Mycobacterium tuberculosis (MTB), an infectious illness that causes pulmonary tuberculosis (TB), is still an issue around the world, particularly in Asian nations like Indonesia. For the treatment of TB, antibiotic therapy is still an option. However, prolonged and ineffective treatment can cause one or perhaps more anti-tuberculosis medications to become resistant to treatment. Multi-drug-resistant (MDR) TB was identified in an estimated 500,000 cases in 2019, and 1.4 million people died from the disease, making it the infectious disease with the highest mortality rate. Antimicrobial resistance is a factor in the death caused by pulmonary tuberculosis as well. The rise in drug-resistant tuberculosis (DR-TB) cases poses one of the major risks to global efforts to treat and prevent the disease, with 480,000 cases of TB being multi-resistant to at least two first-line treatments or resistant to at least one OAT (isoniazid and rifampicin) 1.
Using thoracic radiography and computed tomography, MDR-TB patients frequently have lesions such as cavities and fibrosis (CT). Thoracic radiography is the first imaging modality used to diagnose patients with suspected pulmonary tuberculosis, screen them for the disease, assess OAT, and look for suspicious masses. However, it has limitations because it cannot detect active lesions in the distal respiratory tract or diagnose patients with advanced disease progression. A thoracic CT scan is an imaging technique that can detect both active and inactive lesions as well as small lung lesions, distal (endobronchial) respiratory system involvement and significant lung parenchymal damage. Thoracic CT showed a sensitivity and specificity of 98%, which was greater than thoracic radiography's sensitivity and specificity of approximately 19–58% 2,3.
According to the literature, cavities were discovered in 50.8% of MDR-TB patients, although the appearance of thoracic High-Resolution Computerized Tomography (HRCT) in MDR-TB differs from patient to patient 4. According Park et al.5, observed that MDR-TB patients accounted for 75% of the cavities, and the cavities were highly contaminated with MTB germs. Another study in Peru discovered that 66.6% of patients had bilateral lung abnormalities, with MDR-TB patients having numerous cavities more frequently than TB-Drug Sensitive (DS-TB) to OAT patients 6,7. These findings are similar to those of Joshi et al8. who reported that 52% of patients had extensive lung damage and 88% of patients had multiple cavities, while Song's findings with thoracic CT examination in tuberculosis patients with type 2 diabetes showed consolidation in several lung segments and bronchial damage.
An inflammatory reaction from the host is a hallmark of MTB lesions. According to Parasa et al.9, granulomas liquefy into necrotic tissue that is ejected to create voids. In advanced pulmonary TB or MDR-TB, where even small lesions can cause irreversible harm to lung structures like bronchiectasis, bronchovascular distortion, or fibrosis, leading to emphysema, the cavity is thought to be responsible for the subsequent transmission of infection. Increased extracellular matrix (ECM) turnover and tissue healing are frequently linked to this disease process. The majority of type I collagen and elastin are found in the lungs' extracellular matrix. Proteolytic enzymes must break down the ECM for mycobacteria to spread from the lung parenchyma to the airways for cavities to form 10. The only enzymes that can break down ECM are matrix metalloproteinases (MMPs) but type I collagen is extremely hard to break down by proteolytic enzymes. Therefore, it appears likely that MMPs have a significant impact on how cavities and fibrosis develop 11.
One of the enzymes responsible for the lung parenchyma being damaged is the MMP protein. Most MMPs were not expressed under normal circumstances, however, subsequent analysis revealed that overexpression in the inflammatory process was present. Anti-inflammatory cytokines and bacterial lipopolysaccharides control how much MMP is expressed 12–15. Proteases regulated by tissue inhibitors of metalloproteinases (TIMPs) and 2-macroglobulin are involved in the protein's post-translational activation after it is first produced as a pro-enzyme. The majority of the connective tissue in the lungs, which is the primary structural protein of the lungs, is destroyed in part as a result of MMP molecules 16,17. Monocytes ECM7 release several MMPs, including MMP-1 (interstitial collagenase), MMP-9 (gelatinase B), and MMP-12 (macrophage metalloelastase), which are controlled by cytokines including tumor necrosis factor and interleukin beta to break down collagen fibrils. Monocytic cells infected with MTB secreted more MMP-1, MMP-9, MMP-3, MMP-10, and MMP-11 than MMP-2 and MMP-8. Patients with DS-TB had greater MMP-1 and MMP-9 levels than those with congestive heart failure 18. The airway epithelium next to the TB granuloma also showed increased MMP-1 expression in addition to monocytic cells9. As a result of the ECM's degradation brought on by the elevated MMP-1 expression, the cavity ruptures spread to the surrounding tissue and cause extensive tissue damage 19. According to the study, the MMP-1-1607G polymorphism raises the incidence of tracheobronchial stenosis20, initiates the breakdown of type I collagen21, and is crucial for fibrosis22. Additionally, different metalloproteinase types (MMP-1, -3, -8, and -9) were discovered, with the amounts of each fluctuating according to the severity of lung parenchymal damage 21. MMP-9 activity is directly correlated with the degree of the substantial lung parenchymal damage process, while MMP-8 is a neutrophilic component that affects chemokine activity 23–26.
In a study on DS-TB patients, Wang et al.26 evaluated genetic variables in the form of MMP-1, MMP-9, and MMP-12 gene polymorphisms. In that study, TB patients with moderate to advanced pulmonary fibrosis had a considerably greater frequency of the MMP-1 polymorphism (-1607G) than did TB patients with mild pulmonary fibrosis. There was a 5.0 (95% CI 1.25-20.30) and 9.87 (95% CI 2.39-0.88) fold increase in the probability of moderate to severe fibrosis in individuals with at least one -1607G MMP-1 polymorphism. MMP-9 (‑1562T) and MMP-12 (Asn357Ser) polymorphisms did not correlate with pulmonary fibrosis. In comparison to those with the 2G/2G genotype, subjects with the 1G allele genotype produced more MMP-1 from monocytes treated with interleukin 1 beta. MMP-9 (C1562T) and MMP-12 (Asn357Ser) were not linked to pulmonary fibrosis susceptibility, whereas MMP-9 (C1562T) production was directly proportionate to severe lung damage. Another study by Rius et al.27 and Belton et al.28 demonstrates the relationship between MMP-1 and MMP-9 levels and the cavity, which is a hypoxic region with various gradations in the periphery. Both contribute to inflammation and are mediators of inflammatory cell migration and collagen and elastin breakdown in the immunological response to tuberculosis infection. Another study utilizing transgenic mice as experimental animals revealed that MMP-1 was involved in the development of caseous cavities and severe lung damage as compared to mice of the wild type19,29,30 and that MMP-1 and MMP3 may cause lung parenchymal damage 9,11,12.
The aim of this study was to evaluate genetic polymorphisms and levels of MMP-1 and MMP-9, whose activity has implications for MDR-TB and DS-TB, and their correlation with cavity characteristics (number, diameter, and thickness) and fibrosis by thoracic HRCT examination, based on these studies and their clinical importance.