Control of type I collagen formation in the lung.

Control of type I collagen formation RONALD

in the lung

H. GOLDSTEIN

Pulmonary Center and the Department of Biochemistry, Boston University School of Medicine, Boston 02118 and Boston Veterans Affairs Medical Center, Boston, Massachusetts 02130

cell types, secreted, and become part of a complex extracellular matrix (99). In pulmonary tissues, type I collagen L29-L40, 1991.-Type I collagen is a major structural protein is the most abundant of the collagen types. This collagen in the lung, the accumulation of which is stimulated during type is representative of a class of fibril forming collagens certain inflammatory reactions in the lung. Accumulating evi- and is a hetrotrimer, [ ~yl(I)]~a2( I), composed of 2 idendencesuggeststhat type I collagenformation parallels changes tical a-chains and one cu2-chain. The genes encoding the in steady-statemRNA levels. Specific inflammatory substances modulate transcription of collagen genesand stabilization of two type I a-chains are located on different chromosomes GOLDSTEIN, RONALD H. Control of type I collagen formation in the lung. Am. J. Physiol. 261 (Lung Cell. Mol. Physiol. 5):

collagen mRNA in vitro. However, the precise role for any particular mediator during fibrotic processesis difficult to identify becauseof the complex nature of the inflammatory reaction and potential interaction amongmediators.The signal transduction mechanismsthat regulate collagen accumulation remain to be defined. This review focuseson the regulation of collagen accumulation in the lung by specific inflammatory substances. collagen; signal transduction; lung fibroblasts; pulmonary fibrosis

I COLLAGEN is a major structural protein in the lung interstitium. It is produced in large quantities during lung development and during fibrotic reactions. These fibrotic reactions are part of the repair process that follows injury to the epithelial and endothelial cells in the alveolar wall. In mild localized injuries, the production of collagen is limited and normal lung architecture is restored. When the injury involves pleura and bronchi as well as parenchyma, but is still localized, repair may result in focal scar formation. After severe, widespread injuries, scarring may be generalized and result in extensive disruption of architecture and lung function (for review see 44). As part of the alveolitis following severe injuries, fibroblasts proliferate within the interstitium or within an organizing exudate in the alveolar space and produce large amounts of collagen (29). This process of scar formation may be similar to that which occurs in other injured tissues. The amount of collagen deposited in the lung therefore depends on the extent of cellular damage, the number of proliferating fibroblasts, and the particular effector substances present in the inflammatory milieu. Many additional poorly understood factors also may be involved. These include vascular hypoperfusion, alveolar collapse, and alterations in mechanical forces and oxygen tension that occur during lung injury. Collagen is a family of at least 13 different proteins (for reviews see 1, 23, 140, 168). During growth and development these proteins are synthesized by different TYPE

(168).

Collagen synthesized during fibrotic reaction in the lung is predominantly type I collagen. It was initially thought that this increase in type I collagen was the consequence of increased numbers of fibroblasts present in the inflammatory milieu with each cell secreting collagen at its own basal rate. However, it has now become clear that the rate of collagen formation by individual fibroblasts is increased; this increase is regulated by effector substances present in the inflammatory environment. Transforming growth factor-p (TGF-P) and insulin-related peptides are two such substances that can induce large increases in collagen formation by fibroblasts and smooth muscle cells in culture (57, 70, 80). Leukotriene Cq was recently shown to increase collagen formation by rat lung fibroblasts (132); other inflammatory substances that stimulate collagen formation may be identified in the future. In addition, certain fibrogenic agents such as bleomycin may directly stimulate matrix formation (37). Other molecules such as prostaglandin Ez (PGEJ and y-interferon inhibit collagen accumulation (69, 147, 166). The net accumulation of collagen as a result of inflammation may depend on the interaction of these and other factors. The level of collagen accumulation in the lung and other tissues appears to correlate with steady-state level of collagen mRNA suggesting that factors that affect the rate of transcription of the al(I) collagen genes and the stabilization of the mRNA are of critical importance. In addition to effector substances, other processes likely influence the accumulation of collagen during a fibrogenic reaction. Numerous potential regulatory sites have been identified at points in the biosynthetic pathway of collagen as well as during the assembly of the collagen fiber in the extracellular matrix (23, 168). As examples, collagen peptides inhibit the translation of collagen mRNAs (128, 170) and prolyl hydroxylase and lysyl oxidase activities increase during fibrotic reactions ensuring the formation of stable collagen fibers (43, 90). The exact contribution of these potential regulatory sites to overall collagen accumulation remains to be established (Fig. 1). L29

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PGE2 Y INTERFERON TNF

COLLAGEN FIBER FORMATION 1”““““‘1”‘1fl

\

FIG. 1. Biosynthesis of f’ibrils and fibers is highly sites. Exact contribution collagen accumulation in may act at several sites in

J

POSTTRANSLATIONAL MODIFICATIONS

I

collagen. Synthesis and assembly of collagen complex with numerous potential regulatory for each of these potential sites to overall the lung is unknown. Effector substances the biosynthesis of collagen.

