Table 1.

Dysregulation of MMPs in inflammatory and fibrotic lung disorders ([15,16,17,18,26,30,31,32,33,34,35,36,37] and citations therein).

MMPs	Disease	Suggested MMP Role in Disease
MMP-1	Emphysema, which is a chronic obstructive pulmonary disease that is characterized by extensive tissue remodeling, the destruction of small bronchi and alveolar septa, diminished lung plasticity, and ultimately impaired pulmonary oxygenation. Increased MMP-1 levels have been detected in type II pneumocyte in the lung parenchyma of patients with emphysema, as well as in alveolar lining cells and fibroblasts exposed to smoke.   Asthma, which is a condition associated with lung inflammation, episodic dyspnea, and airway hyperresponsiveness. Increased MMP-1 levels have been detected in airway smooth muscle cells from asthma and emphysema patients.	Drives pulmonary tissue destruction such as the spontaneous development of air space expansion and emphysema-like changes including the coalescence of the alveolar spaces and disruption of the alveolar walls, as shown in transgenic animal models.   Induces airway obstruction and ASMC hyperplasia in asthma by activating the IGF axis.   Contributes to altered contractile response of smooth muscle cells induced by Th2 cytokines (IL-4 and IL-13), chiefly in allergic asthma.
MMP-2	Asthma; increased MMP-2 levels have been detected in sputum of patients with this condition.   Idiopathic pulmonary fibrosis (IPF), which is a chronic condition (usually lethal due to respiratory failure), characterized by disproportionate extracellular matrix degradation, inflammation, and fibrosis of the lung parenchyma.   Pneumonia; increased MMP-2 levels have been detected in an elevated proportion of patients with this condition.	Participates in tissue degradation in emphysema.   Aggravates pulmonary hypertension, which may lead to right heart failure and death.   Involved in collagen deposition in IPF.
MMP-3	Asthma; increased MMP-3 levels have been detected in bronchial lavages of individuals with this condition.	Involved in airway hyperreactivity and diminished lung function in asthmatic patients, which may be related to the activation of MMP-9 and the augmented synthesis of procollagen I.
MMP-7	Asthma; increased MMP-7 levels have been detected in airway epithelial cells and in lung epithelial cells under the effect of osteopontin.   Cystic fibrosis (CF), which is a genetic disorder characterized by malfunctioning of the chloride channels of the airway epithelia and other epithelial linings. Increased MMP-7 levels have been detected in type II pneumocytes in patients with CF	Contributes to airway epithelial damage and inflammation in subjects with severe asthma by cleaving and releasing soluble FasL.   Plays a profibrotic effect in IPF.
MMP-8	Exacerbated chronic obstructive pulmonary disease (COPD); COPD is a progressive pathology that has cigarette smoking as the main triggering factor, and is characterized by airway abnormal inflammation, airway flow obstruction, and pulmonary failure.   Emphysema; increased MMP-8 levels have been detected in the bronchoalveolar lavage (BAL) fluid of smokers with this condition.   Asthma; increased MMP-8 levels have been detected in the BAL fluid of patients with this condition.   Pediatric severe chronic lung disease; increased MMP-8 levels have been detected in BAL fluids from preterm babies (before 28 weeks of gestation) who later developed this disease.	Increases collagenolytic activity, impairing the collagen network of the lung and thus contributing to emphysema in adults.   Associated with severe granulocytic inflammation in airways caused by allergen exposure in MMP-8-deficient mice.   Contributes to the lung harm that happens in the initial phases of chronic lung disease.   Linked to bronchiectasis.   Involved in severe chronic lung illness in preterm babies where the alveolarization of the saccules alveolaris is starting.   Involved in pulmonary fibrosis.   Triggers an inflammatory response in the lungs associated with injurious ventilation.
