Surfactant protein genetics in community-acquired pneumonia: balancing the host inflammatory state

Community-acquired pneumonia is a common disease. Abnormalities in the first step of host defense may severely compromise subsequent steps of successfully combating infections. In the previous issue of Critical Care, García-Laorden and colleagues reported genetic associations between single-nucleotide polymorphisms and haplotypes of the surfactant proteins with susceptibility, severity, and outcome of community-acquired pneumonia. Although the limited information shows regulatory differences among variants, it is currently unknown how the difference in surfactant protein A genotypes in this and other studies affects the individual's phenotype. The lung is continually exposed to a host of irritants yet maintains health. It is plausible that, under physiologic conditions, surfactant protein A, in addition to having a dominant effect on anti-inflammatory processes, mediates a low level of proinflammatory processes that are essential for the health of the lung. Understanding the maintenance of the balance of the inflammatory state may be one of the keys to understanding pulmonary disease progression.

felt to be multifactorial. Th e authors should be commended for this work. Determining who is more likely or less likely to develop CAP, develop ARDS and MODS after CAP, or die from this infection is an important endeavor. Innate immunity clearly plays an important role. Abnormalities in the fi rst step of host defense may severely compromise subsequent steps of successfully combating infections. Th e hope is that novel therapies can target these most susceptible patients, even before the downstream clinical events fully develop. However, before this next step may be taken, certain limitations of the present study require further work. Of paramount importance is whether the results of this study are generalizable to populations other than a relatively homo geneous Spanish Caucasoid group. Before studies such as the present one can be universally accepted, they require validation in a distinct group of individuals.
Th e authors reported genetic associations between single-nucleotide polymorphisms of the surfactant proteins, as well as haplotypes encompassing these genes, with susceptibility, severity, and outcome of CAP. Several associations remain signifi cant even after stringent multiple comparison corrections. Th ese fi ndings are not surprising, given the important role of innate immunity in host defense. Th ere are a signifi cant number of studies in which associations of genetic variants of surfactant protein A (SFTPA) 1, SFTPA2, and SFPD with disease susceptibility have been identifi ed and these cover the entire life span, from birth and childhood through adulthood [2]. Owing to their extensive complexity, the SFTPA genes, in particular, provide a good model with which to study disease susceptibility and severity. Th e extensive complexity makes it a challenge to fully understand and interpret any associa tions made (including those in the present study) but at the same time provides an opportunity to learn about disease pathogenesis. At present, although some insight into mechanisms underlining diff erential regulation of the diff erent variants in response to various insults such as bacteria or oxidative stress (or both) has been gained [3][4][5][6][7], this knowledge is still in the early stages and is insuffi cient for assessing how the diff erence in SFTPA

Abstract
Community-acquired pneumonia is a common disease. Abnormalities in the fi rst step of host defense may severely compromise subsequent steps of successfully combating infections. In the previous issue of Critical Care, García-Laorden and colleagues reported genetic associations between single-nucleotide polymorphisms and haplotypes of the surfactant proteins with susceptibility, severity, and outcome of community-acquired pneumonia. Although the limited information shows regulatory diff erences among variants, it is currently unknown how the diff erence in surfactant protein A genotypes in this and other studies aff ects the individual's phenotype. The lung is continually exposed to a host of irritants yet maintains health. It is plausible that, under physiologic conditions, surfactant protein A, in addition to having a dominant eff ect on anti-infl ammatory processes, mediates a low level of proinfl ammatory processes that are essential for the health of the lung. Understanding the maintenance of the balance of the infl ammatory state may be one of the keys to understanding pulmonary disease progression. genotypes in this and other studies aff ects the individual's phenotype or for contemplating therapeutic points of interventions based on SFTPA genotype.
Th e authors clearly appreciate the dual role of SP-A, its ability to promote proinfl ammatory processes in response to pathogens or other insults, and its ability, under 'basal' conditions, to suppress nuclear factor-kappa-B (NF-κB) activation and infl ammation. However, we would like to raise the point that even under 'basal' physiologic conditions (that is, in the absence of an overbearing pathogen load), the lung is exposed daily to hundreds of thousands of irritants (for example, bacteria, viruses, pollen, and toxins) yet the lung maintains a healthy status. We would like to put forward the idea that, under physiologic conditions, SP-A, in addition to having a dominant eff ect on anti-infl amma tory processes, mediates a low level of proinfl ammatory processes that are essential for the health of the lung. Several in vitro studies have shown the ability of SP-A, in the absence of pathogens, to generate a low-level pro infl ammatory response [8][9][10][11][12][13][14][15][16]. It is possible that the SP-A-mediated proinfl ammatory activity (high or low levels) is 'contextdependent' and refl ects the magnitude of the threat. Whether the mechanisms of this pro infl ammatory activity at low physiologic level overlap with or are completely diff erent from those of the high-level activity generated in the presence of high-load pathogens or other irritants remains to be determined.
Th e collective data, including the data from this study of the association of surfactant proteins with disease risk, beg for a better understanding of the functional and regulatory diff erences among common and rare SPFTA variants. Understanding the underlining regulatory control diff erences among SPFTA variants could identify points amenable to therapeutic intervention, which could lead to treatment options that are truly individualized to the patient's genotype. Th e ultimate goals, once the mechanisms by which these genetic diff erences infl uence outcome have been deter mined, would most likely be to develop novel technolo gies that will allow the addition of SP-A (or even a specifi c SP-A variant) and SP-D into exogenous surfac tant preparations (similar to SP-B and SP-C formulations that are presently being tested) and to target a group of individuals based on both their etiology of lung disease (that is, infection) and their individual genotype.

Competing interests
NJT serves as a consultant and is a member of the Advisory Board for Discovery Laboratories, Warrington, PA. JF has no competing interests.