Fibroblast heterogeneities within lung may also be important determinants of lung collagen production during fibrotic reactions. Fibroblast subtypes within the lung, derived by clonal selection or by cell sorting, have different rates of proliferation and synthesize different amounts and types of collagen (23, 85). Moreover, these fibroblasts may respond differently to effector substances, although fibroblasts derived from explants obtained from normal and fibrotic human lungs were similar in terms of collagen production and response to TGFp (141). Caution must be exercised when generalizing about the effects of specific mediators on fibroblast behavior, particularly when only one fibroblast type is examined. Other lung cells in addition to fibroblasts synthesize collagen, and different processes may regulate the production of collagen by these cells. For example type II alveolar epithelial cells and endothelial cells produce type IV collagen. Fetal type II alveolar epithelial cells produce type I collagen in culture (56). The amount of collagen produced by these cells increases in the presence of epidermal growth factor and retinoic acid (56). Finally, the extracellular matrix may influence collagen accumulation through fibroblasts and effector substance interactions. For example, fibroblast proliferation and matrix deposition is modulated by fibronectin (17, 97, 114). Fibronectin also functions as a cell adhesion molecule (158) and collagen gene expression is dependent on cell adhesion (47). In addition, the amount of extracellular collagen in matrix may influence collagen production by fibroblasts; collagen accumulation is decreased when fibroblasts are grown within collagen gels (113, 121). It is possible that increased extracellular collagen exerts negative feedback control on collagen production. REGULATION

OF

THE

COLLAGEN

GENE

The type I collagen genes have been characterized (for review see 168). The al(I) gene contains 51 exons that code for the triple-helical domain and amino- and car-

REVIEW

boxy-terminal extension peptides (35). Most available information relating to the regulation of gene transcription is derived from studies of cultured fibroblasts. Transcriptional regulation is mediated through complicated interactions of &-acting DNA elements and trans-acting protein factors. These &-acting elements are usually located in the upstream promoter sequences 5’ to the transcription start codon. Control sequences have been found in the promoters located upstream of the transcriptional start site for both type I collagen genes. The promoters contain TATA boxes that orient the RNA polymerase complex and CCAAT-binding regions [ -96 to -100 base pairs in the rat al(I) collagen gene]. Regulatory sequences within the promoters were defined by employing transfected plasmids containing portions of the collagen promoter regions driving a chloramphenicol acetyltransferase (CAT) gene. Deletion of sequences -772 to -108 in the cy2(1) promoter resulted in complete loss of transcriptional activity (19). Both positive and negative regulatory elements were found within the upstream promoter segments. However, the function of regulatory elements may not correspond with the function of the endogenous promoter. For example, methylation of the endogenous promoter prevents association of nuclear-binding proteins with &-acting elements (23, 31, 129). Methylation of the al(I) collagen promoter linked to CAT decreased transcriptional activation by transient expression analysis (165). Type IV collagen gene expression was inhibited by DNA methylation in F9 teratocarcinoma cells (28). Cell-specific gene regulation may be lost in transient transfection studies because of absence of regulatory elements in the transfected promoter or because of specific structural features of the endogenous gene such as chromatin conformation. Additional positive and negative regulatory elements are contained within the first intron of the al(I) and cu2(1) genes. Protein binding sites have been identified within the first intron by DNase I protection assays (11, 115). There is significant species-dependent variation in this region of the collagen gene (157). Major differences in stimulation of CAT activity were found when similar intronic regions were transfected into fibroblasts derived from different species or into fibroblasts derived from different tissues from the same species (21, 22, 143, 149, 150). The intronic elements can increase or decrease the rate of transcription in these different fibroblast types. Olsen et al. (125) reported that deletions in the first intron did not cause large changes in the expression of a minigene version of the gene for the procwl(1) chain in stably transfected mouse fibroblasts. Whether these described regulatory elements are functional during inflammatory reactions is uncertain at this time. Some of the nuclear binding proteins that modulate the collagen gene have also been identified. Maiety et al. (108) described a heterodimeric CCAAT-binding protein, designated CBF, which activates in vitro transcription of al(I) and cu2(1) collagen genes. Mutations in the CCAAT element at -80 in the at2(1) collagen promoter dramatically reduced promoter activity. This CCAAT binding factor was isolated from rat liver and stimulates the transcription of several other promoters. Several negative regulatory sites located immediately upstream