MMP-9	COPD; increased MMP-9 levels have been detected in cells (e.g., alveolar macrophages) and sputum of patients with COPD (e.g., in bronchial epithelium and submucosal areas).   Emphysema; increased MMP-9 levels have been detected in (i) the lung parenchyma of patients with this condition, (ii) alveolar macrophages from smokers, and (iii) cultured airway macrophages from smokers (at baseline and in response to IL-1b and LPS).   Asthma; increased MMP-9 levels have been detected in (i) the sputum of subjects with allergic asthma after flour inhalation; (ii) the BAL fluid (mainly associated with airway neutrophils and less with alveolar macrophages—and maybe with eosinophils), sputum, serum, and bronchial tissues of asthmatic patients who have chronic submucosal inflammation; and (iii) samples from workers exposed to toluene diisocyanate-occupational asthma.   Rapidly progressive IPF and IPF-usual interstitial pneumonia (UIP); increased MMP-9 levels have been detected in BAL fluid and pulmonary tissues in patients with these conditions.   Acute lung injury (ALI), which is a disease characterized by the disruption of the diffuse alveolar–capillary wall, the invasion of circulating inflammatory cells, and deficient oxygenation caused by respiratory syncytial virus (RSV) infection and other viral infections. Increased MMP-9 levels have been detected in respiratory secretions of children with ALI.   Acute respiratory distress syndrome (ARDS), which is the most severe manifestation of ALI and is characterized by excessive systemic inflammation, an augmented permeability of the alveolar epithelial–endothelial capillary barrier, tissue damage, and acute respiratory failure. Increased MMP-9 levels have been detected in (i) the plasma of patients with ARDS, (ii) BAL fluid corresponding to the acute phase of ARDS, and (iii) the BAL fluid of patients with ARDS associated with severe trauma or septic shock.   Mechanically ventilated infants with RSV-induced respiratory failure.   Infection with coronavirus; increased MMP-9 levels have been detected in the circulation of COVID-19 patients with respiratory failure.	Implicated in a variety of illnesses, including COPD, emphysema, asthma (e.g., by enabling cell migration and airway inflammatory reaction, increased susceptibility to airway remodeling upon exposure to cigarette smoke resulting in thickening of airway walls, and bronchopulmonary dysplasia), ALI, CF, neutrophilic inflammation-mediated VILI (which is a severe lung injury associated with high-pressure mechanical ventilation), mechanically ventilated infants with RSV-infected lungs, and interstitial lung diseases (such as IPF-UIP and diffuse alveolar damage).   Promotes eosinophil migration into the airways from asthmatic patients.   Stimulates the degradation of the alveolar capillary barrier and inflammation, further promoting the migration of inflammatory cells (e.g., neutrophil recruitment through the generation of collagen fragments with chemotactic properties) and the damage of lung tissue.   Associated with diffuse alveolar injury in hyperoxia-induced ALI in pigs.   Linked to inflammation-induced tissue remodeling.   Associated with markers of basement membrane disruption, in the acute phase of ARDS.   Exacerbates lung tissue remodeling in rat lungs with hyperoxia.   Implicated, when MMP-9/TIMP-1 ratio is less than 1, in the evolution of ARDS to fibroproliferation.   Contributes to the disruption of alveolar epithelial basement membrane and increases fibroblast migration to alveolar spaces in the initial stage of lung fibrosis.   Associated with respiratory failure in COVID-19 patients.
