the inhibitory effect of SP-A on LPS-induced NF␬␤ activation was independent of the LPS isotype, which is consistent with a previous report (7) showing that SP-A inhibits NO production induced by both smooth and rough LPS. Thus, multiple mechanisms and/or receptors may be important in mediating these responses.

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In the context of the immune challenges faced by the lung, a Yin/Yang balance may be of benefit to the host. For example, in the normal lung, the collectins may downregulate production of inflammatory mediators while enhancing the clearance of pathogens via opsonization (i.e., the Yin). However, when the lung is challenged by an aggressive insult, such as a bacterial or viral infection, induction of an inflammatory response by SPs (i.e., the Yang) would aid in neutralization of the pathogen. How this fine balance is maintained has been partially clarified by the studies described above. However, many unanswered questions remain. Of note, studies from many different laboratories show that SP-A and SP-D have differential effects on inflammatory mediator production depending on the cell type, the presence or absence and type of pathogens, and the activation state of the cell. It remains unclear whether these differential effects are modulated via the different collectin receptors or via other mechanisms. Furthermore, Wu and colleagues’ work (6) convincingly demonstrates that SP-A directly modulates the basal and LPS-coupled inhibitory ␬B-␣ turnover in AMs, but the mechanism by which this signal is transduced is not known. Future studies investigating the mechanisms by which collectins maintain a state of balance between their opposing pro- and anti-inflammatory functions will provide important information that may contribute to development of surfactant replacement therapies for treatment of inflammatory and infectious lung diseases. Conflict of Interest Statement : S.M. has no declared conflicts of interest; J.R.W. has no declared conflicts of interest. Acknowledgments: Supported by work funded by HL 51134, HL-30923, and HL68072 (to J.R.W.), and HL31197, HL51173, and HL72871 (to S.M.).

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