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from the CCAAT region bind to the regulatory proteins IF1 and IF2 (88). Additional negative upstream sequences in the promoter may also be present (88). Another nuclear protein binds to a conserved region in the 3’ untranslated region in the al(I) collagen gene in myogenic cells, although the functional significance of this trans-acting factor remains to be determined (75). Although elastin is another major structural protein in the lung, the nucleotide sequences located in the elastin and collagen promoter regions are not homologous, suggesting differential regulation. Bashir et al. (12) and Kahari et al. (87) sequenced clones of the human elastin gene and analyzed the Y-flanking region. The elastin promoter does not contain a TATA box, but does contain several CCAAT sequences, several SPl binding sites and G+C enriched areas. The elastin gene is therefore unusual, exhibiting features of different classes of TATA-less promoters (52, 154, 159) and appears to be most active primarily during periods of alveolar formation in the lung. Elastin formation is increased during fibrotic reactions in the lung, although to a lesser extent than collagen (30, 162). ACTIVATION

OF

THE

COLLAGEN

GENE

TGF-0

TGF-P-induced collagen formation provides a useful model system to examine the activation of collagen accumulation because dramatic increases in collagen mRNA levels and collagen accumulation occur in most fibroblast subtypes. TGF-P functions through several different receptors, which complicates the problem of sorting out signal transduction pathways for collagen. The type I receptor, as assessed by affinity labeling, is comprised of complexes of 65-kDa, which bind TGF-P1 with high affinity and TGF-& with low affinity (for review see 111). The type II receptor is comprised of affinity-labeled complexes between 85 and 110 kDa, depending on the animal species. This receptor type also binds TGF-& with high affinity and TGF-P2 with lower affinity. The type III TGF-P receptor is larger (250-350 kDa) and unusual in that it has the structure of a proteoglycan (32). This receptor binds both TGF-P, and TGF-P2 with high affinity, and dose-response relations suggest that the type III receptor may be involved in the activation of collagen formation. At least one of these receptors functions through guanine nucleotide regulatory proteins (G proteins) (76, 77). TGF-P1 increased the binding of a GTP analogue to plasma membranes from AKR-2B cells (77). The function of each receptor will be clarified after the receptor proteins are sequenced and the genes for these receptors are cloned. TGF-P increases collagen formation by increasing both the rate of transcription of collagen genes and the stability of the resultant transcripts (81, 130). In the mouse 0.2(I) collagen promoter, the TGF-P response element is located between nucleotides -315 to -295 and resembles a canonical nuclear factor 1 (NF-1) site (148). NF-1 proteins bind to this region in gel shift assays. However, this NF-1 site also binds histone Hl (144), raising the possibility that other proteins are involved in TGF-P-

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induced activation of collagen gene transcription. The al(I) collagen promoter does not have an NF-1 site located at -315, but several other potential NF-1 sites are located in other regions of the promoter. These observations suggest a complex regulatory pathway, perhaps involving multiple binding sites. Indeed, in some cell types, TGF-P induces large increases in al(I) mRNA without inducing similar increases in al(I) mRNA levels (60). The regulatory mechanisms for NF-1 proteins are largely unknown. The rat NF-1 gene promoter recently was cloned and contains an SP-1 binding site (3). The signal transduction pathways that result in the activation of collagen gene transcription are not known and are difficult to study. Signal transduction occurs over seconds to minutes, whereas changes in steady-state collagen mRNA levels require several hours to become evident. TGF-P does induce Ca2+ influx and phosphoinositol turnover in Rat-l fibroblasts (119). However, this effect is delayed, taking hours to develop and is inhibited by actinomycin D. In addition, TGF-P does not significantly increase CAMP levels (93). These data indicate that Ca”’ influx, inositol turnover, or activation of adenylate cyclase activity are not the primary system for TGF-P signal transduction. TGF-P induces increases in steady-state levels of mRNA for several protooncogenes including c-fos, c-jun, and jun B in certain cell types (131). These protooncogenes are involved in the regulation of cell division and the rate of transcription of other genes. Transient transfections of plasmids containing v-fos into fibroblasts activated transcription of type III collagen promoterCAT constructs (155). The effect of v-fos on type I collagen promoter activity is unknown. TGF-P increased the level of c-jun in human lung adenocarcinoma cells but not in mouse embryo fibroblasts. Increases in steadystate levels of c-jun mRNA and in levels of jun proteins probably does not result in increased collagen formation; platelet-derived growth factor (PDGF) causes large increases in c-jun mRNA (152), but does not cause large increases in collagen formation in smooth muscle cells (23) The cellular pathways involved in TGF-P-induced increases in the steady-state levels of al(I) and cu2(1) collagen mRNA do not require protein synthesis (80). These data provide additional evidence that TGF-P signal transduction for collagen accumulation does not involve expression of protooncogenes. TGF-P could increase collagen transcription by inducing enzymatic modifications or phosphorylation reactions involving NF-1 or other nuclear proteins or by inducing proteinprotein interactions such as those found for the NF-KB nuclear binding factor (9, 10, 127). Activation of NF-KB appears to occur by dissociation of the binding protein from a protein inhibitor or possibly by alterations in translocation to the nucleus. IGF-I

and Insulin

Insulin-like growth factor-I (IGF-I) is a major inflammatory substance produced by alveolar macrophages (146) that bind to specific high-affinity IGF-I receptors (61, 63, 83, 163). Culturing fibroblast in the presence of