MMP-12	COPD; increased MMP-12 levels have been detected in the BAL fluids, bronchial biopsy tissue, BAL cells, and sputum of patients with COPD.   Emphysema; increased MMP-12 levels have been detected in dendritic and bronchial epithelial cells in human lung in response to cigarette smoke.	Participates in the pathogenesis of acute and chronic respiratory disorders (such as COPD, cigarette smoke-induced emphysema, and asthma) when they are induced in ASMC by inflammatory cytokines under the regulation of different mechanisms (such as PI3-K, JNK, ERK, and AP-1 signaling pathways).   Partially mediates the IL-13-induced expression of MMP-2, MMP-9, MMP-13, and MMP-14, which results in the development of COPD-related features (such as the accumulation of macrophages, eosinophils, and neutrophils, thus leading to lung inflammation, alveolar enlargement, and increased lung volume).   Involved in smoke-induced inflammation and emphysema (e.g., by causing endothelial activation mediated by the release of TNF-α from macrophages, degrading connective tissue, and facilitating neutrophil influx).   Facilitates airway inflammation by promoting the migration of inflammatory cells (e.g., macrophages and monocytes) to inflammatory zones.   Implicated in airway remodeling by degrading extracellular matrix proteins (e.g., fibronectin, elastin, laminin, type IV collagen, and gelatin) or mediating inflammatory cytokines to stimulate production of other MMPs (MMP-2, MMP-9, MMP-13, and MMP-14) in the lung.   In animal models, it facilitates the development of inflammatory processes involving the recruitment of inflammatory cells, increases in cytokine and chemokine levels, and elevation of MMPs (e.g., MMP-2 and MMP-9) levels in lung samples and BAL fluids.
MMP-14	COPD; increased MMP-14 levels have been detected in samples (e.g., BAL fluid from patients with emphysema) from COPD patients upon acrolein induction.	Implicated in COPD pathogenesis.
MMPsubsets	COPD; levels are elevated for (i) MMP-1   and MMP-2 derived from epithelial cells and macrophages, MMP-8 and MMP-9 derived from neutrophils, MMP-12, and MMP-14—all in the pulmonary tissues of COPD patients; (ii) MMP-1, MMP-2, MMP-8, and MMP-9 in the BAL fluid of patients with COPD; and (iii) MMP-2 and MMP-9 in the sputum of patients with COPD.   Emphysema; levels are elevated for (i) MMP-1 and MMP-9 in the BAL fluid of patients with emphysema; (ii) MMP-8 and MMP-9 in alveolar macrophages from patients with emphysema; and (iii) MMP-9 and MMP-12 induced by cigarette smoke in human lung.   Asthma; levels are elevated for (i) MMP-1, MMP-2, MMP-3, MMP-8, and MMP-9 in the sputum and BAL of asthma patients; (ii) MMP-2, MMP-3, and MMP-14 (and also TIMP-1 and TIMP-2) in the ASMC of patients with bronchial asthma; and (iii) MMP-2 and MMP-12 in the bronchial epithelial, smooth muscle and submucosal glandular cells, BAL fluid, and sputum of subjects with bronchiectasis and asthma.   IPF; levels are elevated for (i) MMP-3,   MMP-7, MMP-8, and MMP-9 in the lavage fluid of patients with IPF.   ALI; levels are elevated for (i) MMP-2, MMP-3, MMP-8, MMP-9, MMP-11, and MMP-12, generated mainly by neutrophil and macrophage cells in the lung secretions of pediatric patients with ALI.   ARDS; levels are elevated for (i) MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, and MMP-13 in patients with ARDS; (ii) MMP-2 and MMP-9 in the lung of newborns with ARDS; and (iii) MMP-8 and MMP-9, and to a limited extent for MMP-3, MMP-11, and MMP-12 in the lung secretions of children with ALI/ARDS.   Pneumonia; levels are elevated for (i) MMP-8 and MMP-9 in the BAL fluid of patients with pneumonia acquired in hospitals.   Ageing lungs; levels are elevated for (i) MMP-9 and MMP-12 (and also TIMP-1 and TIMP-2) in ageing lungs. By contrast, decreased MMP levels are reported for MMP-1 and MMP-2 in ageing lungs.   