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exogenous IGF-I at low concentration or insulin at high concentration results in stimulation of collagen synthesis (70). Insulin can bind with low affinity to the IGF-I receptor and may partly act through IGF-I-like mechanisms. IGF-I may be involved in basal production of collagen by fibroblasts in vitro, through autoregulation, since a number of fibroblast lines synthesize and secrete IGF-I (8, 38, 163). IGF-I also stimulates cellular proliferation directly in some cell types or by acting as a progression factor in combination with other growth factors in other cell types (41, 42). The signal transduction systems involved in IGF-Iinduced collagen formation are also uncertain. The IGFI and insulin-induced signaling pathways are extraordinarily complex and involve G proteins and phospholipid metabolism (55,102). IGF-I also increases the expression of certain protooncogenes including c-fos (126) and cras-Ha (107) and stimulates tyrosine kinase activity. Activation of tyrosine kinase results in the phosphorylation of the insulin receptor and other intracellular proteins. Other phosphorylation events also occur after insulin-induced activation of certain serine/threonine protein kinases (136). Insulin stimulates a S6 protein kinase that phosphorylates the 40s ribosomal subunit protein S6; however, the functional significance of this is unknown; indeed the mechanism whereby insulin increases overall protein synthesis is not completely understood. Insulin affects peptide chain initiation and the number of ribosomes involved in protein synthesis (for review see Ref. 95). For example, insulin increases the translation of ornithine decarboxylase mRNA by altering the phosphorylation state of two initiation factors, eIF-4B and eIF-4E (110). It also affects gene expression for specific proteins including al(I) collagen (Fig. 2). Insulin stimulates transcription of the human glyceraldehyde 3-phosphate gene through a &-acting response element in the promoter (CCCGCCTC) (123), although it is uncertain whether a similar response element is involved in the regulation of collagen promoters. It is noteworthy that insulin, at low concentration, selectively stimulates collagen production but not overall protein synthesis (70). Whether the phosphorylated proteins referred to earlier are involved in regulating collagen accumulation is unknown. However, it is conceivable that one of these proteins is phosphorylated after exposure to insulin or IGF-I and is involved in the signaling cascade for collagen synthesis (156). INHIBITION

OF

THE

COLLAGEN

GENE

EXPRESSION

The rate of collagen turnover in the lung is unknown and difficult to measure but is usually assessed by measuring production of free hydroxyproline (103). However, because lung parenchyma contains several collagen types with unique rates of turnover, it is unclear which collagen types serve as the sources of the hydroxyproline measured during turnover studies. It is likely that the hydroxyproline is derived primarily from newly synthesized molecules rather than from mature collagen fibers. A number of effector substances have been shown to inhibit collagen accumulation by lung fibroblasts in cul-

REVIEW

FIG. 2. Effect of insulin on the steady-state expression of &(I) collagen mRNA. Confluent quiescent embryonic human lung fibroblasts were untreated or treated with insulin (2 pg/ml) for indicated periods of time. mRNA was extracted, electrophorized, and transferred to nitrocellulose paper. Ethidium bromide staining after Northern analysis demonstrated that approximately equal amounts of RNA were loaded on each lane. cDNA probes were labeled, incubated with nitrocellulose paper for 40 h, and an autoradiogram was obtained. Location of the ribosomal RNA subunits (2% and 18s) are indicated by the arrow [Goldstein et al. (70).]

ture. Whether these substances function to inhibit collagen accumulation under basal conditions in the lung or only during inflammatory reactions is unclear. Indeed, the exact processes that limit collagen accumulation during wound healing in the lung or other tissue are unknown. The depletion of substances that activate collagen formation such as TGF-P, activation of protein kinase C, the presence of inhibitory substances such as PGEz (69, 166) or y-interferon (147), and the direct inhibitory effects of the developing extracellular matrix may all interact to limit or reduce collagen synthesis and hence, limit accumulation (113, 121). Protein Kinase C

In quiescent fibroblasts, basal production of collagen by fibroblasts may depend, in part, on the activity of protein kinase C (68, 160). Activation of protein kinase C (PKC) with phorbol esters decreases collagen production in human embryonic lung fibroblasts. This decrease is mediated by inhibition of transcription of al(I) collagen (68). Activation of PKC also blocks the increases in collagen accumulation stimulated by TGF-P (Fig. 3). This effect does not require protein synthesis, suggesting that phorbol may affect collagen formation via altering the state of phosphorylation of key regulatory molecules such as a nuclear protein (62) or the protein product of an oncogene (24). PKC activity is increased by several growth factors


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,-----

+TGF-6

_I

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review see 167). The c-jun protein interacts with the cto form a heterodimeric complex via leucine zipper regions (AP-1) (4,20,64,101). This complex binds to a specific DNA element (AP-1 binding sites) upstream from the transcription start site. Phorbol esters and stimulation of PKC activity increases the activity of preexisting Jun/AP-1 molecules (posttranslational regulation) and increases the total amount of Jun/AP-1 via positive autoregulation (6, 20). Accumulating evidence suggests that transcriptional regulation via AP-1 binding sites may be complex because of potential interaction between members of the jun family of proteins with each other or other proteins (34,153). An-B negatively interacts with c-jun (34,153). In addition, interactions with other binding proteins occur though overlapping DNA binding domains. These complex interactions among binding proteins which utilize similar binding domains can result in either stimulation or inhibition of transcription (48). The al(I) collagen promoter contains several potential AP-l-like binding sequences. The sequences resembling the phorbol response element (TGACTCA) are found in the rat al(I) collagen promoter and first intron, although whether PMA inhibits collagen accumulation by functioning through AP-1 binding proteins at these sites is uncertain at this time. The intronic AP-1 binding elements appear to have functional activity (105). It is also unclear whether a specific PKC isoenzyme is involved in regulating collagen accumulation (124). fos protein

28S-

Prostaglandin 3. Steady-state levels of al(I) collagen mRNA in phorbol 12mvristate 13-acetate (PMA)and TGF-B-treated fibroblast cultures. Confluent quiescent embryonic human lung fibroblasts were unstimulated (lanes 1) or stimulated with TGF-@(lanes 2-5). Cultures were also treated with PMA at 10 nM (lane 3) or cvcloheximide (CHX) at 10 PM (lane 5) or both (lane 4) during 24-h incubation. Ethidium bromide staining after Northern analysis demonstrated that approximately equal amounts of RNA were loaded on each lane. cDNA probe pnlR1 was labeled, incubated with the nitrocellulose filter for 40 h, and an autoradiogram was obtained [From Goldstein et al. (68).]

E2

FIG.

such as PDGF and epidermal growth factor (EGF). PDGF and EGF stimulate phospholipase C, which causes phosphatidylinositol turnover and production of 1,2 diacylglycerol (for review see 109). The diacylglycerol, in turn, stimulates PKC activity. Although the PKC system is complex and involves several isoforms that may be differentially regulated, mitogen-induced PKC activity may negatively regulate collagen accumulation. It is interesting to note that insulin which functions through PKC-independent mechanisms (18, 27) also increases collagen formation perhaps because PKC is not activated (70). Downregulation of PKC activity by prolonged exposure to phorbol esters restores responsiveness to TGF,f3suggesting the TGF-P does not require PKC to stimulate collagen accumulation (68). Phorbol esters regulate several other genes through PKC-mediated transcriptional events. Stimulation of PKC activity activates Jun/AP-1 nuclear binding proteins. These proteins bind to specific DNA sequences stimulating or inhibiting transcription of specific genes (7, 104, 164). The AP-1 protein complex consists of proteins coded by the fos and jun protooncogenes (for

PGE, is released by a variety of cell types including alveolar macrophages, lung fibroblasts, and endothelial cells. Interleukin 1 (IL-l) increases the production of PGEz by stimulating the activity of cyclooxygenase (49, 142). The combination of IL-l and tumor necrosis factor (TNF) synergistically stimulates PGEz production (54). The low concentrations of PGEz required to inhibit collagen formation in tissue culture experiments suggest that PGE, may inhibit collagen formation during inflammatory reaction in the lung. However, there is, as yet, no clear evidence that PGEz limits collagen formation during fibrotic responses. Indeed, PGEz may function primarily to induce the degradation of connective tissue. In certain types of arthritis, PGE, is thought to increase joint damage by stimulating bone resorption and decreasing collagen production (145). PGE, increases intracellular collagen degradation (14) and PGEz decreases amino acid uptake and cell proliferation by lung fibroblasts (58, 71). It is known that PGE, causes large decreases in the steady-state levels of collagen mRNA by inhibiting gene transcription in human lung fibroblasts in culture (59). This effect may be mediated through PGEz-induced increases in CAMP levels (14,98), although not all of PGE effects are CAMP dependent (171). Stimulation of CAMP-dependent protein kinase A (PKA) results in phosphorylation reactions that involve a nuclear binding protein (CREB). Activation of transcription of the somatostatin gene follows CAMP-mediated phosphorylation of CREB (117) with subsequent binding with high