Pulmonary fibrosis; levels are elevated for (i) MMP-2 and MMP-9 in BAL fluid and pulmonary tissue associated with pulmonary fibrosis; (ii) MMP-1 (largely found in bronchiolar and alveolar epithelial cells), MMP-2, MMP-7 (in the epithelium of lungs with IPF and fibrotic lung extracts), and MMP-9 in the lungs of patients with IPF; (iii) MMP-3 and MMP-12 in human alveolar macrophages under the effect of surfactant protein D; and (iv) MMP-2, MMP-8, and MMP-9 in the BAL fluid of patients with CF.   Bronchiolitis obliterans, which is an irreversible condition characterized by obstructive airway remodeling. Levels are elevated for (i) MMP-8 and MMP-9 from neutrophils recruited into the lung (and also for TIMP-1) in patients with advanced bronchiolitis obliterans.	MMP-2 and MMP-9: Involved in the pathogenesis (e.g., excessive tissue remodeling) of COPD.   MMP-1, MMP-8, and MMP-9: associated with the pathogenesis of emphysema.   Predominantly MMP-9 and several other MMPs (such as MMP-1, MMP-2, MMP-7, MMP-8, MMP-12, and MMP-25): associated with asthma pathology.   MMP-3, MMP-7, MMP-8, and MMP-9: implicated in pulmonary fibrosis, by facilitating the release of extracellular matrix-derived VEGF, resulting in abnormal capillary permeability and neoangiogenesis.   MMP-1, MMP-2, MMP-7, and MMP-9 (and also TIMP-1 and TIMP-2): show an active role in IPF.   MMP-8 and MMP-9: associated with the grade of systemic inflammation in patients with ventilator-associated pneumonia.   MMP-9 and MMP-12 (and also TIMP-1 and TIMP-2): associated with deteriorated lung function during ageing.   MMP-3 and MMP-9: associated with pathogenic roles (e.g., interstitial matrix remodeling, rupture of the basement membranes) in ALI.   MMP-2, MMP-9, and MMP-12: mediate structural lung damage (alveolar type I cell injury, pulmonary compliance variations, respiratory failure, and death) in mouse models (e.g., hyperoxia-induced lung disease).   MMP-1, MMP-3, and MMP-12: involved in lung innate immune system; pulmonary surfactant proteins induces the expression of these enzymes in human alveolar macrophages. Activated macrophages in the lung clear offending pathogens (viruses, bacteria, and fungi) that enter the airway.   MMP-9 and MMP-12: implicated in the effects of IL-1β in lungs of asthmatic patients; in the lungs of adult mice, IL-1β contributes to pulmonary inflammation (e.g., macrophage and neutrophil infiltration) and fibrosis in the airway.   MMP-2, MMP-8, MMP-9 (and also TIMP-1) and sometimes MMP-1 and MMP-3: involved in neutrophil-mediated inflammation, extensive tissue remodeling, and the loss of the intercellular junctions and alveolar–capillary barrier that occur in ARDS. These roles are also valid for MMP-3, MMP-7, and MMP-12 in animal models.   MMP-1 and/or MMP-3, together with MMP-2, MMP-8, and MMP-9 (and also TIMP-1): associated with more severe disease progression (i.e., higher indices of disease harshness, widespread multiorgan failure, and more mortality) in patients with ALI/ARDS.   MMP-2 and MMP-9: cause an acute injury pattern in rats treated with bleomycin   MMP-2, MMP-8, and MMP-9: play a role in the pathogenesis of ventilator-provoked lung damage.

MMP: matrix metalloproteinase; ASMC: airway smooth muscle cells; IGFs: insulin-like growth factors; IL: interleukin; IPF: idiopathic pulmonary fibrosis; TIMP: tissue inhibitor of metalloproteinases; CF: cystic fibrosis; FasL: Fas ligand; BAL: bronchoalveolar lavage; COPD: chronic obstructive pulmonary disease; LPS: lipopolysaccharide; UIP: usual interstitial pneumonia; PAF: platelet-activating factor; TNF: tumor necrosis factor; ALI: acute lung injury; RSV: respiratory syncytial virus; ARDS: acute respiratory distress syndrome; COVID: coronavirus disease; VILI: ventilator-induced lung injury; PI3-K: phosphatidylinositol 3-kinase; JNK: c-Jun N-terminal kinase; ERK: extracellular signal-regulated kinase; AP-1: activator protein 1; SP: surfactant protein; VEGF: vascular endothelial growth factor.