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affinity to a specific site in the somatostatin promoter (TGACGTCA) (172). Recent work suggests that a family of CREB proteins exist that modulate the activity of a variety of CAMPdependent genes (73, 117). It is noteworthy that the CREB binding site is similar to the phorbol ester response element. The CREB protein also has some homology with proteins that form the AP-1 complex (73). Moreover, interactions appear to occur between the PKC and PKA driven systems (120, 151). The al(I) collagen promoter has a potential AP-1 and NF-KB site in the region between nucleotides -200 and -400 bp, which could function to down-regulate collagen gene expression. Taken together these data suggest that activation of either the PKC or PKA signal systems converge to inhibit collagen gene transcription though similar binding elements. However, the genetic mechanism whereby PGEz and phorbol esters inhibits transcription of collagen remains to be defined. Interferon

The interferons are produced by mononuclear cells. They decrease collagen accumulation by dermal, synovial, and lung fibroblasts in culture. The y-interferon is more active than CY-or ,&interferon in inhibiting collagen production (147) associated with decreases in steadystate collagen mRNA levels. The effect of interferon on collagen gene transcription is uncertain. Two studies found no change in cy2(1) gene transcription (45, 86), whereas another study found decreases in the rate of al(I) gene transcription (147). However, the al(I) and the at2(1) genes may be regulated independently (60) by interferons, or interferons may influence posttranscriptional processes as in the case of fibronectin (45). Interferon can also act in combination with tumor necrosis factor-a to suppress the TGF-P-induced activation of type I collagen gene expression (86). Finally, interferon also affects the deposition of collagen by increasing the cell surface receptors for collagen (36). The inhibition of collagen formation by y-interferon may have clinical importance. The systemic administration of y-interferon inhibited collagen synthesis, as assessed by quantitative image analysis in murine skin wounds (72). Interferon reduced collagen accumulation, the rate of wound healing, and the extent of polymorphonuclear infiltrations in skin wounds produced by argon laser radiation. The interferon inducer, polyinosinic-polycytidylic acid, caused a small decrease in collagen accumulation in bleomycin lung fibrosis in hamsters (65). TNF and IL-l

The addition of TNF to fibroblast cultures inhibits collagen formation by decreasing transcription and steady-state collagen mRNA levels (86, 161). IL-l directly stimulates collagenase formation (40) and either inhibits (16) or stimulates (67) collagen production depending on the cell line examined. IL-l decreases elastin formation in neonatal rat fibroblasts (15) and decreases the steady-state level of type II collagen mRNA in chon-

REVIEW

drocytes (66). It is noteworthy that both TNF and IL-l stimulate CAMP levels in human fibroblasts (174). It may well be that these mediators, like PGE2, inhibit collagen transcription by functioning through an as yet undefined CAMP-responsive element in the collagen promoter. The various inflammatory mediators interact in complex ways to regulate collagen production. IL-l blocks the TGF-P-induced stimulation of collagen formation in human skin fibroblasts (74). This may be mediated by IL-l-stimulated PGEZ production via activation of cyclooxygenase or by stimulation of collagenase production. Although TNF inhibits collagen production by lung fibroblasts, in vitro, recent data suggest a different role during inflammatory reactions. Anti-TNF antibody markedly decreases collagen deposition in silica-induced or bleomycin-induced lung injury (134, 135). These results suggest that TNF is an important mediator in the initial phases of these injuries (2). TNF may produce an increased capillary permeability or it may potentiate cellular damage. These early injuries would then initiate the cascade of events that cause the accumulation of fibroblasts and inflammatory substances in the alveolar space. Whether the TNF-induced inhibition of collagen transcription in cultured fibroblasts has any physiologic relevance is uncertain at this time. Metalloproteinases

Collagen incorporation into matrix is limited by intraand extracellular degradation of intact collagen chains and fibers. A portion of newly synthesized collagen is degraded intracellularly. Although assembly of collagen fibers involves the formation of cross-links that renders the collagen molecule relatively resistant to protease digestion, mature extracellular collagen can be specifically degraded by mammalian collagenase (for review see 51). Although skin and synovial fibroblasts synthesize collagenase, the source of lung collagenase may well be inflammatory cells such as neutrophils (51). The exact role of collagenase activation in regulating collagen turnover in the lung remains to be determined. Production of collagenase is stimulated by phorbol esters and interleukin 1 (5, 40, 46). The collagenase promoter region contains a phorbol response element close to a TATA box which may mediate positive transacting factor activity (7). Phorbol-induced collagenase production is independent of protein synthesis. The phorbol-responsive element can activate heterologous promoters as an inducible enhancer. Interleukin 1 also stimulates production of c-jun, a component of the AP1 complex, which may also bind to this phorbol response element (40). Taken together, these data suggest that stimulation of fos/jun appears to stimulate promoter function for the collagenase gene through a AP-l-like site. Recent findings suggest that glucocorticoids interfere with collagenase mRNA induction via interactions with AP-1 proteins (84,173). The glucocorticoid receptor binds to the AP-1 complex and renders it inactive. TGF-P, inhibits gene expression of collagenase and transin/stromelysin (91). Transin/stromelysin and collagenase are part of a family of matrix-degrading metal-


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loproteases. TGF-0 functions through an inhibitory region in the transin gene promoter that binds a protein complex which contains the Fos protein (91,92, 112). In addition to inhibiting production of collagenase, TGF-P as well as IL-6 and EGF stimulate the production of an inhibitor of metalloproteinases (TIMP-1) (53, 106). TGF-0 also induces transcription of plasminogen activator inhibitor via two binding elements in the promoter (169). These data indicate that the regulation of connective tissue synthesis and degradation may be coordinated. In particular, TGF-P can potentially regulate collagen formation directly by increasing steady-state levels of collagen mRNA and indirectly by inhibiting the production and activity of collagenase. LUNG

FIBROSIS

Cell Growth

and Fibrosis

Increased collagen deposition in lung results from increases in collagen production due to expanded fibroblast populations as well as increases in the rate of collagen synthesis by each cell. The relation between synthetic capacity of cells and the rate of proliferation is complex. Factors such as TGF-0 and insulin, which stimulate collagen formation, also variably affect cell proliferation. Although TGF-P-induced collagen formation increases with increasing concentration, the effect of TGF-P concentration on proliferation is bimodule. At low concentration, TGF-P stimulates proliferation by inducing the autocrine production of PDGF-AA, at least in some fibroblast and smooth muscle cell types (13). At high concentrations, TGF-P inhibits cell proliferation by possibly decreasing PDGF receptor a-subunits and altering mRNA levels or activation state of cellular protooncogenes (for review see 118). However, these effects are not seen in all fibroblast types (82) or growth conditions, as TGF-P does not block EGF-induced cell proliferation by murine 3T3 fibroblasts (33). TGF-P inhibits transcription of the c-myc protooncogene, which is involved in the activation of cell proliferation (39,133), an effect possibly mediated through the protein product of the retinoblastoma gene (100). These TGF-P-induced growth alterations likely proceed through different cellular pathways than those involved in collagen formation. Additional observations also suggest that growth inhibition is not required for collagen accumulation. The addition of serum to quiescent lung fibroblasts induces large increases in cell proliferation and collagen accumulation. In addition the combination of EGF or PDGF and insulin induces large increases in cell proliferation and collagen formation by lung fibroblasts in culture (unpublished observations). It is conceivable that activation of collagen gene transcription proceeds through one discreet signal pathway. If this is the case, then this pathway could be activated as an associated event during the signalling cascade which produces cell division. General Hypothesis

Bleomycin-induced lung fibrosis is the best-studied experimental animal model of human pulmonary fibrosis. Examination of collagen accumulation in this model

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has yielded insights into some of the molecular mechanisms underlying these changes in connective tissue levels. Available data suggest that fibrosis is the result of increased rates of matrix synthesis which result from the activation of specific genes within interstitial fibroblasts by effector molecules released at sites of injury. Bleomycin injury induces increases in the steady-state levels of collagen, fibronectin, and elastin mRNAs (79). Fibronectin mRNA levels and al( 1) collagen mRNA levels peak between 1 and 3 weeks after bleomycin treatment (89). The increases in collagen formation appear to be relatively selective for type I collagen compared with other collagen types. Bleomycin induces only small increases in type III collagen (138) and little (78) or no significant increase in type IV collagen in the lung (138). Increases in collagen, elastin, and fibronectin mRNAs after bleomycin treatment appear to be related, at least in part, to increases in transcription of their respective genes (139). It may well be that the increases in the mRNAs of these connective tissue proteins are coordinately regulated through the action of one or more DNA binding proteins. Alterations in mRNA stability might also occur, but the mechanisms regulating these processes are largely unknown (25). Khalil et al. (94) examined the amount of TGF-P in the lung as assessed by bioassay employing anti-TGF-P antibody after an acid-ethanol extraction. The amount of TGF-P increased markedly -1 wk after bleomycin treatment. The time course of these increases in TGF-P correlate with the increases in the levels of collagen synthesis. Immunohistochemical staining localized TGFp initially to macrophages and latter to areas of the extracellular matrix associated with repair and collagen deposition. Studies of fibrosis in rat liver employing in situ hybridization and northern analysis (122) have supported the hypothesis that specific effector substances regulate collagen formation during inflammatory reaction. Transcripts for TGF-P were detected before increases in levels of procollagen al(I), and hepatic fibrosis induced by carbon tetrachloride was associated with increases in PHORBOL

ESTERS

PKCt

crf (I) (rZ( I) NFl

I

I

A

TGF-8 /

PROMOTER

EXON 1

INTRON I

FIG. 4. Possible signal transduction pathways involved in regulation of type I collagen gene transcription by effector substances. Relative position of &-acting regulatory sites in the al(I) vs. &2(I) collagen genes are different and are thus not drawn to scale. Effector substances also affect other regulatory sites in collagen biosynthesis. PKA, protein kinase A; PKC, protein kinase C; CREB, CAMP-responsive element binding protein; AP-1, junlfos protein complex. See text for further details.


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both TGF-P and &(I) mRNA levels (122). Additional evidence is provided by the observation that TGF-/3 mRNA colocalized with proa(1) collagen mRNA in skin biopsies from patients with progressive systemic sclerosis (96). The administration of recombinant TGF-P to wounds in pig skin increases the steady-state mRNA levels of type I collagen and fibronectin (l37), lending additional strength to the hypothesis. However, immune complex-induced hepatic injury was associated with increases in type III collagen mRNA and no increase in TGF-P mRNA (116). These results support the concept that some of the variability in collagen formation in fibrotic reactions depends on the type of injury and the multiplicity of effector substances that are produced as a result. SUMMARY

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DIRECTIONS

Available data suggest that the inflammatory reaction is rich in numerous effector substances that interact in a complex manner to regulate fibroblast proliferation and collagen accumulation through direct and indirect modulation of the collagen promoter (Fig. 4). Additional factors serve to regulate deposition of collagen in a mature extracellular matrix. The complexity of these processes make it difficult to determine the precise role of a specific mediator in the regulation of collagen production during an inflammatory reaction. Little information is available about the signaling pathways that mediate increases in collagen formation. Large gaps in knowledge remain regarding the processes that link ligand receptor coupling to alterations in collagen gene transcription. It is likely that additional collagen stimulating substances will be discovered. In situ hybridization studies should help clarify which of these substances are directly influencing the collagen gene expression and contributing to activation of collagen accumulation in the lung. Information related to the cis and tracts-acting factors that are involved in transcriptional activation of collagen genes will shortly become available. Transgenic mice and the technique of in vivo footprinting will be useful in verifying the importance of putative regulatory sites in the collagen promoter during fibrogenic reactions in the lung. Eventually, in vitro observations may be integrated into a comprehensive model of fibrogenesis during inflammatory reactions in the lung. In addition, it is likely that specific therapies will be developed to interrupt collagen accumulation at one of several steps in the sequence of events in which inflammatory reactions progress to fibrosis. It may well be that information related to the regulation of genes encoding structural proteins in the lung will help explain why certain inflammatory reactions result in fibrosis, whereas others result in emphysema. The author thanks Drs. Joel Karlinsky and Gordon L. Snider for their helpful suggestions. This work was supported by National Heart, Lung, and Blood Institute Grant HL-19717 and by the Veterans Administration Research Service. Address for reprint requests: R. H. Goldstein, Pulmonary Center (K600), 80 E. Concord St., Boston, MA 02118.

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Lung collagen heterogeneity. Synthesis of type I and type III collagen by rabbit and human lung cells in culture.

Nanomechanics of Type I Collagen.

X-radiation enhances the collagen type I strap formation and migration potentials of colon cancer cells.

Transcriptional control mechanisms for the expression of type I collagen genes.

Distribution of type I collagen in human kidney diseases in comparison with type III collagen.

Preferential sites for intramolecular glucosepane cross-link formation in type I collagen: A thermodynamic study.

Early assembly pathways of type I collagen.

Nicotine stimulates collagen type I expression in lung via α7 nicotinic acetylcholine receptors.

Ameloblasts express type I collagen during amelogenesis.

Delayed-type hypersensitivity responses regulate collagen deposition in the lung.

Synthesis of type I collagen in healing wounds in humans.

Ordering of cyanogen bromide peptides of type III collagen based on their homology to type I collagen: preservation of sites for crosslink formation during evolution.

Enhanced deposition of predominantly type I collagen in myocardial disease.

Mesangial deposition of type I collagen in human glomerulosclerosis.

Type-I trimer and type-I collagen in neutral-salt-soluble lathyritic-rat dentine.

Genetic control of the immune response to collagen by the major histocompatibility complex in the rat: I. Humoral responses to bovine and chick type II collagen.

Overexpression of type VI collagen in neoplastic lung tissues.

Osteogenesis imperfecta type I is commonly due to a COL1A1 null allele of type I collagen.

Relative rates of biosynthesis of collagen type I, type V and type VI in calf cornea.

Specificity of the antibody response in inbred mice to bovine type I and type II collagen.

Type I collagen fibrils promote rapid vascular tube formation upon contact with the apical side of cultured endothelium.

Chondrocytes expressing intracellular collagen type II enter the cell cycle and co-express collagen type I in monolayer culture.

Changes in type I collagen following laser welding.

Antibody to collagen type I in gingival crevicular fluid.